Trends Neurosci May 1986;9:186-192
Department of Neuroscience, University of Pennsylvania, Philadelphia 19104, USA.
Neurons in cat retina belong to specific types. Each type is characterized by a specific correspondence between morphology and physiology and forms a regular array that connects lawfully to the arrays of certain other types. Two circuits have been traced quantitatively through these arrays from photoreceptors to alpha- and beta- ganglion cells. The 'cone-bipolar circuit' appears to convey the center-surround receptive field to ganglion cells, using cones in daylight and rods (via gap junctions to cones) in twilight. A 'rod-bipolar circuit' appears to convey the quantal signal and the pure center receptive field to the ganglion cells in starlight.
Eur J Neurosci Feb 1992;4:506-520
Department of Neuroscience, University of Pennsylvania, Philadelphia 19104, USA.
Neural integration depends critically upon circuit architecture;
yet the architecture has never been established quantitatively
(numbers of cells and synapses) for any vertibrate local circuit.
Here we describe circuits in the cat retina that connect cones to
the on-beta ganglion cell. This cell type is important because
on- and off-beta cells contribute about 50% of the optic nerve
fibers and the major retinal input to the striate cortex. Three
adjacent on-beta cells in the area centralis and their bipolar
connections to cones were reconstructed from electron micrographs
of 279 serial section. The beta dendritic field is 34±2
micrometers in diameter and encompasses 35 cones. All of these
cones connect to the beta cell via 14-17 bipolar cells. These
bipolar cells were shown previously by cluster analysis to be of
four types (b1-b4); three of these types (b1, b2 and b3) provided
97% of the bipolar contacts to the beta cell, in the ratio
4:2:1. On average, bipolar cells nearest the centre of the beta
dendritic field contribute more synapses than those towards the
edge, but the peaked distribution of bipolar synapses across the
dendritic field is only slightly broader than the optical
pointspread function of the cat's eye, and is narrower by half
than the centre of the ganglion cell receptive field. This
implies that the distribution of bipolar synapses across the beta
cell dendritic field contributes little to the extent or shape of
the receptive field. Since all three bipolar circuits connect to
the same set of cones, they must carry the same spatial and
chromatic information; they might convey different temporal
frequencies. The numbers of bipolar synapses (mean±SD =
154±8) and amacrine synapses (59±5) converging on three
adjacent beta cells are remarkably constant (SD approx. equals
5% of the mean). Thus, as the circuits repeat locally, the
fundamental design is accurately reproduced.
Vis Neurosci 1994 Mar;11(2):261-269 Laboratory of Neurophysiology, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892.
When a bar of light (215 x 5000 microns) illuminates the
receptive field of an ON-beta ganglion cell of cat retina, the
cell depolarizes. Intracellular recording from the cat eyecup
preparation shows that this depolarization is due to an increase
in conductance (2.4 +/- 0.6 nS). Different phases of this
depolarization have different reversal potentials, but all of
these reversal potentials are more positive than the cell's
resting potential in the dark. When the light is turned on, there
is an initial transient depolarization; the reversal potential
measured for this transient is positive (23 +/- 11 mV). As the
light is left on, the cell partially repolarizes to a sustained
depolarization; the reversal potential measured for this
sustained depolarization is close to zero (-1 +/- 5 mV). When the
light is turned off, the cell repolarizes further; the reversal
potential measured for this repolarization is negative (-18 +/- 7
mV), but still above the resting potential in the dark (-50 mV).
To explain this variety of reversal potentials, at least two
different synaptic conductances are required: one to ions which
have a positive reversal potential and another to ions which have
a negative reversal potential. Comparing the responses to broad
and narrow bars suggests that these two conductances are
associated with the center and surround, respectively. Finally,
since an ON-beta cell in the area centralis receives about 200
synapses, these results indicate that a single synapse produces
an average conductance increase of about 15 pS during a
near-maximal depolarization.
J Comp Neurol 1993 Mar 1;329(1):68-84 Laboratory of Neurophysiology, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland 20892.
Six OFF-alpha ganglion cells and a single OFF-beta ganglion cell were penetrated with
intracellular microelectrodes and marked with horseradish peroxidase (HRP) in a perfused cat
eyecup. Gaussian center radii (Rc) ranging from 40 to 217 microns were measured for receptive
fields mapped with slits, values in agreement with previous extracellular reports. ON and OFF
response components revealed nearly identical Rc's and center locations. Although Gaussian
diameters (2Rc) were about 80% of dendritic field diameters overall, in this sample dendritic and
receptive fields were not well correlated. Spatial tuning of ganglion cells was evidenced in peaked
amplitude-vs.-width functions, fit by difference-of-Gaussians models. Such plots yielded Rc
values about 40% less than position-vs amplitude plots. Rs values for surrounds ranged from 200
to 1,700 microns. Rod and cone signals were investigated with flicker. Rod flicker signals in
OFF-alpha cells were larger and of shorter latency than in either horizontal or AII amacrine cells.
Cone flicker signals were also short in latency, with an ON response time constant of 9 msec,
and an OFF response time constant of 3 msec. The OFF-alpha rod-cone transition involved a
latency increase of 20-30 msec. The spontaneous and light-evoked impulse rates of OFF-alpha
responses varied linearly with extrinsic current, but the amplitude of ON hyperpolarization was
little affected. After injection of staining current, the OFF-beta cell transiently depolarized at
ON, suggestive of ON inhibition with reversed chloride gradient, a result not seen in OFF-alpha
responses. Events (peaked, depolarizing voltage fluctuations) of high, low, and intermediate
amplitudes were studied in OFF-alpha responses. High amplitude events (impulses), were
OFF-correlated with the stimulus, and exhibited mean rise times (transit time from 25 to 75% of
peak amplitude) from 255 to 392 microseconds. Intermediate level events (presumed synaptic
origin) were also OFF correlated and had longer rise times (325 microseconds to 1.56
microseconds). Low level events (234-685 microseconds) revealed either ON, ON/OFF, or not
stimulus correlation.
Nature 1996 Jun
13;381(6583):613-615 Department of Neuroscience, University of Pennsylvania, Philadelphia 19104, USA.
Visual information is conveyed to the brain by the retinal
ganglion cells. Midget ganglion cells serve fine spatial vision
by summing excitation from a receptive field 'centre', receiving
input from a single cone in the central retina, with lateral
inhibition from a receptive field 'surround', receiving input
from many surrounding cones. Midget ganglion cells are also
thought to serve colour opponent vision because the centre
excitation is from a cone of one spectral type, while the
surround inhibition is from cones of the other type. The two
major cone types, middle(M)- and long-(L)wavelength sensitive,
are equally numerous and randomly distributed in the primate
central retina, so a spectrally homogeneous surround requires
that the cells mediating la teral interactions (horizontal or
amacrine cells) receive selective input from only one cone type.
Horizontal cells cannot do this because they receive input
indiscriminately from M and L cones. Here we report that the
amacrine cells connected to midget g anglion cells are similarly
indiscriminate. The absence of spectral specificity in the
inhibitory wiring raises doubt about the involvement of midget
ganglion cells in colour vision and suggest that colour opponency
may instead be conveyed by a different type of ganglion cell.
Vision Res 1996 Nov;36(21):3373-3381 Mahoney Institute for Neurological Sciences, University of Pennsylvania, Philadelphia 19104-6058, USA. calkins@mpih-frank-furt.mpg.d400.de
The response of a mammalian bipolar cell is generally thought to be determined by the location and morphology of synapses from the cone terminal: ON bipolar cells are believed to be depolarized strictly at invaginating contacts and OFF bipolar cells hy
perpolarized at basal contacts. This hypothesis was re-investigated in the macaque fovea (1 deg nasal) using electron micrographs of serial sections. We determined the number of invaginating sites available and then identified the contacts to bipolar cell
s with axons in the ON level of the inner plexiform layer. A cone terminal forms about 20 active zones marked by ribbons. A few active zones house two invaginating dendrites, so there are 22 invaginating sites per cone. A midget ON bipolar cell collects 1
8 invaginating contacts from one cone, thus only about four invaginating sites remain for diffuse ON bipolar cells. Two diffuse ON cells were reconstructed; each collects about 25 contacts from an estimated 10 cones. Only three or four of these contacts a
re invaginating; the rest are basal, adjacent to the triad. This suggests that basal contacts can be depolarizing. The distance from the vesicle release site at active zones to an invaginating contact is 140 +/- 40 nm; to a basal contact adjacent to the t
riad is 500 +/- 160 nm, and to the next nearest basal contact is 950 +/- 370 nm.
Nature 1994 Sep 1;371(6492):70-72 Department of Neuroscience, University of Pennsylvania, Philadelphia 19104.
Visual acuity depends on the fine-grained neural image set by the foveal cone mosaic. To preserve this spatial detail, cones transmit through non-divergent pathways: cone-->midget bipolar cell-->midget ganglion cell. Adequate gain must be establi
shed along each pathway; crosstalk and sources of variation between pathways must be minimized. These requirements raise fundamental questions regarding the synaptic connections: (1) how many synapses from bipolar to ganglion cell transmit a cone signal a
nd with what degree of crosstalk between adjacent pathways; (2) how accurately these connections are reproduced across the mosaic; and (3) whether the midget circuits for middle (M) and long (L) wavelength sensitive cones are the same. We report here that
the midget ganglion cell collects without crosstalk either 28 +/- 4 or 47 +/- 3 midget bipolar synapses. Two cone types are defined by this difference; being about equal in number and distributing randomly in small clusters of like type, they are probabl
y M and L.
J Comp Neurol 1986 Aug 1;250(1):1-7 Cone bipolar neurons in the cat retina were studied in serial sections prepared as electron microscope autoradiograms following intravitreal injection of (3H)glycine. The goal was to learn whether the cone bipolar types that accumulate glycine correspo
nd to the types thought on other grounds to be inhibitory. About half of the cone bipolars in a given patch of retina showed specific accumulation of silver grains. The specificity of accumulation was similar to that shown by glycine-accumulating amacrine
s. All of the cone bipolars arborizing in sublamina b accumulated glycine but none of the cone bipolars arborizing in sublamina a did so. The types of cone bipolars accumulating glycine did not match the types thought to be inhibitory. Cone bipolar types
CBb1 and CBb2 both form gap junctions with the glycine-accumulating AII amacrine, thus raising the possibility that glycine might accumulate in these cone bipolars by diffusion from the AII cell or vice versa. Thus it is logically impossible to tell which
of these three cells contains a high-affinity uptake mechanism for glycine and consequently which of the three might actually use glycine as a neurotransmitter.
Philos Trans R Soc Lond B Biol Sci 1990 Dec 29;330(1258):305-321 Department of Anatomy, University of Pennsylvania, Philadelphia 19104.
We identified all the cone bipolar cells (80) in a small patch of one retina and then studied in detail the complete subset (42) that sends axons to sublamina b of the inner plexiform layer. The point was to learn whether the 'types' suggested previous
ly, based on a few examples from a large population, could be substantiated or whether there would be intermediate forms. Tissue from the area centralis (1 degree eccentricity), was prepared as a series of 279 ultrathin sections and photographed in the el
ectron microscope. Thirteen cells were reconstructed completely and parcelled into five categories (b1-b5) based on external morphology. For nine of these cells (two from categories b1-b4 and one from b5) most of the synaptic inputs and outputs were ident
ified. When these nine cells were parcelled according to their synaptic patterns, they sorted into the same five categories. The remaining 29 cells in the population, though not reconstructed, were studied in detail by tracing their processes through the
series. Ten of these cells, those near the margin of the series, were incomplete. The other 19 cells had essentially the same distribution of morphologies and synaptic patterns as the subset studied by total reconstruction: when plotted in multiparametric
space, they formed distinct clusters corresponding to the five morphological categories. There was no hint of intermediate forms. That all the neurons in the population sort into some cluster (no intermediate forms), and that each neuron sorts into the s
ame cluster by different criteria, argues that the clusters represent natural types. Each type forms a regular array in the region studied with an axonal 'coverage factor' that is close to one.
Philos Trans R Soc Lond B Biol Sci 1990 Dec 29;330(1258):323-328 Department of Anatomy, University of Pennsylvania, Philadelphia 19104.
In the central area of cat retina the cone bipolar cells that innervate sublamina b of the inner plexiform layer comprise five types, four with narrow dendritic fields and one with a wide dendritic field. This was shown in the preceding paper (Cohen &a
mp; Sterling 1990 a) by reconstruction from electron micrographs of serial sections. Here we show by further analysis of the same material that the coverage factor (dendritic spread x cell density) is about one for each of the narrow-field types (b1, b2,
and b4). The same is probably true for the other narrow-field type (b3), but this could not be proved because its dendrites were too fine to trace. The dendrites of types b1, b2, and b4 collect from all the cone pedicles within their reach and do not bypa
ss local pedicles in favour of more distant ones. The dendrites of type b5, the wide-field cell, bypass many pedicles. On average 5.1 +/- 1.0 pedicles coverage on a b1 bipolar cell; 6.0 +/- 1.2 converge on a b2 cell and 5.7 +/- 1.5 converge on a b4 cell.
Divergence within a type is minimal: one pedicle contacts only 1.2 b1 cells, 1.0 b2 cells, and 1.0 b4 cells. Divergence across types is broad: each pedicle apparently contacts all four types of the narrow-field bipolar cells that innervate sublamina b. Ea
ch pedicle probably also contacts an additional 4-5 types of narrow-field bipolar cell that innervate sublamina a. There are several possible advantages to encoding the cone signal into multiple, parallel, narrow-field pathways.
J Neurophysiol 1991 Feb;65(2):352-359 Department of Anatomy, School of Medicine, University of Pennsylvania, Philadelphia 19104.
1. We have investigated the anatomic basis for the Gaussian-like receptive field center of the on-beta ("X") ganglion cell in the area centralis of cat retina. Three adjacent on-beta cells were reconstructed from electron micrographs of 279 s
erial sections cut vertically through a patch of retina at approximately 1 degree eccentricity. 2. All the bipolar synapses on these cells were identified, and about one-half of these were traced to type b1 bipolar cells, which formed a regular array in t
he plane of the retina. 3. On average, seven b1 cells contributed to a beta cell: bipolar axons near the middle of the beta dendritic field tended to give many contacts (12-33 contacts); axons near the edge of the field tended to give few contacts (3-4 co
ntacts). 4. Each b1 cell collected from four to seven cones, and
the mean number of cones converging through the b1 array to a
beta cell was 30. 5. Assuming equal effectiveness for all b1->beta cell synapses, a spatial weighting function was derived fro
m these results. The mean radius of this function at 1/e amplitude for three beta cells was 18.0 +/- 1.1 (SD) microns. This is considerably narrower than the corresponding measurements of the beta cell receptive field center (28 +/- 3 microns) at this ecc
entricity. 6. It is concluded, in agreement with previous work, that all cones encompassed by the beta cell's dendritic field and those slightly beyond it connect directly to the beta cell via the b1 bipolar cell array. However, the center of the beta cel
l receptive field is still broader by approximately 60%. This suggests that pooling of cone signals may occur at the level of the outer plexiform layer.
J Comp Neurol 1979 Dec 15;188(4):599-627 Neurons in the cerebral cortex have been classified primarily by their differences in axonal and dendritic branching patterns observed in material impregnated by the Golgi method. Although these morphological differences are widely believed to reflect
differences in connectivity, very little is actually known about the patterns of synaptic input to different cell types. We have obtained such information for 32 adjacent neurons in layer IVab of cat cortical area 17 by reconstructing them from electron m
icrographs of 150 serial sections. Synaptic terminals from the lateral geniculate nucleus were labeled in this material by anterograde degeneration and their distribution, as well as that of normal terminals containing flat or round vesicles, was recorded
. The neurons were divided into seven classes based on differences in size, shape, dendritic branching pattern and synaptic input. Class I cells were pyramidal with apical and basilar dendrites, dendritic spines, exclusively flat-vesicle terminals on the
somas (11/100 micron2), and geniculate terminals on the basilar dendrites. Class II cells were large stellates (20 micron diameter) with dark cytoplasm and numerous flat-vesicle and round-vesicle terminals on the somas (48/100 micron2). Geniculate termin
als contacted the cell bodies and primary, secondary, and tertiary dendrites. The Class III cell was stellate with varicose dendrites, a sparse distribution of flat-vesicle terminals (8/100 micron2) on the soma, and both geniculate and round-vesicle termi
nals on the dendrites. Class IV cells had radially elongated somas with sharply tapered apical and basilar dendrites bearing spines. There was a medium distribution of flat-vesicles terminals (17/100 mu2), to the somas while geniculate terminals were rest
ricted to the secondary dendrites. Class V cells were multipolar with flat-vesicle terminals on the somas (11/100 micron2) and a few geniculate terminals on the dendrites. Class VI cells were mostly small (as small as 7 micron diameter), with a sparse dis
tribution on the somas of both flat-vesicle terminals (7/100 micron2). Two cells had geniculate terminals on their somas. Class VII cells had sharply tapered apical and basilar dendrites, both flat-vesicle and round-vesicle terminals on the somas (14/100
micron2), and no geniculate input. The results make clear that the neurons in layer IVab are quite heterogeneous, not merely in their intrinsic morphology, but also in their patterns of connectivity. The geniculate input is not funneled to a single type o
f neuron but diverges widely, contacting at least six different cell types, and may form on each a pattern that is characteristic for the type. The reconstruction approach, in providing a detailed identification of the synaptic patterns on substantial num
bers of adjacent cells, should make it possible to address directly certain unanswered questions about cortical circuitry...
J Comp Neurol 1987 Jun
1;260(1):76-86 The distribution of geniculate synapses on neuron cell bodies
in layers IVab and IVc of cat area 17 was studied. Electron
microscope autoradiography was used to identify geniculate
terminals that were labeled by anterograde transport of
radioactivity i njected into the A-laminae of the lateral
geniculate nucleus. Thirty-eight cell bodies (19 in layer IVab
and 19 in layer IVc) were examined in a series of 138 consecutive
sections. Two pyramidal somas were studied and had no geniculate
contacts. All of th e other somas studied were nonpyramidal, and
of these, 85% received geniculate contacts. The proportion of
somas receiving somatic geniculate input differed in layers IVab
and IVc. In layer IVab, 70% of the nonpyramidal somas received
geniculate contacts; in IVc, 100%. Such high percentages indicate
that geniculate afferents synapse with more types of layer IV
neuron than the aspinous neurons that synthesize
gamma-aminobutyric acid (GABA) (Freund et al., '85b). The pattern
of input to somas was so diverse that it was impossible to form
groups of neurons based on only this criterion. We wondered if it
would be possible to form groups of neurons based on a range of
characteristics among which would be pattern of synaptic input.
To this end, pyramidal neuron s and neurons that contained a
cytoplasmic laminated body (CLB) (Winfield, '79; Einstein et al.,
'84) were treated as two separate classes. We found fair
agreement among the features of these neurons within their own
classes, with the CLB-cells in layer I Vab and IVc forming
separate groups. Among the remaining neurons there was too little
agreement within the range of features to enable us to treat them
in this manner. Geniculate somatic contacts in both sublayers
were of 2 forms, those with round vesicle s and asymmetric
thickenings (RA) and those with pleomorphic vesicles and
symmetric thickenings (PS) (Einstein et al., '87). The
distribution of these forms varied: some cells received contacts
exclusively from one form or the other; other cells received
contacts from both. On one cell that bore 33 somatic geniculate
terminals, 61% were RA and 39% were PS. Such substantial numbers
of geniculate contacts located near the site of impulse
initiation are likely to contribute significantly to the
receptive fie ld properties of this neuron, and the possible
effects are discussed.
J Comp Neurol 1987 Jun
1;260(1):76-86 The distribution of geniculate synapses on neuron cell bodies
in layers IVab and IVc of cat area 17 was studied. Electron
microscope autoradiography was used to identify geniculate
terminals that were labeled by anterograde transport of
radioactivity i njected into the A-laminae of the lateral
geniculate nucleus. Thirty-eight cell bodies (19 in layer IVab
and 19 in layer IVc) were examined in a series of 138 consecutive
sections. Two pyramidal somas were studied and had no geniculate
contacts. All of th e other somas studied were nonpyramidal, and
of these, 85% received geniculate contacts. The proportion of
somas receiving somatic geniculate input differed in layers IVab
and IVc. In layer IVab, 70% of the nonpyramidal somas received
geniculate contacts; in IVc, 100%. Such high percentages indicate
that geniculate afferents synapse with more types of layer IV
neuron than the aspinous neurons that synthesize
gamma-aminobutyric acid (GABA) (Freund et al., '85b). The pattern
of input to somas was so diverse that it was impossible to form
groups of neurons based on only this criterion. We wondered if it
would be possible to form groups of neurons based on a range of
characteristics among which would be pattern of synaptic input.
To this end, pyramidal neuron s and neurons that contained a
cytoplasmic laminated body (CLB) (Winfield, '79; Einstein et al.,
'84) were treated as two separate classes. We found fair
agreement among the features of these neurons within their own
classes, with the CLB-cells in layer I Vab and IVc forming
separate groups. Among the remaining neurons there was too little
agreement within the range of features to enable us to treat them
in this manner. Geniculate somatic contacts in both sublayers
were of 2 forms, those with round vesicle s and asymmetric
thickenings (RA) and those with pleomorphic vesicles and
symmetric thickenings (PS) (Einstein et al., '87). The
distribution of these forms varied: some cells received contacts
exclusively from one form or the other; other cells received
contacts from both. On one cell that bore 33 somatic geniculate
terminals, 61% were RA and 39% were PS. Such substantial numbers
of geniculate contacts located near the site of impulse
initiation are likely to contribute significantly to the
receptive fie ld properties of this neuron, and the possible
effects are discussed. J Comp Neurol 1996 Jan 15;364(3):556-566 National Institute of Neurological Disorders and Stroke, Maryland 20892, USA.
We studied the morphology, photic responses, and synaptic connections of ON-OFF amacrine cells in the cat retina by penetrating them with intracellular electrodes, staining them with horseradish peroxidase, and examining them with the electron microsco
pe. In a sample of seven cells, we found two different morphological types: the A19, which ramifies narrowly in stratum 2 (sublamina a) of the inner plexiform layer, and the A22, which ramifies mostly in stratum 4 (sublamina b) but extends some dendrites
to sublamina a. Both of these cell types have axon-like processes that extend > 800 microns from the conventional dendritic arbor. ON-OFF amacrine cells in our sample had receptive fields (1.7 +/- 0.3 mm diameter) that were broader than their dendritic
arbors (425 +/- 35 microns diameter) and that extended over the region of axon-like processes. In addition, we found many features in common with ON-OFF amacrine cells in poikilotherm vertebrates: a broad receptive field without surround antagonism, two
sizes of spike-like events, narrow dynamic range (1 log unit intensity), and excitatory postsynaptic potentials at light on and light off. Two A19 amacrine cells were examined in the electron microscope: most synaptic inputs (93 and 76%, respectively) to
either cell were from amacrine cells, with minor inputs from cone bipolar cells. Synaptic outputs were to bipolar, amacrine, and ganglion cells, including the OFF-alpha cell.
J Comp Neurol 1983 Sep 20;219(3):295-304 Roughly one-quarter of neurons in the amacrine cell layer accumulate exogenous gamma-aminobutyric acid (GABA). Some of these (8%) are interplexiform cells; the remainder are true amacrine cells. We partially reconstructed, from serial electron microsco
py autoradiograms, 25 GABA-accumulating amacrines and distinguished four types based on cytoplasmic appearance, soma size and shape, and the form of primary and secondary processes. Type 1 had a large (609 +/- 60 microns3), dark soma, and multiple, medium
-diameter (0.6 microns) processes splayed from the soma margins like the appendages from a crab. Type 2 had a medium (360 +/- 40 microns3), helmet-shaped, pale soma, and medium-diameter (0.8 microns) processes that branched in sublamina alpha. Type 3 had
a small (267 +/- 44 microns3), dark, pyriform soma. The latter formed a single stout (3.0 microns) process that bifurcated in the middle of sublamina alpha. Type 4 had a very large, pale soma (860 microns3). This was pyriform, tapering into a stout (2.0 m
icrons) process that descended into the middle of sublamina alpha where it emitted smaller tangential processes. It is to be expected that each of these amacrine cell types will have distinct functions in neurotransmitter retinal circuitry.
J Comp Neurol 1987 Dec 15;266(3):445-455 Department of Anatomy, University of Pennsylvania, Philadelphia 19104.
The potential and actual connections between rod and rod bipolar arrays in the area centralis of the cat retina were studied by electron microscopy of serial ultrathin sections. In the region studied there were about 378,000 rods/mm2 and 36,000-47,000
rod bipolars/mm2. The tangential spread of rod bipolar dendrites was 11.2 microns in diameter, and the "coverage factor" for the rod bipolar cell was 3.5-4.6. We estimate that about 37 rods potentially converge on a rod bipolar cell and that one
rod potentially diverges to about four rod bipolar cells. The actual connections, however, are less than this by about half: 16-20 rods actually converge on a bipolar cell and one rod actually diverges to slightly less than two rod bipolar cells. The deg
ree of convergence appears to reflect a compromise between the need to signal graded stimulus intensities (requiring wide convergence) and the need to maintain a good signal/noise ratio (requiring narrow convergence). Amacrine varicosities that provide re
ciprocal contact at the rod bipolar dyad were studied in serial electron microscopic autoradiograms following intraocular administration of 3H-GABA or 3H-glycine. More that 90% of the reciprocal amacrine processes accumulated GABA in a specific fashion. T
his information, in conjunction with Nelson's recordings from the rod bipolar and amacrine cells postsynaptic at the dyad (Nelson et al: Invest. Ophthalmol. 15:946-953, '76; Kolb and Nelson: Vision Res. 23:301-312, '83), suggests that feedback at the rod
bipolar output might be positive.
Proc Natl Acad Sci U S A 1992 Jan 1;89(1):236-240
Laboratory of Neurophysiology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
The on-alpha ganglion cell in the area centralis of the cat
retina receives approximately 450 synapses from type b1 cone
bipolar cells. This bipolar type forms a closely spaced array (9
microns), which contributes from 1 to 7 synapses per b1 cell
throu ghout the on-alpha dendritic field. Here we use a
compartmental model of an on-alpha cell, based on a
reconstruction from electron micrographs of serial sections, to
compute the contribution of the b1 array to the on-alpha
receptive field. The computation shows that, for a physiologic
range of specific membrane resistance (9500-68,000 omega.cm2) and
a linear synapse, inputs are equally effective at all points on
the on-alpha dendritic tree. This implies that the electrotonic
properties of the dendritic tree contribute very little to the
domed shapes of the receptive field center and surround. Rather,
these shapes arise from the domed distribution of synapses across
the on-alpha dendritic field. Various sources of
"jitter" in the anatomical circu it, such as variation
in bipolar cell spacing and fluctuations in the number of
synapses per bipolar cell, are smoothed by the overall circuit
design. However, the computed center retains some minor
asymmetries and lumps, due to anatomical jitter, as found in
actual alpha-cell receptive fields.
J Neurosci 1988 Jul;8(7):2303-2320 University of Pennsylvania Medical School, Department of Anatomy, Philadelphia 19104.
Anatomical circuits converging onto the ON-alpha (Y) ganglion cell were studied by computer-assisted reconstruction of substantial portions of 2 alpha cells from electron micrographs of serial sections. The alpha cells in the area centralis were labele
d by a Golgi-like retrograde filling with horseradish peroxidase, and certain presynaptic amacrine processes were labeled by uptake of 3H-glycine. About 4400 synapses contacted the alpha cell. Eighty-six percent were from amacrine cells; the rest were fro
m bipolar cells. About one-quarter of the amacrine synapses were specifically labeled by 3H-glycine and probably belong to the A4 amacrine. The bipolar inputs were provided by several types: cone bipolar CBb1 (85%), cone bipolar CBb5 (2%), the rod bipolar
(5%), and some unidentified cone bipolars (11%). Contacts from each type occurred in specific strata, with the consequence that they tended to form spots or annulli over the alpha dendritic field. The CBb1 bipolars formed a moderately dense array (8000/m
m2), with a nearest-neighbor distance of 8.6 +/- 1.3 microns. Most members of the array (84%) contacted the alpha cell, providing 1-7 synapses (average, 2.7 +/- 1.6). The placement of contacts from an individual CBb1 followed certain rules: they were rest
ricted to a parent branch of the alpha arbor or to 2 daughter branches, but almost never crossed a branch of the alpha arbor. The synaptic territory of an individual CBb1 was not shared with other b1s (or cone bipolars of any sort), although it was shared
with amacrine contacts. Rod bipolar cells also formed a very dense array (54,500/mm2) in the alpha dendritic field, but only a few of these (3%) contacted the alpha cell. The concentric receptive field of the CBb1, combined with the spatial organization
of its array, is used to predict the CBb1 contribution to the alpha cell receptive field; this contribution resembles the spatial and temporal organization of the alpha receptive field itself.
Proc Natl Acad Sci U S A 1996 Dec
10;93(25):14598-14601 Department of Pharmacology and Physiology, University of Rochester, NY 14642, USA.
Expression of G protein-regulated phospholipase C (PLC) beta 4
in the retina, lateral geniculate nucleus, and superior
colliculus implies that PLC beta 4 may play a role in the
mammalian visual process. A mouse line that lacks PLC beta 4 was
generated and the physiological significance of PLC beta 4 in
murine visual function was investigated. Behavioral tests using a
shuttle box demonstrated that the mice lacking PLC beta 4 were
impaired in their visual processing abilities, whereas they
showed no defi cit in their auditory abilities. In addition, the
PLC beta 4-null mice showed 4-fold reduction in the maximal
amplitude of the rod a- and b-wave components of their
electroretinograms relative to their littermate controls.
However, recording from single r od photoreceptors did not reveal
any significant differences between the PLC beta 4-null and
wild-type littermates, nor were there any apparent differences in
retinas examined with light microscopy. While the behavioral and
electroretinographic results in dicate that PLC beta 4 plays a
significant role in mammalian visual signal processing, isolated
rod recording shows little or no apparent deficit, suggesting
that the effect of PLC beta 4 deficiency on the rod signaling
pathway occurs at some stage after the initial phototransduction
cascade and may require cell-cell interactions between rods and
other retinal cells.
J Neurosci 1995 Nov;15(11):7673-7683 Department of Bioengineering, University of Pennsylvania, School of Medicine, Philadelphia 19104, USA.
Ganglion cell receptive field centers are small in central retina and larger toward periphery. Accompanying this expansion, the distribution of sensitivity across the centers remain Gaussian, but peak sensitivities decline. To identify circuitry that might explain this physiology, we measured the density of bipolar cell synapses on the dendritic membrane of beta (X) and alpha (Y) ganglion cells and the distribution of dendritic membrane across their dendritic fields. Both central and peripheral beta cells receive bipolar cell synapses at a density of approximately 28/100 microns2 of dendritic membrane; central and peripheral alpha cells receive approximately 13/100 microns2. The distribution of dendritic membrane across the dendritic field is dome-like; therefore, the distribution of bipolar cell synapses is also dome-like. As the dendritic field enlarges, total postsynaptic membrane increases with field radius, but only linearly. Consequently, density of postsynaptic membrane in the dendritic field declines, and so does density of synapses within the field. The results suggest a simple model in which the receptive field center's Gaussian profile and peak sensitivity are both set by the density of bipolar cell synapses across the dendritic field.
J Comp Neurol 1983 Apr 20;215(4):465-471 The rat olfactory tubercle contains high concentrations of gamma-aminobutyric acid (GABA) and its synthetic enzyme, glutamic acid decarboxylase (GAD). We previously demonstrated that GABA and GAD are most concentrated in the polymorphic layer of the tubercle and relatively absent from the plexiform and pyramidal layers. Here we report that the granule cells (the islands of Calleja) in the polymorphic layer accumulate 3H-GABA. 3H-GABA (34.5 Ci/mmole; 1.5 microliter) was injected into the tubercle and an hour later the rat was perfused with a mixture of paraformaldehyde and glutaraldehyde. The tissue was osmicated, dehydrated, and embedded in epon. Silver grains were sparse over the pyramidal and polymorphic cell bodies but numerous over the granule cell bodies in the islands of Calleja and dendrites in the surrounding neuropil. Grain densities for the granule cells were 41/100 micrometer3 compared to 4.2 for the pyramidal and polymorphic cells. Within the island, all the granule cells appeared to be labeled. These results, combined with previous demonstrations of the presence in this region of endogenous GABA and GAD, suggest that the granule neurons of the rat olfactory tubercle are GABA-ergic. These neurons also appear to receive dopamine input and therefore form part of a circuit that includes targets for both major and minor tranquilizers.
J Neurosci 1984 Dec;4(12):2920-2938 We have studied 15 bipolar neurons from a small patch (14 X
120 micron) of adult cat retina located within the area
centralis. From electron micrographs of 189 serial ultrathin
sections, the axon of each bipolar cell was substantially
reconstructed with its synaptic inputs and outputs by means of a
computer-controlled reconstruction system. Based on differences
in stratification, cytology, and synaptic connections, we
identified eight different cell types among the group of 15
neurons: one type of rod bipolar and seven types of cone bipolar
neurons. These types correspond to those identified by the Golgi
method and by intracellular recording. Those bipolar cell types
for which we reconstructed three or four examples were extremely
regular in form, size, and cytology, and also in the quantitative
details of their synaptic connections. They appeared quite as
specific in these respects as invertebrate "identified"
neurons. The synaptic patterns observed for each type of bipolar
neuron were complex but may be summarized as follows: the rod
bipolar axon ended in sublamina b of the inner plexiform layer
and provided major input to the AII amacrine cell. The axons of
three types of cone bipolar cells also terminated in sublamina b
and provided contacts to dendrites of on-beta and other ganglion
cells. All three types, but especially the Cb1, received gap
junction contacts from the AII amacrine cell. Axons of four types
of cone bipolar cells terminated in sublamina a of the inner
plexiform layer and contacted dendrites of off-beta and other
ganglion cells. One of these cone bipolar cell types, CBa1, made
reciprocal chemical contacts with the lobular appendage of the
AII amacrine cell. These results show that the pattern of cone
bipolar cell input to beta (X) and probably alpha (Y) ganglion
cells is substantially more complex than had been suspected. At
least two types of cone bipolar contribute to each type of
ganglion cell where only a single type had been anticipated. In
addition, many of the cone bipolar cell pathways in the inner
plexiform layer are available to the rod system, since at least
four types of cone bipolar receive electrical or chemical inputs
from the AII amacrine cell. This may help to explain why, in a
retina where rods far outnumber the cones, there should be so
many types of cone bipolar cells.
J Neurosci 1986 Apr;6(4):907-918 We reconstructed from electron micrographs of 189 serial
ultrathin sections a major portion of the dendritic tree of an
on-beta ganglion cell through its sixth order of branching. One
hundred three contacts from three cone bipolar cells were
identified. Forty-seven contacts were from a single CBb1 cone
bipolar. These were distributed widely over the dendritic tree
but were frequently found on the slender "basal tuft"
dendrites. Twenty-two additional contacts from a second CBb1 cell
were found but not studied in detail. Thirty-four contacts were
from a single CBb2 cone bipolar; these also were distributed
widely but were primarily on the branches of the main dendritic
arborization. A major portion of the dendritic tree of an
off-beta cell was also reconstructed through its seventh order of
branching. Thirty-five contacts from two cone bipolar cells were
identified. Twenty-three contacts were from a single CBa1 cone
bipolar and 12 widely distributed over the off-beta cell
dendritic tree. We propose that the photopic receptive field
center of a beta cell corresponds to the envelope of the
receptive fields of the bipolar cells that connect it to the
cones. The center response of a beta cell may be generated by a
"push-pull" mechanism. For the on-beta cell there would
be excitation at light on from CBb1 and disinhibition from CBb2
and the reverse at light off. For the off-beta cell there would
be inhibition at light on from CBa2 and withdrawal of excitation
from CBa1. Should the bipolars have antagonistic surrounds (so
far reported only for CBb1), the beta cell surrounds as well as
their centers might be generated by this push-pull mechanism.
J Comp Neurol 1981 Nov 1;202(3):385-396 We have examined by autoradiography the labeling pattern in the cat superior colliculus following injection of tritiated gamma-aminobutyric acid (GABA). Silver grains were heavily distributed within the zonal layer and the upper 200 micrometer of the superficial gray. Fewer grains were observed deeper within the superficial gray, and still fewer were found within the optic and intermediate gray layers. The accumulation of label was restricted to certain classes of neuron and glia. Densely labeled neurons were small (8-12 micrometer in diameter) and located primarily within the upper 200 micrometer. Dark oligodendrocytes and astrocytes showed a moderate accumulation of label while pale oligodendrocytes and microglia were unlabeled. Label was also selectively accumulated over several other types of profile within the neuropil, including presynaptic dendrites, axons, and axon terminals.
J Comp Neurol 1982 Apr 1;206(2):180-192 Two types of neuron in the upper superficial gray layer of the cat superior colliculus accumulated exogenous 3H-gamma-aminobutyric acid intensely. The first type was a horizontal cell with a fusiform cell body, horizontal dendrites, a low synaptic density, but a high percentage of cortical synaptic contacts. This cell had presynaptic dendrites. The second type was a granule cell (type A) with a small round cell body, thin and obliquely oriented dendrites, a moderate synaptic density, and few cortical synaptic contacts. These two types differed in size, shape, dendritic morphology, and patterns of synaptic input. They likely participate in different inhibitory mechanisms. Four types of unlabeled neurons were also identified. Type B granule cells were found only within the upper subdivision of the superficial gray layer. They had moderate-sized cell bodies, a high synaptic density, and numerous somatic spines. A third type of granule cell (type C) was found only in the deep subdivision of the superficial gray. This type had a low synaptic density and spines that contained synaptic vesicles. Vertical fusiform and stellate forms were also found. We conclude that at least six types of neurons populate the upper superficial gray layer of the cat superior colliculus.
Proc Natl Acad Sci U S A 1980 Jan;77(1):658-661 After intravitreal injection of gamma-[3H] aminobutyric acid (GAB), 2% of the neurons at the outer margin of the inner plexiform layer were intensely labeled. Reconstructions of these neurons from serial electron microscope autoradiograms showed that they are interplexiform cells, which synapse on bipolar processes in the outer plexiform layer and on amacrine and bipolar processes in the inner plexiform layer.
J Comp Neurol 1995 Oct 23;361(3):479-490 Department of Neuroscience, University of Pennsylvania, Philadelphia 19104-6058, USA.
Many branched patterns in nature are hypothesized to be fractal, i.e., statistically self-similar across a range of scales. We tested this hypothesis on the two-dimensional arbors of retinal neurons and blood vessels. First, we measured fractalness on synthetic fractal and nonfractal patterns. The synthetic fractal patterns exhibited self-similarity over a decade of scale, but the nonfractal "controls" showed hardly any self-similarity. Neuronal and vascular patterns showed no greater self-similarity than the controls. Second, we manipulated a synthetic fractal pattern to remove its self-similarity and found this to be reflected in a loss of measured fractalness. The same manipulation of the nonfractal control and also of the neural and vascular patterns did not alter their measured fractalness. Third, we "grew" patterns of branched line segments according to a variety of nonfractal algorithms. These patterns were, if anything slightly more fractal than the neural and vascular patterns. We conclude that the biological patterns studied here are not fractal. Finally, we measured extended versions of these patterns: a contiguous array of homotypic neuron arbors and a vascular pattern with a high degree of total detail. These patterns showed a "fractal dimension" of 2, which implies that down to some cut-off scale they fill space completely. Thus, neural and vascular patterns might best be described as quasi-regular lattices.
Biophys J 1994 Jul;67(1):57-63 Department of Bioengineering, University of Pennsylvania, Philadelphia 19104.
Under scotopic conditions, the mammalian rod encodes either one photon or none within its integration time. Consequently the signal presented to its synaptic terminal is binary. The synapse has a single active zone that releases neurotransmitter quanta tonically in darkness and pauses briefly in response to a rhodopsin isomerization by a photon. We asked: what minimum tonic rate would allow the postsynaptic bipolar cell to distinguish this pause from an extra-long interval between quanta due to the stochastic timing of release? The answer required a model of the circuit that included the rod convergence onto the bipolar cell and the bipolar cell's signal-to-noise ratio. Calculations from the model suggest that tonic release must be at least 40 quanta/s. This tonic rate is much higher than at conventional synapses where reliability is achieved by employing multiple active zones. The rod's synaptic mechanism makes efficient use of space, which in the retina is at a premium.
Neuron 1995 Mar;14(3):561-569 Department of Neuroscience, University of Pennsylvania, Philadelphia 19104.
The mammalian rod synapse transmits a binary signal (one photon or none) using tonic, rapid exocytosis. We constructed a quantitative, physical model of the synapse. Presynaptically, a single, linear active zone provides docking sites for approximately 130 vesicles, and a "ribbon" anchored to the active zone provides a depot for approximately 640 vesicles. Postsynaptically, 4 processes invaginate the terminal: 2 (known to have low affinity glutamate receptors) lie near the active zone (16 nm), and 2 (known to have high affinity glutamate receptors) lie at a distance (130-640 nm). The presynaptic structure seems designed to minimize fluctuations in tonic rate owing to empty docking sites, whereas the postsynaptic geometry may permit 1 vesicle to evoke an all-or-none response at all 4 postsynaptic processes.
In: Neurobiology and clinical aspects of the outer
retina (Archer S, Djamgoz MBA, Vallerga S eds), pp 325-348.
London UK: Chapman & Hall, Ltd. Department of Neuroscience, School of Medicine, University of
Pennsylvania, Philadelphia 19104-6058.
Function in the outer retina has mainly gbeen studied by
recording in situ from single neurons. In lower
vertebrates this approach to bipolar cells has been extremely
fruitful (e.g. Chapter 12), but in mammals bipolar cell
recordings can be counted on the fingers of (at most) two hands
(Nelson and Kolb, 1983; Dacheux and Raviola, 1986). And,
considering that the recordings include both rod bipolar and
multiple types of cone bipolar cell (Chapter 11), the
electrophysiological data regarding mammalian bipolar neurons are
thinly spread. On the other hand, in lower vertebrates
information essential to understanding the contribution of the
outer retina to image processing (such as optics, sampling
frequencies, and synaptic circuitry) hardly exists. So, in lower
vertebrates how single neuron responses in the outer contribute
to vision remains unclear.
Yet, single cell recording is not the only possible approach to
understanding retinal function. An alternative strategy is to
determine complete circuit structure ('wiring diagram') plus the
chemical architecture and to incorporate this informatlion,
together with the optics and ganglion cell electrophysiology,
into various computational models. Then, one might calculate
backwards to the properties of the bipolar cells and
photoreceptors. Such an effort leads to specific predictions
regarding the photoreceptor and bipolar cell function, and with
this approach a little electrophysiology goes a surprisingly long
way. At least, that is our argument in this review. We emphasize
cat retina, which is known in most detail, but also note recent
data from reabbit and primate that indicate conservation of
certain basic circuits and functions.
In the exact center of the area centralis, cone density reaches
30,000-40,000/mm2 (Wassle and Riemann, 1978; Williams et al.,
1993), but the circuitry has been studied slightly off center (1
deg eccentricity) where the cone density is about 24,000/mm2 and
rod density is about 350,000/mm2 (Sterling et al., 1988). Here,
due to the natural blur of the cat's optics (Wassle, 1971; Robson
and Enroth-Cugell, 1978), the minimum number of photoreceptors
stimulated from a point source is about 10 cones and 140 rods
(Figure 13.1a, 2b). This is many more receptors than converging
on a single bipolar cell, so even the finest spatial stimulus
falling on either type of receptor will affect many bipolar
cells. We review first the circuits for daylight that lead
from cones because various portions of this circuit are
parasitized by the circuits for twilight and starlight that lead
from rods (Figure 13.2).
J Neurosci Methods 1987 Sep;21(1):55-69 Department of Anatomy, School of Medicine, University of Pennsylvania, Philadelphia 19104-6058.
This paper describes a simplified system for serial section three-dimensional (3-D) reconstruction. A set of 9 software programs runs on a standard personal computer and produces camera-ready illustrations suitable for publication. The user enters trace points on a digitizing tablet from sections that have been already aligned. A 3-D view of the reconstructed object is generated which can be displayed with hidden lines removed. Analysis of volume, surface area and autoradiographic grain density are performed automatically. A relational database query language allows display and analysis of a selected subset of the data. The system runs under the UNIX operating system which allows the programs to be easily transported to new hardware or modified for other purposes.
J Neurosci Methods 1992 Jul;43(2-3):83-108 Department of Anatomy, University of Pennsylvania, Philadelphia 19104-6058.
A computational language was developed to simulate neural circuits. A model of a neural circuit with up to 50,000 compartments is constructed from predefined parts of neurons, called "neural elements". A 2-dimensional (2-D) light stimulus and a photoreceptor model allow simulating a visual physiology experiment. Circuit function is computed by integrating difference equations according to standard methods. Large-scale structure in the neural circuit, such as whole neurons, their synaptic connections, and arrays of neurons, are constructed with procedural rules. The language was evaluated with a simulation of the receptive field of a single cone in cat retina, which required a model of cone-horizontal cell network on the order of 1000 neurons. The model was calibrated by adjusting biophysical parameters to match known physiological data. Eliminating specific synaptic connections from the circuit suggested the influence of individual neuron types on the receptive field of a single cone. An advantage of using neural elements in such a model is to simplify the description of a neuron's structure. An advantage of using procedural rules to define connections between neurons is to simplify the network definition.
Vis Neurosci 1995 May;12(3):545-561 Department of Neuroscience, University of Pennsylvania, Philadelphia 19104-6058, USA.
The outer plexiform layer of the retina contains a neural
circuit in which cone synaptic terminals are electrically coupled
and release glutamate onto wide-field and narrow-field horizontal
cells. These are also electrically coupled and feed back through
a GABAergic synapse to cones. In cat this circuit's structure is
known in some detail, and much of the chemical architecture and
neural responses are also known, yet there has been no attempt to
synthesize this knowledge. We constructed a large-scale
compartmental model (up to 50,000 compartments) to incorporate
the known anatomical and biophysical facts. The goal was to
discover how the various circuit components interact to form the
cone receptive field, and thereby what possible function is
implied. The simulation reproduced many features known from
intracellular recordings: (1) linear response of cone and
horizontal cell to intensity, (2) some aspects of temporal
responses of cone and horizontal cell, (3) broad receptive field
of the wide-field horizontal cell, and (4) center-surround cone
receptive field (derived from a "deconvolution model").
With the network calibrated in this manner, we determined which
of its features are necessary to give the cone receptive field a
Gaussian center-surround shape. A Gaussian-like center that
matches the center derived from the ganglion cell requires both
optical blur and cone coupling: blur alone is too narrow,
coupling alone gives an exponential shape without a central
dome-shaped peak. A Gaussian-like surround requires both types of
horizontal cell: the narrow-field type for the deep, proximal
region and the wide-field type for the shallow, distal region.
These results suggest that the function of the cone-horizontal
cell circuit is to reduce the influence of noise by
spatio-temporally filtering the cone signal before it passes
through the first chemical synapse on the pathway to the brain.
Download pdf file of this article
J Neurosci 1986 Dec;6(12):3505-3517 The structure of the rod-cone network in the area centralis of
cat retina was studied by reconstruction from serial electron
micrographs. About 48 rods converge on each cone via gap
junctions between the rod spherules and the basal processes of
the cone pedicle. One rod diverges to 2.4 cones through these gap
junctions, and each cone connects to 8 other cones, also through
gap junctions. A static cable model of this network showed that
at mesopic intensities, when all rods converging on a cone
pedicle are continuously active, the collective rod signal would
be efficiently conveyed to the pedicle. At scotopic intensities
sufficiently low for only one of the converging rods to receive a
single photon within its integration time, the quantal rod signal
would be poorly transmitted to the cone pedicle. This is because
the tiny signal would be dissipated by the large network into
which the individual rod diverges. Under this condition, the rod
signal would also be poorly conveyed to the rod spherule. If,
however, the rods are electrically disconnected from the network,
the quantal signal would be efficiently conveyed to the rod
spherule. This analysis suggests that the rod signal is conveyed
at mesopic intensities by the cone bipolar pathway and, at
scotopic intensities, by the rod bipolar pathway, in accordance
with the results of Nelson (1977, 1982; Nelson and Kolb, 1985).
Download pdf file of this article Vis Neurosci 1990 Nov;5(5):453-461
The receptive-field profile of the cone in cat-retina was computed. The computation
was based on (1) the known anatomical circuit connecting cones via narrow-field
bipolar cells to the on-beta ganglion cell; (2) the known physiological receptive-field
profile of the on-beta (X) cell at the corresponding eccentricity; and (3) a model in
which the beta receptive field arises by linear superposition of cone receptive fields.
The computed cone receptive field has a center/surround organization with a center
almost as broad as that of the beta cell center. The cone surround is comparably broad
to that of the beta cell but somewhat lower in peak amplitude. The problems to which
the center/surround receptive field are the solution, namely, signal compression and
noise reduction, apparently must be solved before the first synapse of the visual
pathway.
Download
pdf file of this article Vis Neurosci 1995 Sep;12(5):851-860 Department of Neuroscience, University of Pennsylvania, Philadelphia 19104-6058, USA.
The AII amacrine cell of mammalian retina collects signals from several hundred rods
and is hypothesized to transmit quantal "single-photon" signals at scotopic (starlight)
intensities. One problem for this theory is that the quantal signal from one rod when
summed with noise from neighboring rods would be lost if some mechanism did not
exist for removing the noise. Several features of the AII might together accomplish
such a noise removal operation: The AII is interconnected into a syncytial network by
gap junctions, suggesting a noise-averaging function, and a quantal signal from one rod
appears in five AII cells due to anatomical divergence. Furthermore, the AII contains
voltage-gated Na+ and K+ channels and fires slow action potentials in vitro,
suggesting that it could selectively amplify quantal photon signals embedded in
uncorrelated noise. To test this hypothesis, we simulated a square array of AII somas
(Rm = 25,000 Ohm-cm2) interconnected by gap junctions using a compartmental
model. Simulated noisy inputs to the AII produced noise (3.5 mV) uncorrelated
between adjacent cells, and a gap junction conductance of 200 pS reduced the noise by
a factor of 2.5, consistent with theory. Voltage-gated Na+ and K+ channels (Na+: 4
nS, K+: 0.4 nS) produced slow action potentials similar to those found in vitro in the
presence of noise. For a narrow range of Na+ and coupling conductance, quantal
photon events (approximately 5-10 mV) were amplified nonlinearly by subthreshold
regenerative events in the presence of noise. A lower coupling conductance produced
spurious action potentials, and a greater conductance reduced amplification. Since the
presence of noise in the weakly coupled circuit readily initiates action potentials that
tend to spread throughout the AII network, we speculate that this tendency might be
controlled in a negative feedback loop by up-modulating coupling or other synaptic
conductances in response to spiking activity.
Proc Natl Acad Sci U S A 1984 Jun;81(12):3898-3900 Layer IVab of the visual cortex (area 17) of the cat contains about 51,400 neurons per mm3, including about 400-1200 per mm3 of each of three categories of neuron believed from previous work to represent discrete types. Each type forms about 0.5-1.5% of all the IVab neurons, which suggests that the total number of types in this layer might be much greater than previously supposed, perhaps as many as 50 or more. From their densities and estimates of their dendritic fields, we calculate that each type completely "covers" layer IVab in the tangential plane but only by a small factor (1.3-4.2).
Department of Neuroscience, University of Pennsylvania Medical
School, Philadelphia 19104-6058.
As a device for extracting information from a visual image, the
vertebrate retina is unparalleled in its range, reliability, and
compactness. Signaling in the retina is slower by six orders of
magnitude than in an integrated digital circuit. The advantage
of the biological structure must therefore derive from the
variety of its fundamental elements and from the subtlety of
their connections. Each of the five major classes of retinal
neuron, whose synaptic contacts were first described
systematically by Dowling & Boycott (1966) is now known to have
multiple types, totaling in the cat about 60. Specific local
circuits involving about one-third of these neurons have been
recognized in the electron microscope. Physiological responses
have also been documented for about one-third of the types, and
evidence regarding the neural transmitter, or at least the sign
of the synapse, has accumulated also for about one-third.
These discoveries have abundantly supported certain concepts of
retina function developed in the 1960s by Lettvin & Maturana.
The function of the retina, they proposed, "is not to transmit
information about the point-to-point distribution of light and
dark in the image, but to analyze this image at every point in
terms of ... arbitrary contexts ..." (Maturana et al., 1960).
Each of these "contexts," they suggested, corresonds to some
operation on the local image performed by a ganglion cell of
particular size and shape (Lettvin et al., 1961). This idea,
based on studies of the frog, seemed for a time inapplicable to
the cat, which was thought to have a "simple" retina with only
center-surround type ganglion cells. Subsequent studies to be
reviewed here have firmly established for the cat the validity of
this idea.
Lettvin & Maturana also paid special attention to the
stratification of processes in the frog's inner plexiform layer,
believing tthat the operation performed by a ganglion cell is
determined by specific bipolar inputs delivered to the strata of
its dendritic arbor. This idea, too, was thought to be
inapplicable to the cat, whose inner plexiform layer is less
obvioiusly stratified than the frog's. Sutdies to be reviewed
here now strongly support this concept for the cat.
Nothing of the actual circuits between particular neuron types
was known to Lettvin & Maturana, but fragments of such knowledge
accumulated for the cat during the 1970s. Some of the first
observations were extremely puzzling. It turned out, for
example, that rods and ccones have separate bipolars and thus
apparently separate pathways to ganglion cells. But rod signals
are also transmitted directly to cones, so why the separate
bipolars? Further, the rod bipolar does not contact most
ganglion cells, as one might have anticipated, but contacts an
amacrine, which in turn contacts, not ganglion cells, but cone
bipolar axons! What could be the meaning of this second
convergence of rod and cone pathways, and why send the rod signal
through such a tortuous route?
The functions of such apparently bizarre paths have been
difficult to comprehend for the same reasons that fragments of an
integrated circuit cannot be grasped except in the context of its
larger diagram. Now, however, with links established between
about one-third of the neuron types, broad pathways can be
identified and specific hypotheses can be suggested regarding
their function. The outline of a detailed mechanistic account of
retinal function emerges, and many of the necessary strategies
and techniques for achieving it seem at hand. In reviewing this
subject now, when many puzzling findings of the past 15 years
begin to fit, one is deeply impressed with the intelligence and
care of the many individual studies from laboratories that
literally girdle the globe.
In this article the first section reviews our knowledge of
particular cell types comprising each major class of retinal
neuron. Information is presented, where available, for each type
regarding morphology, circuitry, distribution, transmitter, and
physiology. Such details constitute the primary evidence that
the retina is composed of many discrete cell types arranged in a
regular mosaic. This section also serves in effect as a "parts
list" for the second section, which describes a complex circuit
involving thirteen types of neuron and suggests how the circuit
might function. Department of Neuroscience, University of Pennsylvania Medical School, Philadelphia 19104-6058.
Neurons in the cat retina belong to specific types. Each type is
characterized by a specific corresponddence between morphology
and physiology and forms a regular array that connects lawfully
to the arrays of certain other types. Two circuits have been
traced quantitatively through these arrays from photoreceptors to
alpha- and beta-ganglion cells. The 'cone-bipolar circuit'
appears to convery the centre-surround receptive field to gangion
cells, using cones in daylight and rods (via gap junctions to
cones) in twilight. A 'rod-bipolar circuit' appears to convey
the quantal signal and the pure center receptive field to the
ganglion cells in starlight. Download
pdf file of this article Neurosci Res Suppl 1987;6:S269-S285 Department of Anatomy, University of Pennsylvania Medical School, Philadelphia 19104-6058.
Between noon and the end of nightfall, the intensity of light
in the environment declines by about ten billion-fold. MOst of
the drama in the human experience of this change occurs during
the hours that we call "twilight". Colors gradually shift in hue
and then desaturate, but spatial resolution is preserved for a
while longer. Thus, in a garden the red roses turn purple and
then black, but the structure of the bush remains distinct. Only
later, as the stars appear, do the details of the foliage
dissolve into shadow.
Our experience of these transitions is paralleled to some
extent by the behavior of individual ganglion cells in cat
retina. So remarkable is their capacity to adapt that they
remain responsive to visual stimuli over the full ten log unit
range of envioronmental light intensity [1]. In this essay, we
review some salient features of this adaptation process. We then
summarize recent anatomical studies of the circuits connecting
photoreceptors to the ganglion cells and speculate upon the
relation of the neural architecture to the function. Only one
type of ganglion cell is considered: the ON-center cell known to
physiologists as "X" or "brisk-sustained" and to morphologists
as "beta" [2-5]. All of the measurements considered here, both
physiological and anatomical, refer to neurons in the area
centralis.
J Comp Neurol 1980 Aug 15;192(4):737-749 About one-quarter of the neurons in the A-laminae of the cat lateral geniculate selectively accumulate exogenous [3H]-gamma-aminobutyric acid (GABA), its analog, [3H]-2,4-diaminobutyric acid (DABA), and the GABA agonist, [3H] muscimol. These neurons are small (12-18 micrometers diameter) and lack a laminar body, which suggests that they correspond to the class III cell identified in Golgi material. GABA and DABA are also accumulated by F-terminals which are post-synaptic to retinal terminals and presynaptic to relay cell dendrites. It is suggested that GABA may be the transmitter for these small neurons which appear to mediate by means of local circuits a feed-forward inhibition onto the relay cells.
J Neurosci 1988 Feb;8(2):623-642
Department of Anatomy, University of Pennsylvania, Philadelphia 19104.
Photoreceptors connect to the on-beta ganglion cell through
parallel circuits involving rod bipolar (RB) and cone bipolar
(CB) neurons. We estimated for a small patch in the area
centralis of one retina the 3-dimensional architecture of both
circuits. This was accomplished by reconstructing neurons and
synapses from electron micrographs of 189 serial sections. There
were (per mm2) 27,000 cones, 450,000 rods, 6500 CBb1, 30,300 RB,
4100 All amacrines, and 2000 on-beta ganglion cells. The
tangential spread of processes was determined for each cell type,
and, with the densities, this allowed us to calculate the
potential convergence and divergence of each array upon the next.
The actual numbers of cells converging and diverging were
estimated from serial sections, as were the approximate numbers
of chemical synapses involved. The cone bipolar circuit showed
narrow convergence and divergence: 16 cones->4 CBb1->1
on-beta 1 cone->1 CBb1->1.2 on-beta This circuit is thought
to contribute significantly to the on-beta cell's photopic
receptive field because the CBb1 has a center-surround receptive
field whose center diameter is greater than the spacing between
adjacent CBb1s. Consequently, the receptive fields of the CBb1s
converging on a beta cell are probably largely concentric and
thus mutually reinforcing in their contributions to the on-beta.
The rod bipolar circuit showed a wider convergence and
divergence: 1500 rods->100 RB->5 AII->4 CBb1->1 on-beta 1
rod->2 RB->5 AII->8 CBb1->2 on-beta The 1500 rods
converging via this circuit account for the spatial extent of the
beta cell's dark-adapted receptive field. This convergence also
accounts for the ganglion cell's maintained discharge, which is
thought to arise from about 6 quantal "dark events" per second.
This many dark events would appear in the ganglion cell if each
rod in the circuit contributed 0.004 dark events per second, and
this is close to what has been measured in monkey rods (Baylor et
al., 1984). Divergence in this circuit serves to expand the
number of copies of the quantal signal (1 rod->8 CBb1) and so
to engage large numbers of chemical synapses that provide
amplification. Reconvergence at the last stage (8 CBb1->2
on-beta) may reduce (by signal averaging) the synaptic noise that
would otherwise accumulate along the pathway.
J Neurosci 1986 May;6(5):1314-1324
The inner plexiform layer of cat retina contains synaptic
structures belonging to 50 or more types of "identified" neurons.
To learn whether there are antigens confined to subsets of these
synaptic structures, we raised monoclonal antibodies to
homogenates of neural retina. Binding patterns of these
antibodies were visualized by the peroxidase-antiperoxidase
method and studied in serial, ultrathin sections by electron
microscopy. Four antibodies stained the synaptic varicosities of
certain amacrine cells. Many of the stained varicosities formed
reciprocal synapses with a rod bipolar axon terminal, but only
about half of the reciprocal synapses associated with a rod
bipolar were stained. Other stained varicosities formed synapses
with cone bipolar axons, ganglion cell dendrites, and unstained
amacrine processes. The patterns were essentially the same for
each antibody and were not altered by staining with the
antibodies two at a time; therefore, it is likely that all four
antibodies stain the same subset of synaptic structures. These
patterns would be accounted for if there were staining of all the
synaptic varicosities of three of the four types of identified
amacrine reciprocally connected to the rod bipolar (A6, A8, A13).
This localization suggests that the antigen responsible for the
binding pattern is not associated with synaptic transmission.
Staining is present in the inner plexiform layer during the
period of synaptogenesis and consequently the antibodies are
serving as markers for following the development of identified
synapses in an identified neural circuit.
Brain Res 1980 Dec;2(3):265-293
To observe certain quantitative features of neuronal geometry and
microcircuitry, it is necessary to reconstruct neurons from
electron micrographs of serial, ultra-thin sections. We describe
here an approach to preparing, photographing, and analyzing
moderately long series (100-500 sections). A series is prepared
using an assembly line approach: one operator cuts while a second
mounts ribbons of sections using various mechanical aids.
Photographs are taken in the electron microscope at low
magnification and high accelerating voltage. Sequential negatives
are aligned using an image combiner and copied, using
quasi-coherent illumination, onto 35 mm film. The resulting
"movie' is mounted on a precision film transport mounted on an
X-Y stage controlled by stepping motors. The movie is viewed
through a high resolution video system while a video storage
device and switching system permit rapid alternation between
frames for comparisons. The profiles of a process in successive
frames are "microaligned' by small adjustments of the transport's
X-Y position. The absolute X-Y biological coordinates for each
frame and the correction necessary to bring it into alignment are
stored in a Z80 microprocessor as a process vector. When the
movie is re-examined with the stepping motors under control of
the computer, the microaligned process shows almost no
frame-to-frame jitter. The process vector may be used to generate
a "branch schematic' of the neuron. The microaligned profiles can
also be digitized and displayed as a reconstruction using a PDP
11/34 computer. Uses of the approach are presented with examples
from the cat retina and visual cortex.
Science 1980 Jan 18;207(4428):317-319 Twenty adjacent ganglion cells in cat retina were partially
reconstructed from electron micrographs of serial thin sections.
Cells were classified by size and by dendritic branching patterns
as alpha, beta, or gamma cells. The alpha and beta cells were
further subdivided by differences in the laminar distribution of
their dendrites in the inner plexiform layer. The distribution of
synaptic contacts on the cells was distinctive for each of the
five major classes. Contacts on the alpha and beta cells were
mainly on the dendrites in the sublamina in which a cell's major
dendritic arborization was contained.
Vision Res 1992 Oct;32(10):1809-1815 Department of Anatomy, Hyogo College of Medicine, Japan.
Cone terminals ("pedicles") in the fovea of macaque retina
were studied in electron micrographs of serial sections. Pedicles
were sheathed in glia except for small (0.2 microns 2)
fenestrations, 4.8 +/- 1.7 per pedicle. At each fenestration the
membranes of adjacent pedicles were contiguous and marked by an
adherent junction, which in turn was invariably associated with
gap junctions. There were 3.2 +/- 1.4 gap junctions per adherent
junction and thus, about fifteen gap junctions per pedicle. The
gap junctions were small, 1.6 x 10(-3) +/- 1.8 x 10(-3) microns 2
(mean +/- SD) and were formed indiscriminately with all
neighboring pedicles. An upper bound was estimated of 170
connexons per pedicle and thus a coupling conductance of 1.7 x
10(4) pS. Available psychophysical data suggest that the
junctions are uncoupled at high luminance. They may couple at
lower luminance where spatial averaging would improve contrast
sensitivity without cost to spatial acuity.
Proc Natl Acad Sci U S A 1990 Mar;87(5):1860-1864 Department of Anatomy, School of Medicine, University of Pennsylvania, Philadelphia 19104.
The signals in neighboring cones are partially correlated due
to local correlations of luminance in the visual scene. By
summing these partially correlated signals, the retinal ganglion
cell improves its signal/noise ratio (compared to the
signal/noise ratio in a cone) and expands the variance of its
response to fill its dynamic range. Our computations prove that
the optimal weighting function for this summation is dome-shaped.
The computations also show that (assuming a particular space
constant for the correlation function) ganglion cell collecting
area and cone density are matched at all eccentricities such that
the signal/noise ratio improves by a constant factor. The
signal/noise improvement factor for beta ganglion cells in cat
retina is about 4.
J Comp Neurol 1995 Jan 16;351(3):374-384 Department of Neuroscience, University of Pennsylvania, Philadelphia 19104.
We studied the expression of glutamate decarboxylase (GAD), GAD65
and GAD67, in cat retina by immunocytochemistry. About 10% of
GABAergic amacrine cells express only GAD65 and 30% express only
GAD67. Roughly 60% contain both forms of the enzyme, but GAD67 is
present only at low levels in the majority of these
double-labeled amacrine cells. The staining pattern in the inner
plexiform layer (IPL) for the two GAD forms was also different.
GAD65 was restricted to strata 1-4, and GAD67 was apparent
throughout the IPL but was strongest in strata 1 and 5. This
indicates that somas, as well as their processes, are
differentially stained for the two forms of GAD. Cell types
expressing only GAD65 include interplexiform cells, one type of
cone bipolar cell, and at least one type of
serotonin-accumulating amacrine cell. Cell types expressing only
GAD67 include amacrine cells synthesizing dopamine, amacrine
cells synthesizing nitric oxide (NO), and amacrine cells
accumulating serotonin. Cholinergic amacrine cells express a low
level of both GAD forms. Our findings in the retina are
consistent with previous observations in the brain that GAD65
expression is greater in terminals than in somas. In addition, in
retina most neurons expressing GAD67 also contain a second
neurotransmitter as well as GABA, and they tend to be larger than
neurons expressing GAD65. We propose that large cells have a
greater demand for GABA than small cells, and thus require the
constant, relatively unmodulated level of GABA that is provided
by GAD67.
Vis Neurosci 1994 Jan;11(1):135-142 Department of Neuroscience, University of Pennsylvania, Philadelphia 19104.
The neurotransmitter used by horizontal cells in mammals has
not been identified. GABA has been the leading candidate, but
doubt has remained because of failure to clearly demonstrate the
GABA synthetic enzyme, glutamic acid decarboxylase (GAD) in these
cells. Because GAD was recently shown to exist as two isoforms,
65 kDa and 67 kDa, we considered whether there might be a
mismatch between the forms of GAD expressed in horizontal cells
and the probes used to detect it. Accordingly, we stained
sections of mammalian retina with antibodies specific for each
isoform. Cat horizontal cells of both types (A and B) were
immunoreactive for GAD67 but negative for GAD65; monkey
horizontal cells of both types (H(I) and HII) were positive for
GAD65 and negative for GAD67. The findings reconcile previous,
apparently conflicting, observations and strengthen considerably
the hypothesis that mammalian horizontal cells are GABAergic.
J Comp Neurol 1989 Oct 22;288(4):601-611 Department of Anatomy, School of Medicine, University of Pennsylvania, Philadelphia 19104-6058.
To investigate indirect pathways to ganglion cells we studied
the starburst amacrine cell network and its relationship to the
alpha ganglion cell. Starburst cells were identified by an
antiserum to choline acetyltransferase and alpha cells by
injection of Lucifer yellow. The density of on and off starburst
cells peaks at the area centralis and decreases with eccentricity
by a factor of seven. The fine amacrine processes, interrupted by
distinct varicosities, arborize in a planar fashion in the inner
plexiform layer. The on network, at the junction of strata 3 and
4, and the off network, in stratum 2, have a similar appearance.
Neighboring starburst processes run in intimate association to
form a network of bundles. As bundles cross each other, loops of
irregular size and shape are formed. The loops are smallest in
the area centralis and increase by a factor of three towards the
periphery; correspondingly, bundle length per unit area decreases
with eccentricity. However, the number of varicosities/bundle
length stays constant with eccentricity as does the number of
processes per bundle. Segments of the starburst network
associate over fairly long distances with dendrites of alpha
ganglion cells. About 26% of the alpha ganglion dendritic tree
shows such association, and this is significantly greater than
would be expected if the alpha and starburst processes were
independent. We conclude that the functional unit of the
starburst cell is a linear bundle of processes and that the
starburst network may connect synaptically to the alpha cell.
J Comp Neurol 1992 Jun 15;320(3):394-397 Department of Anatomy, University of Pennsylvania, Philadelphia 19104-6058.
The distribution of GABAA receptor in the outer plexiform
layer of cat retina was studied by immunocytochemistry with
monoclonal antibodies. Staining was observed at the base of the
cone pedicle, extracellularly, in association with the
"triad" synaptic complex. Some bipolar dendrites and
the basal processes that interconnect the cone pedicles were also
stained. Rod spherules and horizontal cells were negative. The
findings support the idea that the cone horizontal cells are
GABAergic.
Vis Neurosci 1993 May;10(3):473-478 Department of Anatomy, University of Pennsylvania, Philadelphia 19104-6058.
Synaptic transmission from photoreceptors to depolarizing
bipolar cells is mediated by the APB glutamate receptor. This
receptor apparently is coupled to a G-protein which activates
cGMP-phosphodiesterase to modulate cGMP levels and thus a
cGMP-gated cation channel. We attempted to localize this system
immunocytochemically using antibodies to various components of
the rod phototransduction cascade, including Gt (transducin),
phosphodiesterase, the cGMP-gated channel, and arrestin. All of
these antibodies reacted strongly with rods, but none reacted
with bipolar cells. Antibodies to a different G-protein, G(o),
reacted strongly with rod bipolar cells of three mammalian
species (which are depolarizing and APB-sensitive). Also stained
were subpopulations of cone bipolar cells but not the major
depolarizing type in cat (b1). G(o) antibody also stained certain
salamander bipolar cells. Thus, across a wide range of species,
G(o) is present in retinal bipolar cells, and at least some of
these are depolarizing and APB-sensitive.
Download
pdf file of this article
Vision Res 1996 Dec;36(23):3743-3757 Department of Neuroscience, University of Pennsylvania, Philadelphia 19104, USA. noga@retina.anatomy.upenn.edu
Retinal ganglion cells in the cat respond to single rhodopsin
isomerizations with one to three spikes. This quantal signal is
transmitted in the retina by the rod bipolar pathway: rod-->rod
bipolar-->AII-->cone bipolar-->ganglion cell. The two-dimensional
circuit underlying this pathway includes extensive convergence
from rods to an AII amacrine cell, divergence from a rod to
several AII and ganglion cells, and coupling between the AII
amacrine cells. In this study we explored the function of
coupling by reconstructing several AII amacrine cells and the gap
junctions between them from electron micrographs; and simulating
the AII network with and without coupling. The simulation showed
that coupling in the AII network can: (1) improve the
signal/noise ratio in the AII network; (2) improve the
signal/noise ratio for a single rhodopsin isomerization striking
in the periphery of the ganglion cell receptive field center, and
therefore in most ganglion cells responding to a single
isomerization; (3) expand the AII and ganglion cells' receptive
field center; and (4) expand the "correlation field". All of
these effects have one major outcome: an increase in correlation
between ganglion cell activity. Well correlated activity between
the ganglion cells could improve the brain's ability to
discriminate few absorbed external photons from the high
background of spontaneous thermal isomerizations. Based on the
possible benefits of coupling in the AII network, we suggest that
coupling occurs at low scotopic luminances.
Vision Res 1994 May;34(10):1235-1246 Department of Neuroscience, University of Pennsylvania, Philadelphia 19104-6058.
The subcellular distribution of GABAA receptor in the macaque
and human retina was studied by immunocytochemistry with
monoclonal antibodies for the alpha and beta subunits with a
particular focus on bipolar cells. Immunoreactivity to GABAA
receptor was present on dendritic tips of all bipolar cells. The
stain was strongest on bipolar membranes in apposition to
horizontal cell processes. Stain was concentrated on the tips of
flat and invaginating cone bipolar cells at the base of the cone
pedicle and on the invaginating tips of rod bipolar cells. Stain
on the cone pedicle membrane was restricted to sites of
apposition to stained bipolar dendrites; pedicle membrane in
apposition to horizontal cell processes was unstained. Stain was
also present on bipolar axon terminals in both on and off strata
of the inner plexiform layer. All bipolar cell somas stained
faintly; horizontal and Muller cell somas were unstained. The
alpha and beta subunits distributed similarly in monkey and human
retina. Presence of GABAA receptor on the bipolar dendritic tips
suggests that horizontal cells directly affect bipolar cells.
Thus, GABAA receptor might mediate the receptive field surround
of both off and on bipolar cells. Presence of GABAA receptor on
bipolar axon terminals suggests that much of the inhibition
feeding back from GABAergic amacrine to bipolar cells is
GABAA-mediated.
Neuron 1996 Jun;16(6):1221-1227 Department of Neurobiology and Behavior, State University of New York, Stony Brook, 11794-5230, USA.
We relate the ultrastructure of the giant bipolar synapse in
goldfish retina to the jump in capacitance that accompanies
depolarization-evoked exocytosis. Mean vesicle diameter is 29 +/-
4 nm, giving 26.4 aF/vesicle, so the maximum evoked capacitance
(150 fF within 200 ms) represents fusion of about 5700 vesicles.
Two terminals contained, respectively, 45 and 65 ribbon-type
synaptic outputs, and a fully loaded ribbon tethers about 110
vesicles. Thus, the tethered pool, about 6000 vesicles,
corresponds to the rapidly released pool. Further, the difference
between small and large terminals in number of tethered vesicles
matches their difference in capacitance jump. This suggests,
within a "fire and reload" model of exocytosis, that
the ribbon translocates synaptic vesicles very rapidly to
membrane docking sites, supporting a maximum release rate of 500
vesicles/active zone/s, until the population of tethered vesicles
is exhausted.
Department of Neuroscience, University of Pennsylvania,
Philadelphia 19104, USA.
The rod bipolar cell and about five types of ON cone bipolar
cells depolarize to light by employing a sign-reversing
metabotropic glutamate receptor. Glutamate responses are similar
in both rod bipolar and cone bipolar cells, but the receptor
mediating this response (mGluR6) was so far demonstrated only in
rod bipolar cells. To test if ON cone bipolar cells also express
mGluR6, we immunoreacted rat retina with an antibody specific for
mGluR6, and studied the staining from serial ultrathin sections.
We demonstrate that mGluR6 is indeed expressed in the dendritic
tips of cone bipolar cells, the majority of which receive a
ribbon synapse, and thus probably are ON cone bipolar cells. We
further show that half of the dendritic tips contacting the cones
stain for mGluR6, thus implying that all ON cone bipolar cell
types express mGluR6.
The retina is a thin sheet of neural tissue lining the posterior
hemisphere of the eyeball. It is actually part of the brain
itself (~0.5%), evaginating from the lateral wall of the neural
tube during embryonic development. The optic stalk grows out
from the brain toward the ectoderm, inducing it to form an
optical system (cornea, pupil, lens), which projects a physical
image of the world onto the retina. The retina's task is to
convert this optical image into a "neural image" for transmission
down the optic nerve to a multitude of centers for further
analysis. The task is complex - which is reflected in the
synaptic organization.
A closer look at this apparently simple design (three
interconnected layers and five broad classes of neuron) reveals
additional complexity (Figs. 6.2, 6.3). Each neuron class is
represented by several or many specific types. Each cell
type is distinguished from others in its class by its
characteristic morphology, connections, neurochemistry, and
function (Rodieck and Brening, 1983; Sterling, 1983). This
diversity, amounting to some 80 cellular types (Kolb et al.,
1981; Sterling, 1983; Vaney, 1990), was puzzling at first, but a
broad explanation has gradually emerged: it is impossible to
encode all the information in an optical image using a single
neural image. Therefore, the retina uses different cell types to
create parallel circuits for different light levels - daylight,
twilight, and starlight - but these share certain circuit
compaonents and use the same final pathways to the brain (Smith
et al., 1986). This chapter describes key cell types and their
interconnection in parallel circuits. It also discusses how the
functional architecture of a circuit depends on the functional
architecture of its synapses. Finally, it suggests how the flow
of visual information shifts between circuits that are
specialized for different light levels and how the circuits are
switched. The chapter focuses on mammalian retina because that
is where the combined knowledge of circuitry and cell physiology
is best known. Early efforts centered on cat, so specific
measurements, counts, etc., cited here refer to cat central
retina. But recent efforts have broadened to include rabbit, rat,
monkey, and human. These demonstrate strongly conserved patterns
in the circuitry, as well as special adaptations, and some of
both will be mentioned. Department of Neuroscience, University of Pennsylvania,
Philadelphia 19104, USA.
The metabotropic glutamate receptor (mGluR6), expressed by rod
bipolar cells and ON cone bipolar cells, activates a trimeric
guanine nucleotide-binding protein (G-protein) that ultimately
closes a cation channel. The G-protein remains unidentified, but
the alpha subunit of Go (Go(alpha)) has been suggested as a
candidate because it is present in rod bipolar cells. However,
the precise subcellular distribution of Go within the rod bipolar
cell, and its distribution among cone bipolar cells was not
determined. This information is important in assessing the
hypothesis that Go couple mGluR6 to its effector. Here I report
the distribution of Go (alpha subunit) by immunostaining in
several mammalian retinas. The overall distribution is conserved
across mammalian species: strongest in the dendrites of ON
bipolar cells, moderate in their somas, weak in their axons, and
absent from their terminals. Go(alpha) is also present in some
amacrine somas and processes. In monkey fovea, where rods and rod
bipolar cells are absent, Go(alpha) is present in about half of
the bipolar somas which occupy the upper tiers of the bipolar
layer, and are therefore identified as ON cone bipolar cells.
Ultrastructurally, in monkey and cat, Go(alpha) is present in the
dendritic tips of rod bipolar cells and ON cone bipolar cells,
which are identified by their invaginating contacts. It is absent
from OFF cone bipolar dendrites, which are identified by their
flat contacts. It is also absent from axons entering the inner
plexiform layer, and their terminals. In the primary dendrites,
stain for Go(alpha) mainly associates with the plasma membrane,
but in the dendritic tips it is also present in the cytosol.
Apparently, Go(alpha) is expressed by the same bipolar cells that
also express mGluR6, and is concentrated at the same subcellular
location. Thus, Go(alpha) could serve to couple mGluR6 to later
stages of its signaling cascade. Download
pdf file of this article Visual Neurosci. (1998) Sep-Oct 15(5):809-21
Dept. Neuroscience, University of Pennsylvania,
Philadelphia 19104-6058, USA.
Mammalian rods respond to single photons with a hyperpolarization
of about 1 mV which is accompanied by continuous noise. Since the
mammalian rod bipolar cell collects signals from 20-100 rods, the
noise from the converging rods would overwhelm the single-photon
signal from one rod at scotopic intensities (starlight) if the
bipolar cell summed signals linearly (Baylor et al., 1984).
However, it is known that at scotopic intensities the retina
preserves single-photon responses (Barlow et al., 1971;
Mastronarde, 1983). To explore noise summation in the rod
bipolar pathway, we simulated an array of rods synaptically
connected to a rod bipolar cell using a compartmental model. The
performance of the circuit was evaluated with a discriminator
measuring errors in photon detection as false positives and false
negatives, which were compared to physiologically and
psychophysically measured error rates. When only one rod was
connected to the rod bipolar, a Poisson rate of 80 vesicles/s was
necessary for reliable transmission of the single-photon signal.
When 25 rods converged through a linear synapse the noise caused
an unacceptably high false positive rate, even when either dark
continuous noise or synaptic noise where completely removed. We
propose that a threshold nonlinearity is provided by the mGluR6
receptor in the rod bipolar dendrite (Shiells & Falk, 1994) to
yield a synapse with a noise removing mechanism. With the
threshold nonlinearity the synapse removed most of the noise.
These results suggest that a threshold provided by the mGluR6
receptor in the rod bipolar cell is necessary for proper
functioning of the retina at scotopic intensities and that the
metabotropic domains in the rod bipolar are distinct. Such a
nonlinear threshold could also reduce synaptic noise for cortical
circuits in which sparse signals converge.
Department of Neuroscience, University of Pennsylvania,
Philadelphia 19104-6058, USA.
Mammalian horizontal cells are believed to be GABAergic because,
in most species, they contain both GABA and glutamic acid
decarboxylase (GAD), and their terminals are presynaptic to GABA
receptors. In adult rabbit, however, GABA and GAD
immunoreactivity have not been consistently demonstrated in
horizontal cells, casting doubts on the assumption that they too
are GABAergic. Here we demonstrate that all rabbit horizontal
cell terminals--dendritic terminals of type A, and both dendritic
and axonal terminals of type B--immunostain for one isoform of
GAD, GAD67, In addition, we show that type A horizontal cell
somas and primary dendrites in the visual streak (identified by
their immunoreactivity to calbindin) are immunoreactive for the
other GAD isoform, GAD65. Double-labeling experiments for GAD65
and GABA reveal that every cell that stains for GAD65 also stains
for GABA. The presence of GAD67 in horizontal cell terminals
suggests that rabbit horizontal cells are GABAergic. The
segregation of the two GAD isoforms to different cell
compartments suggests that GABA is released at different sites,
possibly by two different mechanisms.
Department of Ophthalmology, University of Rochester Medical
Center, New York
Perception of hue is opponent, involving the antagonistic
comparison of signals from different cone types. For blue versus
yellow opponency, the antagonism is first evident at a ganglion
cell with firing that increases to stimulation of short
wavelength-sensitive (S) cones and decreases to stimulation of
middle wavelength-sensitive (M) and long wavelength-sensitive (L)
cones. This ganglion cell, termed blue-yellow (B-Y), has a
distinctive morphology with dendrites in both ON and OFF strata
of the inner plexiform layer (Dacey and Lee, 1994). Here we
report the synaptic circuitry of the cell and its spatial
density. Reconstructing neurons in macaque fovea from electron
micrographs of serial sections, we identified six ganglion cells
that branch in both strata and have similar circuitry. In the ON
stratum each cell collects approximately 33 synapses from bipolar
cells traced back exclusively to invaginating contacts from S
cones, and in the OFF stratum each cell collects approximately 14
synapses from bipolar cells (types DB2 and DB3) traced to basal
synapses from approximately 20 M and L cones. This circuitry
predicts that spatially coincident blue-yellow opponency arises
at the level of the cone output via expression of different
glutamate receptors. S cone stimuli suppress glutamate release
onto metabotropic receptors of the S cone bipolar cell dendrite,
thereby opening cation channels, whereas M and L cone stimuli
suppress glutamate release onto ionotropic glutamate receptors of
DB2 and DB3 cell dendrites, thereby closing cation channels.
Although the B-Y cell is relatively rare (3% of foveal ganglion
cells), its spatial density equals that of the S cone; thus it
could support psychophysical discrimination of a blue-yellow
grating down to the spatial cutoff of the S cone mosaic. Department of Neuroscience, University of Pennsylvania School
of Medicine, Philadelphia, 19104-6058, USA.
The cone 'synaptic complex' is a unique structure in which a
single presynaptic axon secretes glutamate onto processes of
bipolar cells (both ON and OFF) and horizontal cells. In turn,
the horizontal cell processes antagonize cone and bipolar
responses to glutamate (probably by GABA). What still remains
largely unknown is the molecular identity of the postsynaptic
receptors and their exact locations. We identified several
subunits of the glutamate receptor and the GABAA receptor
expressed at the cone synaptic complex and localized them
ultrastructurally. Glutamate receptors: (i) Invaginating
(probably ON) bipolar dendrites in the monkey and rat express the
metabotropic glutamate receptor, mGluR6. The stain is intense on
the dendritic membrane where it first enters the invagination,
and weak at the tip nearest to the ribbon. The cone membrane is
electron-dense where it apposes the intense stain for mGluR6.
Surprisingly, invaginating bipolar dendrites in the cat also
express the AMPA receptor subunits, GluR2/3 and GluR4. (ii)
Dendrites forming basal contacts in the cat (probably OFF)
express the AMPA subunits GluR2/3, GluR4, and also the kainate
subunit, GluR6/7. The stain is especially intense at the
dendritic tips in apposition to electron-dense regions of cone
membrane. (iii) Horizontal cells in the cat express the AMPA
subunits GluR2/3, GluR4 and the kainate subunit, GluR6/7. The
stain is strongest in the cytosol of somas and primary dendrites,
but is also present in the invaginating terminals where it
localizes to the membrane subjacent to the ribbon. GABAA
receptors: (i) ON and OFF bipolar dendrites in the monkey express
the alpha 1 and beta 2/3 subunits. The stain is localized to the
bipolar cell membrane in apposition to horizontal cell processes.
(ii) Cones did not express the GABAA subunits tested by
immunocytochemistry, but beta 3 mRNA was amplified by RT-PCR from
rat photoreceptors. Conclusions: (i) mGluR6 receptors
concentrate on dendrites at the base of the invagination rather
than at the apex. This implies that receptors at both
'invaginating' and 'basal' contacts lie roughly equidistant from
the release sites and should therefore receive similar
spatiotemporal concentrations of glutamate. (ii) The 'cone'
membrane is electron-dense opposite to the receptor sites on both
ON and OFF bipolar cells. This suggests a special role for this
region in synaptic transmission. Possibly, these densities
signify a transporter that would regulate glutamate concentration
at sites remote (> 200 nm) from the locus of vesicle release. Department of Neuroscience, University of Pennsylvania,
Philadelphia 19104, USA.
Although the visual system occupies nearly half of the mammalian
brain, we still do not completely understand its first synaptic
stage. One reason is that the dendrites postsynaptic to
photoreceptors comprise such a maze of fine processes that doubt
remains whether all the second oreder circuits have been
identified - even after 4 decades of electron microscopy. Now
advanced functional methods applied to a mammalian rod pathway
suggest a circuit previously unsuspected from anatomy.
Department of Bioengineering, University of Pennsylvania,
Philadelphia, Pennsylvania 19104, USA.
intensities from starlight to 1000-fold brighter, the
mammalian rod synapse transmits a binary signal, the capture of 0
or 1 photon. Zero is signified by tonic exocytosis, and 1 is
signified by a brief pause. The synapse is three dimensional:
vesicles discharge at the apex of a deep cleft created by the
invagination of four postsynaptic processes. Two horizontal cell
spines bearing alpha-amino-3-hydroxy-5- methyl-
4-isoxazolepropionic acid (AMPA) receptors reach near to the
release sites (16 nm), and two bipolar dendrites bearing mGluR6
receptors end far from the release sites (up to 640 nm). We
considered two hypotheses for signal transfer: transmitter quanta
might be integrated in the cleft and sensed as a steady
concentration (high for 0 and low for 1); or quanta might be
sensed at the postsynaptic membrane as discrete postsynaptic
potentials (PSPs) and integrated within the dendrite. We
calculate from a passive diffusion model that the invagination
empties rapidly (tau approximately 1.7 ms). Further calculations
suggest that a glutamate concentration high enough to hold a
bipolar cell in darkness at one end of its response range would
require approximately 4,000 vesicles/s. On the other hand, the
glutamate pulse from a single vesicle would reach both nearby
AMPA receptors (low affinity) and distant mGluR6 receptors (high
affinity) at spatiotemporal concentrations matched to their
apparent binding affinities. Thus one vesicle could evoke a
discrete PSP in all four postsynaptic processes. We calculate
from a stochastic model that PSPs could transfer the binary
signal at approximately 100 vesicles/s. Thus dendritic
integration of unitary PSPs is both plausible and 40-fold more
efficient than the alternative mechanism. The rod's deep
invagination, rather than serving to pool transmitter, may serve
to prevent "spillover" of transmitter to neighboring rods.
Spillover, by pooling the noise from neighboring rods, would
impair transmission of their binary signals.
Department of Physiology, Osaka University Medical School, Japan.
Ionotropic glutamate receptors (iGluRs) are extremely diverse in
their subunit compositions. To understand the functional
consequences of this diversity, it is necessary to know the
subunits that are expressed by known cell types. By using
immunocytochemistry with light and electron microscopy, we
localized several subunits (GluR2/3, GluR4, and GluR6/7) in cat
retinal neurons, postsynaptic to photoreceptors. Type A
horizontal cells express all three subunits strongly, whereas
type B horizontal cells express GluR2/3 strongly, GluR6/7 weakly,
and do not express GluR4. When they are present, the subunits are
expressed strongly throughout the cytoplasm of the somata and
primary dendrites; however, in the terminals, they are
concentrated at the postsynaptic region, just opposite the
presumed site of photoreceptor glutamate release. Surprisingly,
all bipolar cell classes (OFF cone bipolar cells, ON cone bipolar
cells, and rod bipolar cells) express at least one iGluR subunit
at their dendritic tips. Cone bipolar cells forming basal
contacts with the cones (presumably OFF cells) express all three
subunits in association with the electron-dense postsynaptic
membrane. Invaginating dendrites of cone bipolar cells
(presumably ON cells) express GluR2/3 and GluR4. Rod bipolar
cells (ON cells) express GluR2/3 in their invaginating dendrites.
The function of iGluRs in horizontal cells and OFF bipolar cells
clearly is to mediate their light responses. GluR6/7 subunit in
the receptor of these cells may be responsible for the
dopamine-mediated enhancement of glutamate responses that have
been observed previously in these cells. The function of iGluRs
in ON bipolar cells remains an enigma.
Department of Neuroscience, University of Pennsylvania,
Philadelphia, Pennsylvania 19104, USA.
Calcium enters the outer segment of a vertebrate photoreceptor
through a cGMP-gated channel and is extruded via a Na/Ca, K
exchanger. We have identified another element in mammalian cones
that might help to control cytoplasmic calcium. Reverse
transcription-PCR performed on isolated photoreceptors identified
mRNA for the SII- splice variant of the type I receptor for
inositol 1,4,5-triphosphate (IP3), and Western blots showed that
the protein also is expressed in outer segments.
Immunocytochemistry showed type I IP3 receptor to be abundant in
red-sensitive and green-sensitive cones of the trichromatic
monkey retina, but it was negative or weakly expressed in
blue-sensitive cones and rods. Similarly, the green-sensitive
cones expressed the receptor in dichromatic retina (cat, rabbit,
and rat), but the blue-sensitive cones did not. Immunostain was
localized to disk and plasma membranes on the cytoplasmic face.
To restore sensitivity after a light flash, cytoplasmic cGMP must
rise to its basal level, and this requires cytoplasmic calcium to
fall. Cessation of calcium release via the IP3 receptor might
accelerate this fall and thus explain why the cone recovers much
faster than the rod. Furthermore, because its own activity of the
IP3 receptor depends partly on cytoplasmic calcium, the receptor
might control the set point of cytoplasmic calcium and thus
affect cone sensitivity. Department of Neuroscience, University of Pennsylvania, 123
Anatomy/Chemistry Bldg., Philadelphia, Pennsylvania 19104-6058, USA.
By simultaneously recording from retinal ganglion cells while
stimulating a single cone, Chichilnisky and Baylor demonstrate
that the strength of physiological connections within a retinal
microcircuit is linearly proportional to the number of
anatomically defined synapses.
Over the last few decades, considerable effort has been devoted
to constructing a detailed 'wiring diagram' for the retina, that
is, a quantitative map of all its excitatory and inhibitory
synaptic connections1, 2. Propelling this effort has been a faith
that the diagram would ultimately make functional sensethat we
would be able to 'read' the diagram of a neural circuit just as
we do for an electronic circuit. Were this faith to prove
unjustifiedif, for example, the physiological strength of an
input proved to be unrelated to the number of anatomically
defined synapsesthen the retina's synaptic diagram would be far
less informative than we might otherwise hope. It is certainly
reasonable to question the usefulness of a purely structural
diagram, given that neurons contain nonlinear elements such as
voltage-gated channels and second-messenger cascades. However, a
report by Chichilnisky and Baylor in this issue of Nature
Neuroscience3 provides reassurance. By analyzing how individual
cones contribute to the receptive field of a retinal gangion
cell, the authors provide support for a key hypothesis derived
from the wiring diagram, that the strength of an excitatory input
is proportional to the number of chemical synapses that underlie
it.
Retinal ganglion cells are the output neurons of the retina.
They are separated by two synapses from the photoreceptors, and
the intervening wiring suggests that ganglion cells are capable
of considerable integration. Cones are connected laterally to
each other through electrical synapses, and they project forward
via glutamatergic synapses onto bipolar cells. Similarly, the
bipolar cells are connected laterally via electrical synapses and
also make forward connections via glutamatergic synapses onto the
wide-spreading dendrites of ganglion cells. Thus, a ganglion cell
receives connections, via bipolar cells, from many cones
(convergence), whereas a given cone is connected to several
ganglion cells (divergence). Quantitative anatomical studies have
revealed that a ganglion cell receives many synapses from a
bipolar cell that is aligned with the center of its dendritic
tree, but few synapses from bipolar cells at the edge of the
dendritic tree. Most of the synapses formed by these bipolar
cells are onto neighboring ganglion cells with which they are
more closely aligned.
This wiring causes a 'dome-like' distribution of excitatory
synapses across a ganglion cell's dendritic tree. The
distribution of light sensitivity across the central region of a
ganglion cell's receptive field is also dome-shaped, and so it
was natural to hypothesize that this might reflect the
distribution of synaptic inputs4, 5. Furthermore, the fact that a
single bipolar cell can form synapses with more than one ganglion
cell suggests an explanation for the overlap between the
receptive field centers of neighboring ganglion cells6, 7. These
hypotheses could be tested by recording simultaneously from
several adjacent ganglion cells while stimulating the overlying
cones one at a time. A method for multiple recordings has been
available for several years8, but cones are so closely packed in
the intact retina that it is difficult to stimulate them one at a
time. That is what Chichilnisky and Baylor have now achieved in a
technical and analytical tour de force that confirms both
hypotheses.
The authors placed a small piece of peripheral retina from a
macaque monkey in a perfusion chamber, with the ganglion cell
layer contacting a multi-electrode array. This allowed
simultaneous recording of the spike trains from many ganglion
cells. To stimulate individual cones, they projected the image of
a color monitor onto the photoreceptors through reducing optics,
so that a single pixel would span about 25 m, comparable to the
distance between adjacent cones. Each pixel could be driven by
the monitor's red, green and blue guns, and by adjusting their
relative intensities, a given pixel could be made to emit light
that was optimal for one of the three cone types, which are
sensitive to short (S), medium (M) or long (L) wavelengths. By
using a variety of flickering patterns, it was possible to
calculate the average stimulus displayed in the period just
preceding a spike and hence to identify the combination of gun
intensities that was most likely to trigger a spike in a given
ganglion cell.
This approach allowed the authors to cleanly identify the well
known 'blue/yellow' (BY) ganglion cells9. These cells fire
selectively in response to an increase in the intensity of blue
light and a decrease in the intensity of yellow light (that is, a
mixture of red and green light; Fig. 1a). The cell responds
oppositely to excitation of S and M+L cones, despite the fact
that all bipolar synapses excite the BY cell. The reason is that
bipolar types selective for S or M+L cones respond oppositely to
the glutamate released from cones. S bipolar dendrites express a
metabotropic receptor (mGluR6) that closes a cation channel,
whereas M+L bipolar dendrites express an ionotropic receptor that
opens a cation channel. This molecular difference between the
two classes of bipolar cells is largely responsible for the
spectral opponency of the BY ganglion cells, and thus represents
a key mechanism for blue/yellow perception10.
The BY ganglion cell was ideal for the authors' purpose. S cones
comprise only ten percent of all cones, and in the coarse mosaic
of peripheral retina (Fig. 1b), they are spaced widely enough to
be stimulated individually by the flash of a single pixel. By
stimulating individual S cones and recording from BY ganglion
cells, the authors could probe for divergence and convergence of
the inputs to the ganglion cells, and they could directly test
for linearity of S-cone summation.
A single S cone signal did indeed diverge to provide input to
adjacent BY ganglion cells, contributing strongly to one BY cell
and weakly to another. Because the two BY cells were recorded
simultaneously, their different responses to stimulation of the
same cone could not be attributed to a change in cone
photosensitivity; rather, it must have been caused by a
difference in the cone's synaptic connections. Furthermore, two
S cones did indeed converge onto a given BY cell, with one cone
always dominating and the other contributing only weakly.
Finally, a plot of the BY cell's average spike rate versus
stimulus intensity for illumination of both S cones neatly
superimposed onto plots of rate versus stimulus intensity for
illumination of either S cone separately. The finding that all
three curves superimpose proves that the signals from both S
cones combine linearly. Thus, despite the existence of nonlinear
mechanisms, such as sodium action potentials in ganglion cell
dendrites11, the overall circuit provides a linear summation of S
cone signals.
These functional results clearly match the structural
microcircuit (Figs. 1c and 2). An S cone provides most of its
synapses to one S bipolar cell and a few synapses to the
neighboring bipolar cells10. In turn, an S bipolar cell provides
most of its synapses to one BY ganglion cell and a few synapses
to the neighbors10. Thus, the synaptic connections from one S
cone diverge to several BY cells, and connections from several S
cones converge upon one BY cell, with one cone predominating. The
structural circuit also shows the BY cell receiving twofold more
synapses from S bipolar cells than from M+L bipolar cells10. This
might explain why a BY cell responds faster to S cones than to M
and L cones3 ( Fig. 1a), because speed increases with
amplification.
The BY cell's microcircuit, now based on functional as well as
structural evidence, suggests an explanation for a striking
result from human psychophysics13. When M and L cones are
desensitized by exposure to yellow light, it is possible to
perceive a tiny blue flash that is designed to excite a single S
cone. Sensitivity to this flash shows a punctate distribution,
corresponding to the distribution of S cones14. This punctate
perceptual sensitivity might now be explained by two simple
facts: the density of the BY mosaic is the same as the S cone
mosaic10, 14, and each BY cell is dominated by one of the several
converging S cones3, 10. Thus, perception of the colored flash
seems attributable to sharply increased firing by a single BY
cell, plus a smaller increase by its nearest neighbors. If this
explanation is correct (others are possible but more
complicated), it implies that this color percept results from
activity in a 'labeled line'. An important goal of neuroscience
is to correlate neural structure and function with behavior, so
this result is deeply satisfying.
Why should ganglion cell circuits have evolved to create
dome-like receptive fields with partial overlap? For example,
what is gained by having several S cones converge onto one BY
cell, with one S cone predominant, and by having each cone
provide divergent inputs to several ganglion cells? Signals in
adjacent photoreceptors tend to be correlated because of
correlations in the natural scene. Calculations suggest that,
when partially correlated signals sum in a ganglion cell, a
dome-like weighting of the inputs leads to an optimal
signal-to-noise ratio15. The same might be true for more central
mechanisms that sum the partially correlated signals of ganglion
cells. This hypothesis might be tested directly using the
efficient experimental system that Chichilnisky and Baylor have
provided.
The structurefunction relationship shown here is unlikely to
prove completely general. For example, ganglion cells are known
to show nonlinear responses to certain stimuli, and it would be
surprising if these were to be predicted simply from reading the
anatomical circuit. Similarly, it is unlikely that the functions
of cortical circuits will be obvious from their wiring, given
that cortical synapses can undergo plastic changes in their
physiological strength. Despite this, the present results
encourage one to press on with the effort to correlate structure
and function. Department of Neuroscience, University of Pennsylvania, Philadelphia,
Pennsylvania 19104-6058, USA.
The AMPA receptor, ubiquitous in brain, is termed "ionotropic"
because it gates an ion channel directly. We found that an AMPA
receptor can also modulate a G-protein to gate an ion channel
indirectly. Glutamate applied to a retinal ganglion cell briefly
suppresses the inward current through a cGMP-gated channel. AMPA
and kainate also suppress the current, an effect that is blocked
both by their general antagonist CNQX and also by the relatively
specific AMPA receptor antagonist GYKI-52466. Neither NMDA nor
agonists of metabotropic glutamate receptors are effective. The
AMPA-induced suppression of the cGMP-gated current is blocked
when the patch pipette includes GDP-beta-S, whereas the
suppression is irreversible when the pipette contains
GTP-gamma-S. This suggests a G-protein mediator, and, consistent
with this, pertussis toxin blocks the current suppression. Nitric
oxide (NO) donors induce the current suppressed by AMPA, and
phosphodiesterase inhibitors prevent the suppression.
Apparently, the AMPA receptor can exhibit a "metabotropic"
activity that allows it to antagonize excitation evoked by NO.
Neuron 1999 Oct;24(2):313-21.
Department of Ophthalmology, University of Rochester Medical
Center, New York
Different psychophysical "channels mediate our perception of
fine spatial patterns and color. The spatial channel compares
the photon catch betwen adjacent cones, regardless of type, and
thus supports perceptions as fine as the cone mosaic (Williams,
1986). Color channels compare the photon catch between diffeent
cone types (Hurvich and Jameson, 1957; Krauskopf et al., 1982).
The "blue/yellow" channel compares the catch in cones sensitive
to short (S) wavelengths with the catch in neighboring cones
sensitive to middle (M) and long (L) wavelengths (Pugh and
Mollon, 1979). The "red/green" channel compares the photon catch
in L and S cones with that in neighboring M cones (Thornton and
Pugh, 1983; Calkins et al., 1992). Each comparison is equivalent
to a subtraction: for blue/yellow, S-(M+L); for red/green,
L-M+(S). The color channels are rather coarse, with an acuity of
about one-third that of the spatial channel (Anderson et al.,
1991; Sekiguchi et al., 1993). What neural circuits servie the psychophysical channels for
spatial acuity and color? The standard view is that messages for
both channels are conveyed by one type of ganglion cell, termed
"P", because it projects to a parvocellular neuron in
the lateral geniculate nucleus. The parvocellular neuron would
relay both messages to primary visual cortex where, finally,
spatial and color information would begin to segregate (Ingling
and Martinez-Uriegas, 1983; Lennie and D'Zmura, 1988; Hubel and
Livingstone, 1990; De Valois and De Valois, 1993). This circuit
design, by compressing two messages on one axon, would minimize
the number of axons in the optic nerve and geniculo-striate
radiation. But it would also compromise the filtering of one or
both messages and would reduce their shares of bandwidth (Atick,
1992).
Although this "double duty" hypothesis for the P cell still
predominates (e.g., Boycott and Wassle, 1999), its anatomical and
physiological basis has recently been eroded. Meanwhile new
evidence has accumulated for an alternative view, that the
densely distributed P cell serves only the fine spatial channel
and that sparsely distributed ganglion cells serve the color
channels (Rodieck, 1991). This circuit design would optimize
filtering and bandwidth at the cost of additional axons. Here, we
summarize the current evidence for both views, starting with the
origin of the P cell hypothesis. Download
pdf file of this article
J. Neurosci. 1999 Nov 15;19(22):9756-9767
Department of Neuroscience, University of Pennsylvania School of
Medicine, Philadelphia, Pennsylvania 19104-6058, USA.
A retinal ganglion cell commonly expresses two spatially
overlapping receptive field mechanisms. One is the familiar
"center/surround," which sums excitation and inhibition across a
region somewhat broader than the ganglion cell's dendritic field.
This mechanism responds to a drifting grating by modulating
firing at the drift frequency (linear response). Less familiar is
the "nonlinear" mechanism, which sums the rectified output of
many small subunits that extend for millimeters beyond the
dendritic field. This mechanism responds to a contrast-reversing
grating by modulating firing at twice the reversal frequency
(nonlinear response). We investigated this nonlinear mechanism by
presenting visual stimuli to the intact guinea pig retina in
vitro while recording intracellularly from large brisk and
sluggish ganglion cells. A contrast-reversing grating modulated
the membrane potential (in addition to the firing rate) at twice
the reversal frequency. This response was initially
hyperpolarizing for some cells (either ON or OFF center) and
initially depolarizing for others. Experiments in which responses
to bars were summed in-phase or out-of-phase suggested that the
single class of bipolar cells (either ON or OFF) that drives the
center/surround response also drives the nonlinear response.
Consistent with this, nonlinear responses persisted in OFF
ganglion cells when ON bipolar cell responses were blocked by
L-AP-4. Nonlinear responses evoked from millimeters beyond the
ganglion cell were eliminated by tetrodotoxin. Thus, to relay the
response from distant regions of the receptive field requires a
spiking interneuron. Nonlinear responses from different regions
of the receptive field added linearly.
A basic feature of retinal structure is the anatomical
convergence of cones onto ganglion cells. This was appreciated
by 19th Century anatomists, Cajal formost among them, and it was
demonstrated functionally as "spatial summation" by physiologists
starting about 50 years ago with Hartline (14) and later Barlow
(3) and Kuffler (17). The processes of anatomical convergence
and phnhysiological summation are accomplished through
architecturally precise circuits. That is, for a particular type
of ganglion cell at a given retinal locus, the dendritic spread,
number of cones, and receptive field dimensions are invariant
(7-11, 13, 23, 25). Each locus has several types of ganglion
cell that form parallel systems, summming signals from the same
cone array through equally precise, but quantitatively different
ar4chitectures. Across the retina, on the other hand, the
details of each circuit vary markedly and systematically (7, 20,
25, 37). We hypothesize that the local precision of the ganglion
cell circuit and its variation with eccentricity reflect tunint
(through evolution) fo efficiency in the enciding of natural
scenes. The pressure to achieve a certain level of efficiency
arises from the need to achieve a certain standard of performance
on the one hand and physical constraints on the encoding
processes on the other. In this essay we review both the
standards of performance and the constraints and summarize the
circkuit architecture used by the on-beta ganglion cell in cat
area centralis for spatially summing cone signals. We compare
this architecture to that of beta cells across the retina and to
that of two other types of ganglion cell: the on-alpha cell (cat)
and the parasol cell (monkey). The goal is to discover some
consequences of these architectures for the efficient coding of
natural scenes. Department of Neuroscience, University of Pennsylvania School of
Medicine, Philadelphia, Pennsylvania 19104-6058, USA.
This chapter's theme is that GABAergic circuits modify signals
running through both rod and cone bipolar pathways. These
modifiying circuits, in keeping with their name, are often
circular chains of neurons, as distinct from the linear bipolar
pathways, and therefore seem to mediate feedback. Another
function of these modifying circuits can be understood in the
context that, since each neuronal type is repeated across the
retina, rod and cone bipolar pathways represent many parallel
routes: the modifying circuits convey information laterally
between these parallel routes. One modifying circuit cell is the
horizontal cell, which interacts with rods, cones and bipolar
cells in some manner not fully understood. In mammals, there are
at least 2 types of horizontal cell (Ramon Y Cajal, 1972). There
is equivocal evidence that both types of horizontal cell are
GABAergic. Another modifying circuit cell is the amacrine cell,
which interacts with bipolar cells, ganglion cells and other
amacrine cells. There is good evidence that specific types of
amacrine cells are GABAergic. A third kind of modifying neuron,
the interplexiform cell, receives synapses from amacrine cells in
the inner plexiform layer and synapses upon bipolar cell
dendrites in the outer plexiform layer, constituting a longer
feedback loop. In mammals, there is good evidence that 2 types
of interplexiform cell are GABAergic. Download
pdf file of this article
J Optical Soc. Am. A 2000 Mar 17:(3) 635-640.
Cone synaptic terminals couple electrically to their neighbors.
This reduces the amplitude of temporally uncorrelated voltage
differences between neighbors. For an achromatic stimulus coarser
than the cone mosaic, the uncorrelated voltage difference between
neighbors represents mostly noise; so noise is reduced more than
the signal. Here coupling improves signal-to-noise ratio and
enhances contrast sensitivity. But for a chromatic stimulus the
uncorrelated voltage difference between neighbors of different
spectral type represents mostly signal; so signal would be
reduced more than the noise. This cost of cone coupling to
encoding chromatic signals was evaluated using a compartmental
model of the foveal cone array. When cones sensitive to middle
(M) and long (L) wavelengths alternated regularly, and the
conductance between a cone and all of its immediate neighbors was
1000 pS (similar to 2 connexons/cone pair), coupling reduced the
difference between the L and M action spectra by nearly fivefold,
from about 38% to 8%. However, L and M cones distribute randomly
in the mosaic, forming small patches of like type, and within a
patch the responses to a chromatic stimulus are correlated. In
such a mosaic, coupling still reduced the difference between the
L and M action spectra, but only by 2.4-fold, to about 18%. This
result is independent of the L/M ratio. Thus "patchiness" of the
L/M mosaic allows cone coupling to improve achromatic contrast
sensitivity while minimizing the cost to chromatic sensitivity.
Department of Neuroscience, University of Pennsylvania School of
Medicine, Philadelphia, Pennsylvania 19104-6058, USA.
To determine the rate and statistics of light-evoked transmitter
release from bipolar synapses, intracellular recordings were made
from On-alpha ganglion cells in the periphery of the intact,
superfused, cat retina. Sodium channels were blocked with
tetrodotoxin to prevent action potentials. A light bar covering
the receptive field center excited the bipolar cells that contact
the alpha cell and evoked a transient then a sustained
depolarization. The sustained depolarization was quantified as
change in mean voltage (), and the increase in voltage noise that
accompanied it was quantified as change in voltage variance (2).
As light intensity increased, and 2 both increased, but their
ratio held constant. This behavior is consistent with Poisson
arrival of transmitter quanta at the ganglion cell. The response
component attributable to glutamate quanta from bipolar synapses
was isolated by application of CNQX (6-cyano-7-nitroquinoxaline).
As CNQX concentration increased, the signal/noise ratio of this
response component (CNQX/CNQX) held constant. This is also
consistent with Poisson arrival and justified the application of
fluctuation analysis. Two different methods of fluctuation
analysis applied to CNQX and CNQX produced similar results,
leading to an estimate that a just-maximal sustained response was
caused by about 3700 quanta s-1. The transient response was
caused by a rate which was no more than 10-fold greater. Since
the On-alpha cell at this retinal locus has about 2200 bipolar
synapses, one synapse released about 1.7 quanta s-1 for the
sustained response and no more than 17 quanta s-1 for the
transient. Consequently, within the ganglion cell's integration
interval, here calculated to be about 16 ms, a bipolar synapse
rarely releases more than one quantum. Thus for just-maximal
sustained and transient depolarizations, the conductance
modulated by a single bipolar cell synapse is limited to the
quantal conductance (about 100 pS at its peak). This helps
preserve linear summation of quanta. The 2/ ratio remained
constant even as the ganglion cell's response saturated, which
suggested that even at the peak of sensory input, summation
remains linear, and that saturation occurs before the bipolar
synapse. Department of Neuroscience, University of Pennsylvania School of
Medicine, Philadelphia, Pennsylvania 19104-6058, USA.
The cone signal reaches the cat's On-beta (X) ganglion cell via
several parallel circuits (bipolar cell types b1, b2, and b3).
These circuits might convey different regions of the cone's
temporal bandwidth. To test this, I presented a step of light
which elicited a transient depolarization followed by a sustained
depolarization. The contribution of bipolar cells to these
response components was isolated by blocking action potentials
with tetrodotoxin and by blocking inhibitory synaptic potentials
with bicuculline and strychnine. Stationary fluctuation analysis
of the sustained depolarization gave the rate of quantal
bombardment: about 5,100 quanta s-1 for small central cells and
about 45,000 quanta s-1 for large peripheral cells. Normalizing
these rates for the vastly different numbers of bipolar synapses
(150-370 per small cell vs. 2000 per large cell), quantal rate
was constant across the retina, about 22 quanta synapse-1 s-1.
Non-stationary fluctuation analysis gave the mean quantal EPSP
amplitude: about 240 microvolt for the transient depolarization
and 30 microVolt for the sustained depolarization. The b1 bipolar
cell is known from noise analysis of the On-alpha ganglion cell
to have a near-maximal sustained release of only about 2 quanta
synapse-1 s-1. This implies that the other bipolar types (b2 and
b3) contribute many more quanta to the sustained depolarization
(more than 46 synapse-1 s-1). Type b1 probably contributes large
quanta to the transient depolarization. Thus, bipolar cell types
b1 and b2/b3 apparently constitute parallel circuits that convey,
respectively, high and low frequencies.
Department of Neuroscience, University of Pennsylvania School of
Medicine, Philadelphia, Pennsylvania 19104-6058, USA.
A natural scene contains fine spatial detail at low contrast
(Srinivasan et al., 1982), and to represent it as an optical
image on the retina requires quite a lot of light. This is
because the number of photons arriving at a given locus
fluctuates according to Poisson statistics. For an image to
emerge above this fluctuating background of "photon noise" an
object must be brighter than the mean luminance by at least one
standard deviation (corresponding to the square root of the mean
luminance) (Rose, 1973). Consider an example from baseball, a
high fly ball just barely visible against the bright sky. At 100
meters from the outfielder's eye the ball subtends only 12 cones
and is brighter than the sky by about 0.3%. To represent this low
contrast spot requires that the ball reflect onto the retina at
least 12,000 photons per cone integration time (sqrt(12000) /
12000 = 0.3%). The number of extra photons per cone above the mean
is only 30.
Were an outfielder to wear sunglasses (which they do
not, except to follow the ball directly across the sun),
the mean luminance would be reduced by, say, ten-fold. The least
detectable contrast at 100 meters would then be 0.9%
(sqrt(1200)/1200=0.9%). Since the contrast of the ball against
the sky is independent of mean luminance (and thus still only
0.3%) the ball would be invisible. To provide the minimum number
of photons requisite for detection (12,000) the ball's image on
the retina must be larger. Now it must subtend 120 cones but
this occurs only when the ball closes the distance to 32 meters.
Thus, for the optical image on the outfielder's retina, every
photon is precious, even in broad daylight (see Pelli, 1990;
Banks et al., 1987).
Noise in the optical image from photon fluctuations is only
the first problem, however, because creating the neural
image involves additional noise. Each step in visual
transduction and synaptic transmission involves Poisson
statistics whose noise levels also follow the "square root law"
(Attwell, 1986). Thus, how soon the outfielder sees the ball
will depend on the efficiency of transduction and also on
efficient encoding by the neural circuits leading from the cones.
One anticipates that the urgent need to preserve the signal/noise
(S/N) ratio of the neural image would be expressed in the design
of these circuits.
Here we review the functional archkitecture of the circuit in
cat retina that connects cones to one type of ganglion cell.
This is the "on-beta" ("X") cell (Boycott and Wassle, 1974),
which responds linearly (Enroth-Cugell and Robson, 1966), and
whose receptive field is fitted by a difference-of-Gaussians
function (Linsenmeier et al., 1982). The on-beta cell and its
complement, the "off-beta", have the highest sampling densities
and the narrowest sampling apertures in the cat retina (Wassle
et al., 1981; Cleland et al., 1979). The beta cell arrays
apparently relay to the higher visual areas the finest grained
neural image. We describe the structure of the cone circuit to
the on-beta and suggest how the architecture might contribute to
efficient coding of a fine, low contrast, neural image.
Vision Res. (1998)38: 2539-2549
The cone axon is nearly four times thicker than the rod axon
(1.6 vs. 0.45 um diameter). To assess how signal transfer and
integration at the terminal depend on cable dimensions, a
transducer (cone = ohmic conductance, rod = current source)
coupled via passive cable to a sphere with a chloride conductance
(representing GABAa receptor) was modelled. For a small signal
in peripheral cone with a short axon, a steady photosignal
transfers independently of axon diameter despite a significant
chloride conductance at the cone terminal. A temporally varying
photosignal also transfers independently of axon diameter up to
20 Hz and is attenuated only 20% at 50 Hz. Thus, to accomplish
the basic electrical functions of a peripheral cone, a thin axon
would suffice. For a foveal cone with a long axon, a steady
photosignal transfers independently of axon diameter, but a
temporally varying photosignal is attenuated 5-fold at 50 Hz for
a thick axon and 10-fold for a thin axon. This might contribute
to the lower sensitivity of central retina to high temporal
frequencies. The cone axon contains 14-fold more microtubules
than the rod axon, and its terminal contains at least 20-fold
more ribbon synapses than the rod's. Since ribbon synapses
sustain high rates of exocytosis, the additional microtubules
(which require a thicker axon) may be needed to support a greater
flux of synaptic vesicle components.
Department of Neuroscience, University of Pennsylvania School of
Medicine, Philadelphia, Pennsylvania 19104-6058, USA.
WHILE studying the retina more than 100 years ago, Santiago Ramon
y Cajal noted that deposits of silver dichromate completely
filled the arborization of a single neuron but stopped at the
cell boundary. He concluded that contiguous neurons are discrete
and that signals between them must cross an extracellular gap,
now known as a chemical synapse. He vigorously defended this idea
against 'reticularism', the view that neurons form continuous
networks, with his penetrating observations and towering
polemics, and by 1935 reticularism was apparently crushed [1].
But we now know that the reticularists were also right: retinal
neurons can couple with one another by means of clusters of fine
intercellular channels called gap junctions [2] and it seems that
this coupling is crucial for retinal function. New results
described on page 734 of this issue by Mills and Massey [3] offer
a deeper insight into reticularism with the demonstration that
these gap junctions differ in pore size at different points in a
circuit and that they are regulated by different second
messengers.
The authors injected tracers of different molecular weights into
an AII amacrine cell of the rabbit retina (maintained in vitro)
and followed their spread into adjacent neurons to which the AII
is known to be coupled. As expected [4], the smaller tracer
spread into the neighbouring AII cells and cone bipolar cells. A
larger tracer with the same charge also spread readily into AII
cells, but penetrated poorly into cone bipolars (see Figure 2 and
Figure 3 of Mills and Massey's paper [3]). High concentrations of
cyclic AMP were already known to curtail tracer spread to AII
cells [4], and the authors found that cyclic GMP had a similar
effect on tracer spread to cone bipolar cells (see their Figure
4).
This discovery of a difference in pore size and in second
messengers raises a host of questions that may eventually link
the architecture of microcircuits to that of their
computationally important molecules. To grasp the key issues
requires some knowledge of the overall circuitry in which the AII
cell is a critical link (see Figure 1).
Figure 1. To convey the full range of environmental intensities
requires three different but partially overlapping neural
circuits. The mammalian retina accomplishes this at no extra cost
in space or noise by using four sets of gap junctions (red), at
least three of which are regulated. In daylight, cone terminals
excite (depolarize) cone bipolar cells that chemically excite the
ganglion cell. This last excitatory stage occupies most of the
ganglion cell's dendritic surface (some space is reserved for
inhibitory synapses). Gap junctions couple the cone terminals
strongly enough to improve signal-to-noise ratio, but not so much
as to degrade acuity. In twilight, cones are less active, but the
50 rods surrounding each cone couple to it via their terminals.
In effect, rods 'parasitize' the cone terminals and thus the rest
of the cone bipolar circuit. In starlight, only one rod per
thousand transduces a photon over one second, so the rod-cone
junction conveys mostly noise. Consequently, this junction
uncouples, and rod terminals excite rod bipolar cells to excite
All amacrine cells chemically. The All cell couples to the cone
bipolar axon, in effect parasitizing the cone bipolar-to-ganglion
cell synapses. Gap junctions couple All cells strongly enough to
spread current widely and thus enlarge the ganglion cell's
summation area well beyond its dendritic tree. This would improve
signal-to-noise ratio in the dimmest light, but degrade acuity in
brighter light, so this junction is also regulated.
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J. Neurophysiol. 2003 89: 2406-2419;
Information in a spike train is limited by variability in the
spike timing. This variability is caused by noise from several
sources including synapses and membrane channels, but how
deleterious each noise source is and how they affect spike train
coding is unknown. Combining physiology and a multi-compartment
model we studied the effect of synaptic input noise and
voltage-gated channel noise on spike train reliability for a
mammalian ganglion cell. For tonic stimuli the standard
deviation of the interspike intervals increased supra-linearly
with increasing interspike interval. Voltage gated channel noise
and synaptic noise caused fluctuations in the interspike interval
of comparable amplitude. Spikes initiated on the dendrites
caused additional spike timing fluctuations. Ca and KCa channels
present in the model reduced spike train variability. For
transient stimuli, synaptic noise was dominant. Spontaneous
background activity strongly increased fluctuations in spike
timing, but decreased the latency before the first spike. These
results constrain the neural coding strategy.
The foveal midget ganglion cell has a receptive field center fed
by one cone. The surround might also be fed by the same center
cone since a cone terminal laterally connects to neighboring
cones through electrical coupling and horizontal cells. To
explore the contributions of the cone lateral connections to the
receptive field, we constructed a compartmental model of the
primate foveal outer plexiform layer based on the known anatomy
and physiology. The similarity between the computed cone
receptive field and the measured midget cell receptive field
suggest that much of the retina's spatial filtering occurs at the
very first synapse.
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Background
Cone photoreceptors are noisy because of random fluctuations of
photon absorption, signaling molecules, and ion channels.
However, each cones noise is independent of the others, whereas
their signals are partially shared. Therefore, electrically
coupling the synaptic terminals prior to forward transmission and
subsequent nonlinear processing can appreciably reduce noise
relative to the signal. This signal-processing strategy has been
demonstrated in lower vertebrates with rather coarse vision, but
its occurrence in mammals with fine acuity has been doubted (even
though gap junctions are present) because coupling would blur the
neural image.
Results
In ground squirrel retina, whose triangular cone lattice
resembles the human fovea, paired electrical recordings from
adjacent cones demonstrated electrical coupling with an average
conductance of approximately 320 pS. Blur caused by this degree
of coupling had a space constant of approximately 0.5 cone
diameters. Psychophysical measurements employing laser
interferometry to bypass the eyes optics suggest that human
foveal cones experience a similar degree of neural blur and that
it is invariant with light intensity. This neural blur is
narrower than the eye's optical blur, and we calculate that it
should improve the signal-to-noise ratio at the cone terminal by
about 77%.
Conclusions
We conclude that the gap junctions observed between mammalian
cones, including those in the human fovea, represent genuine
electrical coupling. Because the space constant of the resulting
neural blur is less than that of the optical blur, the
signal-to-noise ratio can be markedly improved before the
nonlinear stages with little compromise to visual acuity.
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Abstract
We have measured the contrast threshold for a mammalian
brisk-transient ganglion cell. The intact retina (guinea pig) was
maintained in vitro, and extracellular spikes were recorded to a
spot with sharp onset, flashed for 100 ms over the receptive
field center. An "ideal observer" was given the spike responses
from 100 trials at each contrast and then asked to predict the
stimulus contrast on 100 additional trials in a single-interval,
two-alternative forced-choice procedure. The prediction was based
on spike count, latency or temporal pattern. Brisk-transient
cells near 37(C detected contrasts as low as 0.8% (mean ( SEM =
2.8 ( 0.2%) and discriminated contrast increments with about 40%
greater sensitivity. Performance was temperature sensitive,
declining with a Q10 ~2, similar to that of retinal metabolism.
These measurements of performance provide an important benchmark
for comparison to retinal cell types upstream of the ganglion
cell and downstream - to behavior. For example, human
psychophysical threshold for a stimulus that just covers the
dendritic field of one human brisk-transient cell is the same as
found here. This suggests that neural processing across many
levels of noisy central synapses might be highly efficient.
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Summary
In isolation, a presynaptic terminal generally releases quanta
according to Poisson statistics, but in a circuit its release
statistics might be shaped by local feedback. We monitored
quantal release of glutamate from retinal bipolar cell terminals
(which receive GABA-ergic feedback from amacrine cells) by
recording spontaneous EPSCs in their postsynaptic amacrine and
ganglion cells. EPSCs were temporally correlated in about one
third of these cells, arriving in brief bursts (~20 ms) more
often than expected from a Poisson process. Correlations were
suppressed by antagonizing the GABAC receptor (expressed on
bipolar terminals), and correlations were induced by raising
extracellular calcium or osmolarity (which increase release
probability). Simulations of the feedback circuit produced
``bursty'' release when the bipolar cell escaped intermittently
from inhibition. Correlations of similar strength and duration
were also present in light-evoked EPSCs and ganglion cell spikes.
These correlations were also suppressed by a GABAC antagonist,
indicating that bursts of glutamate from bipolar terminals induce
spike bursts in ganglion cells.
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Summary
The quality of the signal a retinal ganglion cell transmits to
the brain is important for preception because it sets the minimum
detectable stimulus. The ganglion cell converts graded potentials
into a spike train with a selective filter but in the process
adds noise. To explorehow efficiently information is transferred
to spikes, we measured contrast detection threshold and increment
threshold from graded potential and spike responses of
brisk-transient ganglion cells. Intracellular responses to a spot
flashed over the receptive field center of the cell were recorded
in an intact mammalian retina maintained in vitro at 37°C.
Thresholds were measured in a single-interval forced-choice
procedure with an ideal observer. The graded potential gave a
detection threshold of 1.5% contrast, whereas spikes gave 3.8%.
The graded potential also gave increment thresholds approximately
twofold lower and carried 60% more gray levels. Increment
threshold dipped below the detection threshold at a low
contrast ( < 5%) but increased rapidly at higher contrasts. The
magnitude of the dipper for both graded potential and spikes
could be predicted from a threshold nonlinearity in the
responses. Depolarization of the cell by current injection
reduced the detection threshold for spikes but also reduced the
range of contrasts they can transmit. This suggests that contrast
sensitivity and dynamic range are related in an essential
trade-off.
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Summary
The retina's visual message is transmitted to the brain by
ganglion cells that integrate noisy synaptic inputs to create a
spike train. We asked how efficiently the retinal ganglion cell
spike generator creates the spike train message. Intracellular
and extracellular recordings were made from in vitro guinea pig
retina, in response to a spot of light flashed over the receptive
field center. Responses were analyzed with an "ideal observer," a
program that discriminated between two contrasts based on an
optimal decision rule. Spike trains from ganglion cells had
thresholds as low as 1% contrast, but thresholds for the
corresponding graded potentials were lower by a factor of 2.
Using a computational model of the ganglion cell, we asked what
factors in the spike generator mechanism are responsible for the
spike train's loss in performance. The model included
dendritic/axonal morphology, noisy synaptic inputs and membrane
channels. Adaptation of spike rate was provided by K(Ca) channels
which were activated by Ca2+ flux during spikes. When K(Ca)
channels were included, they controlled the duration of the
inter-spike interval and thus set the level of noise in the spike
train. These results imply that the spike generator adds noise to
the spike train signal.
Summary
One stimulus that we detect very efficiently is a small square
that just covers the dendritic field of a brisk-transient
ganglion cell. Since this cell type is the most sensitive of the
geniculo-striate projecting ganglion cells, it may largely
mediate this behavior. To compare the neuron's sensitivity to
that of psychophysical detection we measured its visual threshold
with a method borrowed from psychophysics. Recordings were
extracellular from a mammalian brisk-transient ganglion cell
(guinea pig), whose impulse response was nearly identical to that
of the primate brisk-transient cell. The stimulus, a 100 ms spot
covering the receptive field center, was detected by an "ideal
observer" with knowledge of the spike patterns from 100 trials at
each contrast. Based on this knowledge, the ideal observer used a
single-interval, forced-choice procedure to predict the stimulus
contrast on 100 additional trials. Brisk-transient cells at 37°C
detected contrasts as low as 0.8% (mean ± SD = 2.8 % ± 0.2 ) and
discriminated between contrast increments with about 40% greater
sensitivity. These thresholds are the same as human
psychophysical thresholds for comparable stimuli, suggesting that
across many levels of noisy central synapses, little or no
information is lost. Recording intracellularly, we found
detection threshold of the ganglion cell's graded potential to be
about half that of the spike response, implying a considerable
loss in converting the signals from analog-to-digital. To reach
detection threshold ganglion cell needed ~1000 quanta, and to
respond at full contrast it needed ~2000 quanta. Since the ribbon
synapses that contact this cell contain an aggregate of ~10,000
releasable vesicles, the safety factor for this circuit seems to
be about 5.
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Summary
The starburst amacrine cell (SBAC), found in all mammalian
retinas, is thought to provide the directional inhibitory input
recorded in On-Off direction selective ganglion cells (DSGCs).
While voltage recordings from the somas of SBACs have not shown
robust direction selectivity (DS), the dendritic tips of these
cells display direction-selective calcium signals, even when
gamma aminobutyric acid (GABAa,c) channels are blocked, implying
that inhibition is not necessary to generate DS. This suggested
that the distinctive morphology of the starburst could generate a
DS signal at the dendritic tips, where most of its synaptic
output is located. To explore this possibility, we constructed a
compartmental model incorporating realistic morphological
structure, passive membrane properties, and excitatory inputs. We
found robust direction selectivity at the dendritic tips but not
at the soma. Thin bars produced robust DS, but two-spot apparent
motion and annulus radial motion gave little DS. For these
stimuli, DS was caused by the interaction of a local synaptic
input signal with a temporally delayed "global" signal, that is,
an excitatory postsynaptic potential (EPSP) that spread from the
activated inputs into the soma and throughout the dendritic tree.
In the preferred direction the signals in the dendritic tips
coincided, allowing summation, whereas in the null direction the
local signal preceded the global, preventing summation. Sine-wave
gratings gave the greatest amount of DS, especially at high
velocities and low spatial frequencies. The sine-wave DS
responses could be accounted for by a simple model which summed
phase-shifted signals from different parts of the cell. By
testing different artificial morphologies, we discovered DS was
relatively independent of the detailed morphology, but depended
on having a sufficient number of inputs at the distal tips and a
limited electrotonic isolation. Adding voltage-gated calcium
channels to the model showed that their threshold effect can
amplify DS in the intracellular calcium signal.
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Summary
Mammals can see at low scotopic light levels where only 1 rod in
several thousand transduces a photon. The single photon signal is
transmitted to the brain by the ganglion cell, which collects
signals from more than 1000 rods to provide enough amplification.
If the system were linear, such convergence would increase the
neural noise enough to overwhelm the tiny rod signal. Recent
studies provide evidence for a threshold nonlinearity in the rod
to rod bipolar synapse, which removes much of the background
neural noise. We argue that the height of the threshold should be
0.85 times the amplitude of the single photon signal, consistent
with the saturation observed for the single photon signal. At
this level, the rate of false positive events due to neural noise
would be masked by the higher rate of dark thermal events. The
evidence presented suggests that this synapse is optimized to
transmit the single photon signal at low scotopic light levels.
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Summary
At very low light levels the sensitivity of the visual system is
determined by the efficiency with which single photons are
captured, and the resulting signal transmitted from the rod
photoreceptors through the retinal circuitry to the ganglion
cells and on to the brain. Although the tiny electrical signals
due to single photons have been observed in rod photoreceptors,
little is known about how these signals are preserved during
subsequent transmission to the optic nerve. We find that the
synaptic currents elicited by single photons in mouse rod bipolar
cells have a peak amplitude of 5-6 pA, and that about 20 rod
photoreceptors converge upon each rod bipolar cell. The data
indicates that the first synapse, between rod photoreceptors and
rod bipolar cells, signals a binary event: the detection, or not,
of a photon or photons in the connected rod photoreceptors. We
present a simple model that demonstrates how a threshold
nonlinearity during synaptic transfer allows transmission of the
single photon signal, while rejecting the convergent neural noise
from the 20 other rod photoreceptors feeding into this first
synapse.
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Summary
Light-evoked currents were recorded from rod bipolar cells in a
dark-adapted mouse retinal slice preparation. Low-intensity light
steps evoked a sustained inward current. Saturating light steps
evoked an inward current with an initial peak that inactivated,
with a time constant of about 60-70 ms, to a steady plateau level
that was maintained for the duration of the step. The
inactivation was strongest at hyperpolarized potentials, and
absent at positive potentials. Inactivation was mediated by an
increase in the intracellular calcium concentration, as it was
abolished in cells dialyzed with 10 mM BAPTA, but was present in
cells dialyzed with 1 mM EGTA. Moreover, responses to brief
flashes of light were broader in the presence of intracellular
BAPTA indicating that the calcium feedback actively shapes the
time course of the light responses. Recovery from inactivation
observed for paired-pulse stimuli occurred with a time constant
of about 375 ms. Calcium feedback could act to increase the
dynamic range of the bipolar cells, and to reduce variability in
the amplitude and duration of the single-photon signal. This may
be important for nonlinear processing at downstream sites of
convergence from rod bipolar cells to AII amacrine cells. A model
in which intracellular calcium rapidly binds to the light-gated
channel and reduces the conductance can account for the results.
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Summary
Roughly half of all ganglion cells in mammalian retina belong to
the broad class, termed "sluggish". Many of these cells have
small receptive fields and project via lateral geniculate nuclei
to visual cortex. However, their possible contributions to
perception have been largely ignored because sluggish cells seem
to respond weakly compared to the more easily studied "brisk"
cells. By selecting small somas under infrared DIC optics and
recording with a loose seal, we could routinely isolate sluggish
cells. When a spot was matched spatially and temporally to the
receptive field center, most sluggish cells could detect the same
low contrasts as brisk cells. Detection thresholds for the two
groups determined by an "ideal observer" were similar: threshold
contrast for sluggish cells was 4.7 ± 0.5% (mean ± SE), and for
brisk cells was 3.4 ± 0.3% (Mann-Whitney test: p>0.05).
Signal-to-noise ratios for the two classes were also similar at
low contrast. However, sluggish cells saturated at somewhat lower
contrasts (contrast for half-maximum response was 14 ± 1% vs. 19
± 2% for brisk cells) and were less sensitive to higher temporal
frequencies (when the stimulus frequency was increased from 2 Hz
to 4 Hz, the response rate fell by 1.6-fold). Thus the sluggish
cells covered a narrower dynamic range and a narrower temporal
bandwidth, consistent with their reported lower information
rates. Because information per spike is greater at lower firing
rates, sluggish cells may represent "cheaper" channels that
convey less urgent visual information at a lower energy cost.
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Summary
Voltage-gated channels in a retinal ganglion cell are necessary
for spike generation. However, they also add noise to the graded
potential and spike train of the ganglion cell, which may degrade
its contrast sensitivity, and they may also amplify the graded
potential signal. We studied the effect of blocking Na+ channels
in a ganglion cell on its signal and noise amplitudes and its
contrast sensitivity. A spot was flashed at 1- 4 Hz over the
receptive field center of a brisk transient ganglion cell in an
intact mammalian retina maintained in vitro. We measured signal
and noise amplitudes from its intracellularly recorded graded
potential light response and measured its contrast detection
thresholds with an "ideal observer." When Na+ channels in the
ganglion cell were blocked with intracellular lidocaine N-ethyl
bromide (QX-314), the signal-to-noise ratio (SNR) decreased (p <
0.05) at all tested contrasts (2-100%). Likewise, bath
application of tetrodotoxin (TTX) reduced the SNR and contrast
sensitivity but only at lower contrasts (50%), whereas at higher
contrasts, it increased the SNR and sensitivity. The opposite
effect of TTX at high contrasts suggested involvement of an
inhibitory surround mechanism in the inner retina. To test this
hypothesis, we blocked glycinergic and GABAergic inputs with
strychnine and picrotoxin and found that TTX in this case had the
same effect as QX-314: a reduction in the SNR at all contrasts.
Noise analysis suggested that blocking Na+ channels with QX-314
or TTX attenuates the amplitude of quantal synaptic voltages.
These results demonstrate that Na+ channels in a ganglion cell
amplify the synaptic voltage, enhancing the SNR and contrast
sensitivity.
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Summary
In guinea pig retina, immunostaining reveals a dual gradient of
opsins: cones expressing opsin sensitive to medium wavelengths
(M) predominate in the upper retina, whereas cones expressing
opsin sensitive to shorter wavelengths (S) predominate in the
lower retina. Whether these gradients correspond to functional
gradients in postreceptoral neurons is essentially unknown. Using
monochromatic flashes, we measured the relative weights with
which M, S, and rod signals contribute to horizontal cell
responses. For a background that produced 4.76 log10
photoisomerizations per rod per second (Rh*/rod/s), mean weights
in superior retina were 52% (M), 2% (S), and 46% (rod). Mean
weights in inferior retina were 9% (M), 50% (S), and 41% (rod).
In superior retina, cone opsin weights agreed quantitatively with
relative pigment density estimates from immunostaining. In
inferior retina, cone opsin weights agreed qualitatively with
relative pigment density estimates, but quantitative comparison
was impossible because individual cones coexpress both opsins to
varying and unquantifiable degrees. We further characterized the
functional gradients in horizontal and brisk-transient ganglion
cells using flickering stimuli produced by various mixtures of
blue and green primary lights. Cone weights for both cell types
resembled those obtained for horizontal cells using monochromatic
flashes. Because the brisk-transient ganglion cell is thought to
mediate behavioral detection of luminance contrast, our results
are consistent with the hypothesis that the dual gradient of cone
opsins assists achromatic contrast detection against different
spectral backgrounds. In our preparation, rod responses did not
completely saturate, even at background light levels typical of
outdoor sunlight (5.14 log10 Rh*/rod/s).
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Summary
Retinal ganglion cells of a given type overlap their dendritic
fields such that every point in space is covered by three to four
cells. We investigated what function is served by such extensive
overlap. Recording from pairs of ON or OFF brisk-transient
ganglion cells at photopic intensities, we confirmed that this
overlap causes the Gaussian receptive field centers to be spaced
at2 SDs (). This, together with response nonlinearities and
variability, was just sufficient to provide an ideal observer
with uniform contrast sensitivity across the retina for both
threshold and suprathreshold stimuli. We hypothesized that
overlap might maximize the information represented from natural
images, thereby optimizing retinal performance for many tasks.
Indeed, tested with natural images (which contain statistical
correlations), a model ganglion cell array maximized information
represented in its population responses with 2spacing, i.e., the
overlap observed in the retina. Yet, tested with white noise
(which lacks statistical correlations), an array maximized its
information by minimizing overlap. In both cases, optimal overlap
balanced greater signal-to-noise ratio (from larger receptive
fields) against greater redundancy (because of larger receptive
field overlap). Thus, dendritic overlap improves vision by taking
optimal advantage of the statistical correlations of natural
scenes.
Summary
Horizontal cells transmit signals laterally between
photoreceptors. In most vertebrates, horizontal cells comprise
two or more types that differ in their size and synaptic
connectivity. The horizontal cell receives synaptic input signals
exclusively from photoreceptors and transmits back to them an
inverted signal. This signal, called "negative feedback",
modulates the photoreceptors' release of neurotransmitter. The
feedback signal is generated by a specialized chemical synapse
between the photoreceptor terminal and the horizontal cell's
dendritic tip. The horizontal cell is laterally coupled to its
neighbors through gap junctions, which enlarge its receptive
field in dim illumination, reducing noise. The horizontal cell
feedback creates a receptive field surround for bipolar and
ganglion cells and contributes to a higher quality contrast
signal in the ganglion cell.
Summary
PCP2, a member of the GoLoco domain-containing family, is present
exclusively in cerebellar Purkinje cells and retinal ON-bipolar
cells. Its function in these tissues is unknown. Biochemical and
expression system studies suggest that PCP2 is a guanine
nucleotide dissociation inhibitor, though a guanine nucleotide
exchange factor has also been suggested. Here we studied the
function of PCP2 in ON bipolar cells because their light response depends
on Gao1, which is known to interact with PCP2. We identified a
new splice variant of PCP2 (Ret-PCP2) and localized it to rod
bipolar and ON cone bipolar cells. Electroretinogram recordings from PCP2-null
mice showed a normal a-wave but a slower falling phase of the b-wave (generated by
activity of ON bipolar cells) relative to the wild type.
Whole-cell recordings from rod bipolar cells showed, both under
Ames solution and after blocking GABAA/C and glycine receptors,
that PCP2-null rod bipolar cells were more depolarized than wild
type cells with greater inward current when clamped to -60 mV.
Also under both conditions, the rise time of the response to
intense light was slower by 28% (Ames) and 44% (inhibitory
blockers) in the null cells. Under Ames we also observed >30%
longer decay time in the PCP2 null rod bipolar cells. We conclude
that PCP2 facilitates cation channels' closure in the dark,
shortens the rise time of the light response directly, and
accelerates the decay time indirectly via the inhibitory network.
These data can be most easily explained if Ret-PCP2 serves as a
guanine nucleotide exchange factor.
Summary
Most mammals are dichromats, having short-wavelength sensitive
(S) and middle-wavelength sensitive (M) cones. Smaller
terrestrial species commonly express a dual gradient in opsins,
with M opsin concentrated superiorly and declining inferiorly,
and vice-versa for S opsin. Some ganglion cells in these retinas
combine S and M-cone inputs antagonistically, but no direct
evidence links this physiological opponency with morphology; nor
is it known whether opponency varies with the opsin gradients.
By recording from more than 3000 ganglion cells in guinea pig, we
identified small numbers of color-opponent cells. Chromatic
properties were characterized by responses to monochromatic spots
and/or spots produced by mixtures of two primary lights.
Superior retina contained cells with strong S+/M- and M+/S-
opponency, whereas inferior retina contained cells with weak
opponency. In superior retina, the opponent cells had
well-balanced M and S weights, while in inferior retina the
weights were unbalanced, with the M weights being much weaker.
The M and S components of opponent cell receptive fields had
approximately the same diameter. Opponent cells injected with
Lucifer yellow restricted their dendrites to the ON stratum of
the inner plexiform layer and provided sufficient membrane area
(~2.1e+4 µm2) to collect ~3.9e+3 bipolar synapses. Two
bistratified cells studied were non-opponent. The apparent
decline in S/M opponency from superior to inferior retina is
consistent with the dual gradient and a model where photoreceptor
signals in both superior and inferior retina are processed by the
same post-receptoral circuitry.
Summary
A low contrast spot that activates just one ganglion cell in the
retina is detected in the cell's spike train with about the same
sensitivity as it is detected behaviorally. This is consistent
with Barlow's proposal that the ganglion cell and later stages of
spiking neurons transfer information essentially without loss.
Yet, when losses of sensitivity by all preneural factors are
accounted for, predicted sensitivity near threshold is
considerably greater than behavioral sensitivity, implying that
somewhere in the brain information is lost. We hypothesized that
the losses occur mainly in the retina - where graded signals are
processed by analog circuits that transfer information at high
rates and low metabolic cost. To test this, we constructed a
model that included all preneural losses for an in vitro
mammalian retina, and evaluated the model to predict sensitivity
at the cone output. Recording graded responses postsynaptic to
the cones (from the type A horizontal cell) and comparing to
predicted preneural sensitivity, we found substantial loss of
sensitivity (4.2-fold) across the first visual synapse. Recording
spike responses from brisk-transient ganglion cells stimulated
with the same spot, we found a similar loss (3.5-fold) across the
second synapse. The total retinal loss approximated the known
overall loss, supporting the hypothesis that from stimulus to
perception, most loss near threshold is retinal.
Summary
Photoreceptors are the vertebrate retina's primary site for
transduction of light into a neural signal. The cone
photoreceptor plays a crucial role in daylight vision because it
transmits fast changes in light contrast. To improve its
sensitivity over 5 log units of background illumination, the cone
contains several mechanisms for adaptation: the transduction
cascade, biophysical properties, and in the ribbon synapse. The
ribbon is part of a complex local circuit called the triad that
combines adaptation with spatial filtering to maximize the amount
of information the cone transmits to second-order neurons.
Summary
The rod photoreceptor is responsible for vision at night over the
range of starlight through moonlight to twilight. In starlight,
the rod receives a photon about once in 20 minutes, requiring
spatial summation, but this would amplify the dark noise if the
visual pathway were linear. The rod synapse is specialized to
transmit single-photon signals by removing the dark continuous
noise with a threshold nonlinearity. At twilight, the rod
receives more than one photon per integration time (~200 ms in
mammals) and thus cannot transmit single-photon signals. Instead
its signals at twilight are coupled to cones through gap
junctions.
Refereed review article
Summary
The function of the retina is crucial, for it must encode visual
signals so the brain can detect objects in the visual world.
However, the biological mechanisms of the retina add noise to the
visual signal and therefore reduce its quality and capacity to
inform about the world. Because an organism's survival depends on
its ability to unambiguously detect visual stimuli in the
presence of noise, its retinal circuits must have evolved to
maximize signal quality, suggesting that each retinal circuit has
a specific functional role. Here we explain how an ideal observer
can measure signal quality to determine the functional roles of
retinal circuits. In a visual discrimination task the ideal
observer can measure from a neural response the increment
threshold, the number of distinguishable response levels, and the
neural code, which are fundamental measures of signal quality
relevant to behavior. It can compare the signal quality in
stimulus and response to determine the optimal stimulus, and can
measure the specific loss of signal quality by a neuron's
receptive field for non-optimal stimuli. Taking into account
noise correlations, the ideal observer can track the signal to
noise ratio available from one stage to the next, allowing one to
determine each stage's role in preserving signal quality. A
comparison between the ideal performance of the photon flux
absorbed from the stimulus and actual performance of a retinal
ganglion cell shows that in daylight a ganglion cell and its
presynaptic circuit loses a factor of ~10-fold in contrast
sensitivity, suggesting specific signal-processing roles for
synaptic connections and other neural circuit elements. The ideal
observer is a powerful tool for characterizing signal processing
in single neurons and arrays along a neural pathway.
Summary
The outer retina removes the first-order correlation, the background light
level, and thus more efficiently transmits contrast. This removal is
accomplished by negative feedback from horizontal cell to photoreceptors.
However, the optimal feedback gain to maximize the contrast sensitivity and
spatial resolution is not known. The objective of this study was to determine,
from the known structure of the outer retina, the synaptic gains that optimize
the response to spatial and temporal contrast within natural images. We modeled
the outer retina as a continuous 2D extension of the discrete 1D model of Yagi
et al. (Proc Int Joint Conf Neural Netw 1: 787-789, 1989). We determined the
spatio-temporal impulse response of the model using small-signal analysis,
assuming that the stimulus did not perturb the resting state of the feedback
system. In order to maximize the efficiency of the feedback system, we derived
the relationships between time constants, space constants, and synaptic gains
that give the fastest temporal adaptation and the highest spatial resolution of
the photoreceptor input to bipolar cells. We found that feedback which directly
modulated photoreceptor calcium channel activation, as opposed to changing
photoreceptor voltage, provides faster adaptation to light onset and higher
spatial resolution. The optimal solution suggests that the feedback gain from
horizontal cells to photoreceptors should be approximately 0.5. The model can
be extended to retinas that have two or more horizontal cell networks with
different space constants. The theoretical predictions closely match
experimental observations of outer retinal function.
Summary
The On-Off direction-selective ganglion cell (DSGC) in mammalian retinas
responds most strongly to a stimulus moving in a specific direction. The DSGC
initiates spikes in its dendritic tree, which are thought to propagate to the
soma with high probability. Both dendritic and somatic spikes in the DSGC
display strong directional tuning, whereas somatic PSPs (postsynaptic
potentials) are only weakly directional, indicating that spike generation
includes marked enhancement of the directional signal. We used a realistic
computational model based on anatomical and physiological measurements to
determine the source of the enhancement. Our results indicate that the DSGC
dendritic tree is partitioned into separate electrotonic regions, each summing
its local excitatory and inhibitory synaptic inputs to initiate spikes. Within
each local region the local spike threshold nonlinearly amplifies the preferred
response over the null response on the basis of PSP amplitude. Using inhibitory
conductances previously measured in DSGCs, the simulation results showed that
inhibition is only sufficient to prevent spike initiation and cannot affect
spike propagation. Therefore, inhibition will only act locally within the
dendritic arbor. We identified the role of three mechanisms that generate
directional selectivity (DS) in the local dendritic regions. First, a mechanism
for DS intrinsic to the dendritic structure of the DSGC enhances DS on the null
side of the cell's dendritic tree and weakens it on the preferred side. Second,
spatially offset postsynaptic inhibition generates robust DS in the isolated
dendritic tips but weak DS near the soma. Third, presynaptic DS is apparently
necessary because it is more robust across the dendritic tree. The pre- and
postsynaptic mechanisms together can overcome the local intrinsic DS. These
local dendritic mechanisms can perform independent nonlinear computations to
make a decision, and there could be analogous mechanisms within cortical
circuitry.
Summary
This review focuses on recent advances in our understanding
of how neural divergence and convergence give rise to
complex encoding properties of retinal ganglion cells. We
describe the apparent mismatch between the number of cone
bipolar cell types, and the diversity of excitatory input to retinal
ganglion cells, and outline two possible solutions. One
proposal is for diversity in the excitatory pathways to be
generated within axon terminals of cone bipolar cells, and the
second invokes narrow-field glycinergic amacrine cells that can
apparently act like bipolar cells by providing excitatory drive to
ganglion cells. Finally we highlight two advances in technique
that promise to provide future insights; automation of electron
microscope data collection and analysis, and the use of the
ideal observer to quantitatively compare neural performance at
all levels.
Summary
In the retina, presynaptic inhibitory mechanisms that
shape directionally selective (DS) responses in output
ganglion cells are well established. However, the
nature of inhibition-independent forms of directional
selectivity remains poorly defined. Here, we describe
a genetically specified set of ON-OFF DS ganglion
cells (DSGCs) that code anterior motion. This entire
population of DSGCs exhibits asymmetric dendritic
arborizations that orientate toward the preferred
direction. We demonstrate that morphological asym-
metries along with nonlinear dendritic conductances
generate a centrifugal (soma-to-dendrite) preference
that does not critically depend upon, but works in
parallel with the GABAergic circuitry. We also show
that in symmetrical DSGCs, such dendritic DS mech-
anisms are aligned with, or are in opposition to, the
inhibitory DS circuitry in distinct dendritic subfields
where they differentially interact to promote or
weaken directional preferences. Thus, pre- and post-
synaptic DS mechanisms interact uniquely in distinct
ganglion cell populations, enabling efficient DS
coding under diverse conditions.
Summary
Starburst amacrine cells (SBACs) within the adult mammalian retina provide the
critical inhibition that underlies the receptive field properties of
direction-selective ganglion cells (DSGCs). The SBACs generate
direction-selective output of GABA that differentially inhibits the DSGCs. We
review the biophysical mechanisms that produce directional GABA release from
SBACs and test a network model that predicts the effects of reciprocal
inhibition between adjacent SBACs. The results of the model simulations suggest
that reciprocal inhibitory connections between closely spaced SBACs should be
spatially selective, while connections between more widely spaced cells could
be indiscriminate. SBACs were initially identified as cholinergic neurons and
were subsequently shown to contain release both acetylcholine and GABA. While
the role of the GABAergic transmission is well established, the role of the
cholinergic transmission remains unclear.
Summary
Mammalian cones respond to light by closing a cGMP-gated channel via a cascade
that includes a heterotrimeric G-protein, cone transducin, comprising GAt2, GB3
and GGt2 subunits. The function of GBG in this cascade has not been examined.
Here, we investigate the role of GB3 by assessing cone structure and function
in GB3-null mouse (Gnb3 -/-). We found that GB3 is required for the normal
expression of its partners, because in the Gnb3 -/- cone outer segments, the
levels of GAt2 and GGt2 are reduced by fourfold to sixfold, whereas other
components of the cascade remain unaltered. Surprisingly, Gnb3 cones produce
stable responses with normal kinetics and saturating response amplitudes
similar to that of the wild-type, suggesting that cone phototransduction can
function efficiently without a GB subunit. However, light sensitivity was
reduced by approximately fourfold in the knock-out cones. Because the reduction
in sensitivity was similar in magnitude to the reduction in Gat2 level in the
cone outer segment, we conclude that activation of GAt2 in Gnb3-/- cones
proceeds at a rate approximately proportional to its outer segment
concentration, and that activation of phosphodiesterase and downstream cascade
components is normal. These results suggest that the main role of GB3 in cones
is to establish optimal levels of transducin heteromer in the outer segment,
thereby indirectly contributing to robust response properties.
Summary
Retinal ganglion cells receive inputs from multiple bipolar cells which must be
integrated before a decision to fire is made. Theoretical studies have provided
clues about how this integration is accomplished but have not directly
determined the rules regulating summation of closely timed inputs along single
or multiple dendrites. Here we have examined dendritic summation of multiple
inputs along On ganglion cell dendrites in whole mount rat retina. We activated
inputs at targeted locations by uncaging glutamate sequentially to generate
apparent motion along On ganglion cell dendrites in whole mount retina.
Summation was directional and dependent on input sequence. Input moving away
from the soma (centrifugal) resulted in supralinear summation, while activation
sequences moving toward the soma (centripetal) were linear. Enhanced summation
for centrifugal activation was robust as it was also observed in cultured
retinal ganglion cells. This directional summation was dependent on
hyperpolarization activated cyclic nucleotide-gated (HCN) channels as blockade
with ZD7288 eliminated directionality. A computational model confirms that
activation of HCN channels can override a preference for centripetal summation
expected from cell anatomy. This type of direction selectivity could play a
role in coding movement similar to the axial selectivity seen in locust
ganglion cells which detect looming stimuli. More generally, these results
suggest that non-directional retinal ganglion cells can discriminate between
input sequences independent of the retina network.
Summary
In the primate visual system, the ganglion cells of the magnocellular pathway
underlie motion and flicker detection and are relatively transient, while the
more sustained ganglion cells of the parvocellular pathway have comparatively
lower temporal resolution, but encode higher spatial frequencies. Although it
is presumed that functional differences in bipolar cells contribute to the
tuning of the two pathways, the properties of the relevant bipolar cells have
not yet been examined in detail. Here, by making patch-clamp recordings in
acute slices of macaque retina, we show that the bipolar cells within the
magnocellular pathway, but not the parvocellular pathway, exhibit voltage-gated
sodium (NaV), T-type calcium (CaV), and hyperpolarization-activated, cyclic
nucleotide-gated (HCN) currents, and can generate action potentials. Using
immunohistochemistry in macaque and human retinae, we show that NaV1.1 is
concentrated in an axon initial segment (AIS)-like region of magnocellular
pathway bipolar cells, a specialization not seen in transient bipolar cells of
other vertebrates. In contrast, CaV3.1 channels were localized to the
somatodendritic compartment and proximal axon, but were excluded from the AIS,
while HCN1 channels were concentrated in the axon terminal boutons. Simulations
using a compartmental model reproduced physiological results and indicate that
magnocellular pathway bipolar cells initiate spikes in the AIS. Finally, we
demonstrate that NaV channels in bipolar cells augment excitatory input to
parasol ganglion cells of the magnocellular pathway. Overall, the results
demonstrate that selective expression of voltage-gated channels contributes to
the establishment of parallel processing in the major visual pathways of the
primate retina.
Summary
The retina utilizes a variety of dendritic mechanisms to compute direction
from image motion. The computation is accomplished by starburst amacrine cells
(SBACs) which are GABAergic neurons presynaptic to direction-selective ganglion
cells (DSGCs). SBACs are symmetric neurons with several branched dendrites radi-
ating out from the soma. Larger EPSPs are produced in the dendritic tips of SBACs
as a stimulus sequentially activates inputs from the base of each dendrite outwards.
The directional difference in EPSP amplitude is further amplified near the dendritic
tips by voltage-gated channels to produce directional release of GABA. Reciprocal
inhibition between adjacent SBACs may also amplify directional release. Directional
signals in the independent SBAC branches are preserved because each dendrite
makes selective contacts only with DSGCs of the appropriate preferred-direction.
Directional signals are further enhanced within the dendritic arbor of the DSGC,
which essentially comprises an array of distinct dendritic compartments. Each of
these dendritic compartments locally sum excitatory and inhibitory inputs, ampli-
fies them with voltage-gated channels, and generates spikes that propagate to the
axon via the soma. Overall, the computation of direction in the retina is performed
by several local dendritic mechanisms both presynaptic and postsynaptic, with the
result that directional responses are robust over a broad range of stimuli.
The very first rays of the rising sun enrich our visual world with spectacular
detail. A recent study reveals how retinal circuits downstream of
photoreceptors 'functionally re-wire' to trade-off sensitivity for high spatial
acuity during night-day transitions.
Throughout the CNS, gap junction-mediated electrical signals synchronize neural activity on millisecond timescales via cooperative interactions with chemical synapses. However, gap junction-mediated synchrony has rarely been studied in the context of varying spatiotemporal patterns of electrical and chemical synaptic activity. Thus, the mechanism underlying fine-scale synchrony and its relationship to neural coding remain unclear. We examined spike synchrony in pairs of genetically identified, electrically coupled ganglion cells in mouse retina. We found that coincident electrical and chemical synaptic inputs, but not electrical inputs alone, elicited synchronized dendritic spikes in subregions of coupled dendritic trees. The resulting nonlinear integration produced fine-scale synchrony in the cells' spike output, specifically for light stimuli driving input to the regions of dendritic overlap. In addition, the strength of synchrony varied inversely with spike rate. Together, these features may allow synchronized activity to encode information about the spatial distribution of light that is ambiguous on the basis of spike rate alone.
Summary
Direction selective ganglion cells (DSGCs) respond selectively to motion towards a "preferred" direction, but much less to motion towards the opposite "null" direction. Directional signals in the DSGC depend on GABAergic inhibition, and are observed over a wide range of speeds, which precludes motion detection based on a fixed temporal correlation. A voltage-clamp analysis, using narrow bar stimuli similar in width to the receptive field center, demonstrated that inhibition to DSGCs saturates rapidly above a threshold contrast. However, for wide bar stimuli that activate both the center and surround, inhibition depends more linearly on contrast. Excitation for both wide and narrow bars was also more linear. We propose that positive feedback, likely within the starburst amacrine cell or its network, produces steep saturation of inhibition at relatively low contrast, which renders GABA-release essentially contrast and speed invariant, and thereby enhances the signal-to-noise ratio for direction selective signals in the spike train over a wide range of stimulus conditions. This mechanism enhances directional signals at the expense of lower sensitivity to other stimulus features such as contrast and speed. This renders GABA-release essentially contrast and speed invariant, which enhances directional signals for small objects, and thereby increases the signal-to-noise ratio for direction selective signals in the spike train over a wide range of stimulus conditions. The steep saturation of inhibition confers to a neuron immunity to noise in its spike train because when inhibition is strong, no spikes are initiated.
Summary
Direction selectivity in the retina relies critically on directionally asymmetric GABA release from the dendritic tips of starburst amacrine cells (SBACs). GABA release from each radially directed dendrite is larger for motion outward from the soma toward the dendritic tips than for motion inwards toward the soma. The biophysical mechanisms generating these directional signals remain controversial. A model based on electron-microscopic reconstructions of the mouse retina proposed that an ordered arrangement of kinetically distinct bipolar cell inputs to ON and OFF type SBACs could produce directional GABA release. We tested this prediction by measuring the time-course of EPSCs in ON type SBACs in the mouse retina, activated by proximal and distal light stimulation. Contrary to the prediction, the kinetics of the excitatory inputs were independent of dendritic location. Computer simulations based on 3D reconstructions of SBAC dendrites demonstrated that the response kinetics of distal inputs were not significantly altered by dendritic filtering. These direct physiological measurements, do not support the hypothesis that directional signals in SBACs arise from the ordered arrangement of kinetically distinct bipolar cell inputs.
Summary
Directionally tuned signaling in starburst amacrine cell (SAC) dendrites lies at the heart of the direction selective (DS) circuit in the mammalian retina. The relative contributions of intrinsic cellular properties and network connectivity to SAC DS remain unclear. We present a detailed connectomic reconstruction of SAC circuitry in mouse retina and describe previously unknown features of synapse distributions along SAC dendrites: 1) input and output synapses are segregated, with inputs restricted to proximal dendrites; 2) the distribution of inhibitory inputs is fundamentally different from that observed in rabbit retina. An anatomically constrained SAC network model suggests that SAC-SAC wiring differences between mouse and rabbit retina underlie distinct contributions of synaptic inhibition to velocity and contrast tuning and receptive field structure. In particular, the model indicates that mouse connectivity enables SACs to encode lower linear velocities that account for smaller eye diameter, thereby conserving angular velocity tuning. These predictions are confirmed with calcium imaging of mouse SAC dendrites in response to directional stimuli.
Summary
Directional responses in retinal ganglion cells are generated in large part by direction-selective release of GABA from starburst amacrine cells onto direction-selective ganglion cells (DSGCs). The excitatory inputs to DSGCs are also widely reported to be direction-selective, however, recent evidence suggests that glutamate release from bipolar cells is not directional, and directional excitation seen in patch-clamp analyses may be an artifact resulting from incomplete voltage control. Here we test this voltage-clamp-artifact hypothesis in recordings from 62 On-Off DSGCs in the rabbit retina. The strength of the directional excitatory signal varies considerably across the sample of cells, but is not correlated with the strength of directional inhibition, as required for a voltage-clamp artifact. These results implicate additional mechanisms in generating directional excitatory inputs to DSGCs.
doi:10.1016/B978-0-12-809324-5.01516-9
Summary
The rod photoreceptor is responsible for vision at night over the range of starlight through moonlight to twilight. Its structure is specialized to maximize photon capture, optimize metabolic efficiency and sustain continual synaptic activation. Rods are depolarized in the darkness, the light signal induced by capture of photons consists of a hyperpolarization that lowers the concentration of intracellular calcium ions within the rod terminal and suppresses release of the rod neurotransmitter glutamate. Mutations that change rod morphology, calcium signaling and/or glutamate release may compromise their viability and cause blindness.
Summary
An animal's ability to survive depends on its sensory systems being able to adapt to a wide range of environmental conditions, by maximizing the information extracted and reducing the noise transmitted. The visual system does this by adapting to luminance and contrast. While luminance adaptation can begin at the retinal photoreceptors, contrast adaptation has been shown to start at later stages in the retina. Photoreceptors adapt to changes in luminance over multiple time scales ranging from tens of milliseconds to minutes, with the adaptive changes arising from processes within the phototransduction cascade. Here we show a new form of adaptation in cones that is independent of the phototransduction process. Rather, it is mediated by voltage-gated ion channels in the cone membrane and acts by changing the frequency response of cones such that their responses speed up as the membrane potential modulation depth increases and slow down as the membrane potential modulation depth decreases. This mechanism is effectively activated by high-contrast stimuli dominated by low frequencies such as natural stimuli. However, the more generally used Gaussian white noise stimuli were not effective since they did not modulate the cone membrane potential to the same extent. This new adaptive process had a time constant of less than a second. A critical component of the underlying mechanism is the hyperpolarization-activated current, Ih, as pharmacologically blocking it prevented the long- and mid- wavelength sensitive cone photoreceptors (L- and M-cones) from adapting. Consistent with this, short- wavelength sensitive cone photoreceptors (S-cones) did not show the adaptive response, and we found they also lacked a prominent Ih. The adaptive filtering mechanism identified here improves the information flow by removing higher-frequency noise during lower signal-to-noise ratio conditions, as occurs when contrast levels are low. Although this new adaptive mechanism can be driven by contrast, it is not a contrast adaptation mechanism in its strictest sense, as will be argued in the Discussion.
Summary
A persistent change in illumination causes light-adaptive changes in retinal neurons. Light adaptation improves visual encoding by preventing saturation, and by adjusting spatio-temporal integration to increase the signal-to-noise ratio (SNR) and utilize signaling bandwidth efficiently. In dim light, the visual input contains a greater relative amount of quantal noise and vertebrate receptive fields are extended in space and time to increase SNR. While in bright light SNR of the visual input is high, the rate of synaptic vesicle release from the photoreceptors is low so that quantal noise in synaptic output may limit SNR postsynaptically. Whether and how reduced synaptic SNR impacts spatio-temporal integration in postsynaptic neurons remains unclear. To address this, we measured spatio-temporal integration in retinal horizontal cells and ganglion cells in the guinea pig retina across a broad illumination range, from low to high-photopic. In both cell types, the extent of spatial and temporal integration changed according to an inverted U-shaped function consistent with adaptation to low SNR at both low and high light levels. We show how a simple mechanistic model with interacting, opponent filters can generate the observed changes in ganglion cell spatio-temporal receptive fields across light-adaptive states and postulate that retinal neurons postsynaptic to the cones in bright light adopt low-pass spatio-temporal response characteristics to improve visual encoding under conditions of low synaptic SNR.
Summary
In the retina, modulation of the amplitude of dim visual signals primarily occurs at axon terminals of rod bipolar cells (RBCs). These effects are largely facilitated by GABA and glycine inhibitory neurotransmitter receptors and the excitatory amino acid transporter 5 (EAAT5). EAATs clear glutamate from the synapse, but they also have a glutamate-gated chloride conductance. EAAT5, in particular, acts primarily as an inhibitory glutamate-gated chloride channel. The relative role of visually-evoked EAAT5 inhibition compared to GABA and glycine inhibition has not been addressed. In this study, we determine the contribution of EAAT5-mediated inhibition onto RBCs in response to light stimuli in mouse retinal slices. We find differences and similarities in the two forms of inhibition. Our results show that GABA and glycine mediate nearly all lateral inhibition onto RBCs, as EAAT5 is solely a mediator of RBC feedback inhibition. We also find that EAAT5 and conventional GABA inhibition both contribute to feedback inhibition at all stimulus intensities. Finally, our in silico modeling compares and contrasts EAAT5-mediated to GABA- and glycine-mediated feedback inhibition. Both forms of inhibition have a substantial impact on synaptic transmission to the downstream AII amacrine cell. Our results suggest that the late phase EAAT5 inhibition acts with the early phase conventional, reciprocal inhibition to modulate the rod signaling pathway between rod bipolar cells and their downstream synaptic targets.
Summary
While multicompartment models have long been used to study the biophysics of neurons, it is still challenging to infer the parameters of such models from data including uncertainty estimates. Here, we performed Bayesian inference for the parameters of detailed neuron models of a photoreceptor and an OFF- and an ON-cone bipolar cell from the mouse retina based on two-photon imaging data. We obtained multivariate posterior distributions specifying plausible parameter ranges consistent with the data and allowing to identify parameters poorly constrained by the data. To demonstrate the potential of such mechanistic data-driven neuron models, we created a simulation environment for external electrical stimulation of the retina and optimized stimulus waveforms to target OFF- and ON-cone bipolar cells, a current major problem of retinal neuroprosthetics.
Summary
Previously, we found that in the mammalian retina, inhibitory inputs onto starburst amacrine cells (SACs) are required for robust direction selectivity of On-Off direction-selective ganglion cells (On-Off DSGCs) against noisy backgrounds (Chen et al., 2016). However, the source of the inhibitory inputs to SACs and how this inhibition confers noise resilience of DSGCs are unknown. Here, we show that when visual noise is present in the background, the motion-evoked inhibition to an On-Off DSGC is preserved by a disinhibitory motif consisting of a serially connected network of neighboring SACs presynaptic to the DSGC. This preservation of inhibition by a disinhibitory motif arises from the interaction between visually evoked network dynamics and short-term synaptic plasticity at the SAC-DSGC synapse. While the disinhibitory microcircuit is well studied for its disinhibitory function in brain circuits, our results highlight the algorithmic flexibility of this motif beyond disinhibition due to the mutual influence between network and synaptic plasticity mechanisms.
Summary Retinal bipolar cells are second-order neurons that transmit basic features of the visual scene to postsynaptic partners. However, their contribution to motion detection has not been fully appreciated. Here, we demonstrate that cholinergic feedback from starburst amacrine cells (SACs) to certain presynaptic bipolar cells via alpha-7 nicotinic acetylcholine receptors (alpha-7-nAChRs) promotes direction-selective signaling. Patch clamp recordings reveal that distinct bipolar cell types making synapses at proximal SAC dendrites also express alpha-7-nAChRs, producing directionally skewed excitatory inputs. Asymmetric SAC excitation contributes to motion detection in On-Off direction-selective ganglion cells (On-Off DSGCs), predicted by computational modeling of SAC dendrites and supported by patch clamp recordings from On-Off DSGCs when bipolar cell alpha-7-nAChRs is eliminated pharmacologically or by conditional knockout. Altogether, these results show that cholinergic feedback to bipolar cells enhances direction-selective signaling in postsynaptic SACs and DSGCs, illustrating how bipolar cells provide a scaffold for postsynaptic microcircuits to cooperatively enhance retinal motion detection.
Summary In the outer plexiform layer (OPL) of the mammalian retina, cone photoreceptors (cones) provide input to more than a dozen types of cone bipolar cells (CBCs). In the mouse, this transmission is modulated by a single horizontal cell (HC) type. HCs perform global signaling within their laterally coupled network but also provide local, cone-specific feedback. However, it is unknown how HCs provide local feedback to cones at the same time as global forward signaling to CBCs and where the underlying synapses are located. To assess how HCs simultaneously perform different modes of signaling, we reconstructed the dendritic trees of five HCs as well as cone axon terminals and CBC dendrites in a serial block-face electron microscopy volume and analyzed their connectivity. In addition to the fine HC dendritic tips invaginating cone axon terminals, we also identified "bulbs," short segments of increased dendritic diameter on the primary dendrites of HCs. These bulbs are in an OPL stratum well below the cone axon terminal base and make contacts with other HCs and CBCs. Our results from immunolabeling, electron microscopy, and glutamate imaging suggest that HC bulbs represent GABAergic synapses that do not receive any direct photoreceptor input. Together, our data suggest the existence of two synaptic strata in the mouse OPL, spatially separating cone-specific feedback and feedforward signaling to CBCs. A biophysical model of a HC dendritic branch and voltage imaging support the hypothesis that this spatial arrangement of synaptic contacts allows for simultaneous local feedback and global feedforward signaling by HCs.
Summary
In the retina, ON starburst amacrine cells (SACs) play a crucial role in the direction-selective circuit, but the sources of inhibition that shape their response properties remain unclear. Previous studies demonstrate that ~95% of their inhibitory synapses are GABAergic, yet we find that the light-evoked inhibitory currents measured in SACs are predominantly glycinergic. Glycinergic inhibition is extremely slow, relying on non-canonical glycine receptors containing alpha4 subunits, and is driven by both the ON and OFF retinal pathways. These attributes enable glycine inputs to summate and effectively control the output gain of SACs, expanding the range over which they compute direction. Serial electron microscopic reconstructions reveal three specific types of ON and OFF narrow-field amacrine cells as the presumptive sources of glycinergic inhibition. Together, these results establish an unexpected role for specific glycinergic amacrine cells in the retinal computation of stimulus direction by SACs.
Summary
From mouse to primate, there is a striking discontinuity in our current understanding of the neural coding of motion direction. In non-primate mammals, directionally selective cell types and circuits are a signature feature of the retina, situated at the earliest stage of the visual process. In primates, by contrast, direction selectivity is a hallmark of motion processing areas in visual cortex, but has not been found in the retina, despite significant effort. Here we combined functional recordings of light-evoked responses and connectomic reconstruction to identify diverse direction-selective cell types in the macaque monkey retina with distinctive physiological properties and synaptic motifs. This circuitry includes an ON-OFF ganglion cell type, a spiking, ON-OFF polyaxonal amacrine cell and the starburst amacrine cell, all of which show direction selectivity. Moreover, we discovered that macaque starburst cells possess a strong, non-GABAergic, antagonistic surround mediated by input from excitatory bipolar cells that is critical for the generation of radial motion sensitivity in these cells. Our findings open a door to investigation of a precortical circuitry that computes motion direction in the primate visual system.
Summary
Experience-dependent modulation of neuronal responses is a key attribute in sensory processing. In the mammalian retina, the On-Off direction-selective ganglion cell (DSGC) is well known for its robust direction selectivity. However, how the On-Off DSGC light responsiveness dynamically adjusts to the changing visual environment is underexplored. Here, we report that On-Off DSGCs tuned to posterior motion direction [i.e. posterior DSGCs (pDSGCs)] in mice of both sexes can be transiently sensitized by prior stimuli. Notably, distinct sensitization patterns are found in dorsal and ventral pDSGCs. Although responses of both dorsal and ventral pDSGCs to dark stimuli (Off responses) are sensitized, only dorsal cells show the sensitization of responses to bright stimuli (On responses). Visual stimulation to the dorsal retina potentiates a sustained excitatory input from Off bipolar cells, leading to tonic depolarization of pDSGCs. Such tonic depolarization propagates from the Off to the On dendritic arbor of the pDSGC to sensitize its On response. We also identified a previously overlooked feature of DSGC dendritic architecture that can support dendritic integration between On and Off dendritic layers bypassing the soma. By contrast, ventral pDSGCs lack a sensitized tonic depolarization and thus do not exhibit sensitization of their On responses. Our results highlight a topographic difference in Off bipolar cell inputs underlying divergent sensitization patterns of dorsal and ventral pDSGCs. Moreover, substantial crossovers between dendritic layers of On-Off DSGCs suggest an interactive dendritic algorithm for processing On and Off signals before they reach the soma.
Abstract
In a recent study, visual signals were recorded for the first time in starburst amacrine cells of the macaque retina, and, as for mouse and rabbit, a directional bias observed in calcium signals was recorded from near the dendritic tips. Stimulus motion from the soma toward the tip generated a larger calcium signal than motion from the tip toward the soma. Two mechanisms affecting the spatiotemporal summation of excitatory postsynaptic currents have been proposed to contribute to directional signaling at the dendritic tips of starbursts: (1) a "morphological" mechanism in which electrotonic propagation of excitatory synaptic currents along a dendrite sums bipolar cell inputs at the dendritic tip preferentially for stimulus motion in the centrifugal direction; (2) a "space-time" mechanism that relies on differences in the time-courses of proximal and distal bipolar cell inputs to favor centrifugal stimulus motion. To explore the contributions of these two mechanisms in the primate, we developed a realistic computational model based on connectomic reconstruction of a macaque starburst cell and the distribution of its synaptic inputs from sustained and transient bipolar cell types. Our model suggests that both mechanisms can initiate direction selectivity in starburst dendrites, but their contributions differ depending on the spatiotemporal properties of the stimulus. Specifically, the morphological mechanism dominates when small visual objects are moving at high velocities, and the space-time mechanism contributes most for large visual objects moving at low velocities.
http://dx.doi.org/10.1016/b978-0-12-809324-5.21547-2
Summary
Photoreceptors are the vertebrate retina's primary site for transduction of light into a neural signal. The cone photoreceptor plays a crucial role in daylight vision because it transmits fast changes in light contrast. To improve its sensitivity over 5 log units of background illumination, the cone contains several mechanisms for adaptation: the transduction cascade, biophysical properties, and in the ribbon synapse. The ribbon is part of a complex local circuit called the triad that combines adaptation with spatial filtering to maximize the amount of information the cone transmits to second-order neurons.
Parallel Circuits from Cones to the On-Beta Ganglion Cell.
Cohen E, Sterling P
Conductances evoked by light in the ON-beta ganglion cell of cat retina.
Freed MA, Nelson R
OFF-alpha and OFF-beta ganglion cells in cat retina. I: Intracellular electrophysiology and HRP stains.
Nelson R, Kolb H, Freed MA
Absence of spectrally specific lateral inputs to midget ganglion cells in primate retina.
Calkins DJ, Sterling P
Foveal cones form basal as well as invaginating junctions with diffuse ON bipolar cells.
Calkins DJ, Tsukamoto Y, Sterling P
M and L cones in macaque fovea connect to midget ganglion cells by different numbers of excitatory synapses.
Calkins DJ, Schein SJ, Tsukamoto Y, Sterling P
Accumulation of (3H)glycine by cone bipolar neurons in the cat retina.
Cohen E, Sterling P
Demonstration of cell types among cone bipolar neurons of cat retina.
Cohen E, Sterling P
Convergence and divergence of cones onto bipolar cells in the central area of cat retina.
Cohen E, Sterling P
Microcircuitry related to the receptive field center of the on-beta ganglion cell.
Cohen E, Sterling P
Microcircuitry of cat visual cortex: classification of neurons in layer IV of area 17, and identification of the patterns of lateral geniculate input.
Davis TL, Sterling P
Pattern of lateral
geniculate synapses on neuron somata in layer IV of the cat
striate cortex.
Einstein G, Davis TL, Sterling P
Pattern of lateral
geniculate synapses on neuron somata in layer IV of the cat
striate cortex.
Einstein G, Davis TL, Sterling P
ON-OFF amacrine cells in cat retina.
Freed MA, Pflug R, Kolb H, Nelson R
Four types of amacrine in the cat retina that accumulate GABA.
Freed MA, Nakamura Y, Sterling P
Rod bipolar array in the cat retina: pattern of input from rods and GABA-accumulating amacrine cells.
Freed MA, Smith RG, Sterling P
Computational model of the on-alpha ganglion cell
receptive field based on bipolar cell circuitry.
Freed MA, Smith RG, Sterling P
The ON-alpha ganglion cell of the cat retina and its presynaptic cell types.
Freed MA, Sterling P
Phospholipase C
beta 4 is involved in modulating the visual response in
mice.
Jiang H, Lyubarsky A, Dodd R, Vardi N, Pugh E, Baylor D, Simon MI, Wu D
How retinal microcircuits scale for ganglion cells of different size.
Kier CK, Buchsbaum G, Sterling P
Granule cells in the rat olfactory tubercle accumulate 3H-gamma-aminobutyric acid.
Krieger NR, Megill JR, Sterling P
Microcircuitry of bipolar cells in cat retina.
McGuire BA, Stevens JK, Sterling P
Microcircuitry of beta ganglion cells in cat retina.
McGuire BA, Stevens JK, Sterling P
Neurons and glia in cat superior colliculus accumulate [3H]gamma-aminobutyric acid (GABA).
Mize RR, Spencer RF, Sterling P
Two types of GABA-accumulating neurons in the superficial gray layer of the cat superior colliculus.
Mize RR, Spencer RF, Sterling P
Interplexiform cell in cat retina: identification by uptake of gamma-[3H]aminobutyric acid and serial reconstruction.
Nakamura Y, McGuire BA, Sterling P
Retinal neurons and vessels are not fractal but space-filling.
Panico J, Sterling P
Rate of quantal transmitter release at the mammalian rod synapse.
Rao R, Buchsbaum G, Sterling P
Mammalian rod terminal: architecture of a binary synapse.
Rao-Mirotznik R, Harkins AB, Buchsbaum G, Sterling P
Functional architecture of mammalian outer retina and bipolar cells.
Sterling P, Smith RG, Rao R, Vardi N (1995)
Download pdf file of this article
PMID 3309484
Montage: a system for three-dimensional reconstruction by personal computer.
Smith RG
Download pdf file of this article
PMID 1405746
NeuronC: a computational language for investigating functional architecture of neural circuits.
Smith RG
Download pdf file of this article
PMID 7654610
Simulation of an anatomically defined local circuit: the cone-horizontal cell network in cat retina.
Smith RG
Microcircuitry of the dark-adapted cat retina: functional architecture of the rod-cone network.
Smith RG, Freed MA, Sterling P
Cone receptive field in cat retina computed from microcircuitry.
Smith RG, Sterling P
Department of Anatomy, School of Medicine, University of Pennsylvania,
Philadelphia.
Simulation of the AII amacrine cell of mammalian retina: functional consequences of electrical coupling and regenerative membrane properties.
Smith RG, Vardi N
Numbers of specific types of neuron in layer IVab of cat striate cortex.
Solnick B, Davis TL, Sterling P
Ann. Ref. Neurosci. 1983; 6:149-185
Peter Sterling
Trends Neurosci. 1986 9: 186-192.
Sterling P, Freed M, Smith RG
Microcircuitry of the on-beta ganglion cell in daylight, twilight, and starlight.
Sterling P, Cohen E, Freed MA, Smith RG
Neurons in cat lateral geniculate nucleus that concentrate exogenous [3H]-gamma-aminobutyric acid (GABA).
Sterling P, Davis TL
Functional architecture of rod and cone circuits to the on-beta ganglion cell.
Sterling P, Freed MA, Smith RG
Molecular specificity of defined types of amacrine synapse
in cat retina.
Sterling P, Lampson LA
A systematic approach to reconstructing microcircuitry by electron microscopy of serial sections.
Stevens JK, Davis TL, Friedman N, Sterling P
Toward a functional architecture of the retina: serial reconstruction of adjacent ganglion cells.
Stevens JK, McGuire BA, Sterling P
Gap junctions between the pedicles of macaque foveal cones.
Tsukamoto Y, Masarachia P, Schein SJ, Sterling P
"Collective coding" of correlated cone signals in the retinal ganglion cell.
Tsukamoto Y, Smith RG, Sterling P
Specific cell types in cat retina express different forms of glutamic acid decarboxylase.
Vardi N, Auerbach P
Horizontal cells in cat and monkey retina express different isoforms of glutamic acid decarboxylase.
Vardi N, Kaufman DL, Sterling P
Structure of the starburst amacrine network in the cat retina and its association with alpha ganglion cells.
Vardi N, Masarachia PJ, Sterling P
Immunoreactivity to GABAA receptor in the outer plexiform layer of the cat retina.
Vardi N, Masarachia P, Sterling P
Identification of a G-protein in depolarizing rod bipolar cells.
Vardi N, Matesic DF, Manning DR, Liebman PA, Sterling P
The AII amacrine network: coupling can increase correlated activity.
Vardi N, Smith RG
Subcellular localization of GABAA receptor on bipolar cells in macaque and human retina.
Vardi N, Sterling P
Evidence that vesicles on the synaptic ribbon of retinal bipolar neurons can be rapidly released.
von Gersdorff H, Vardi E, Matthews G, Sterling P
Visual Neurosci. 1997 Jul-Aug.14(4):789-94.
Vardi N. Morigiwa K.
ON cone bipolar cells in rat express the metabotropic receptor
mGluR6.
In: The Synaptic Organization of the Brain, 4th Edit.,
Gordon Shepherd, (Ed.), Oxford University Press.
Retina
Peter Sterling
J. Comp. Neurol. , 1998 May 25. 395(1):43-52
Alpha subunit of Go localizes in the dendritic tips of ON
bipolar cells.
Vardi N.
Noise removal at the rod synapse of mammalian retina.
van Rossum MC. and Smith RG.
Visual Neurosci. 1998 Jul-Aug; 15(4):743-53,
Regional differences in GABA and GAD immunoreactivity in
rabbit horizontal cells.
Johnson MA. Vardi N.
J Neurosci. 1998 May 1 18(9):3373-85,
Microcircuitry and mosaic of a blue-yellow ganglion cell in
the primate retina.
Calkins DJ. Tsukamoto Y. Sterling P.
Vision Res. 1998 May 38(10):1359-69, 1998 May.
Neurochemistry of the mammalian cone 'synaptic complex'.
Vardi N. Morigiwa K. Wang TL. Shi YJ. Sterling P.
Neuron. 1998 21(4):643-4.
"Knocking out" a neural circuit.
Sterling P.
J. Neurophysiol. 1998 Dec; 80(6):3163-72.
Transmitter concentration at a three-dimensional synapse.
Rao-Mirotznik R. Buchsbaum G. Sterling P.
J. Comp. Neurol. 1999 Mar 8; 405(2):173-84.
Differential expression of ionotropic glutamate receptor
subunits in the outer retina.
Morigiwa K. Vardi N.
J. Neurosci. 1999 Jun 1 19(11):4221-8.
Localization of type I inositol 1,4,5-triphosphate receptor in
the outer segments of mammalian cones.
Wang TL. Sterling P. Vardi N.
Nature Neuroscience. 1999 Oct; 2(10):851-3.
Deciphering the retina's wiring diagram.
Sterling P.
J. Neurosci. 1999 Apr 15; 19(8):2954-9.
AMPA receptor activates a G-protein that suppresses a
cGMP-gated current.
Kawai F. Sterling P.
Evidence that circuits for spatial and color vision
segregate at the first retinal synapse
Calkins DJ. Sterling P.
Functional circuitry of the retinal ganglion cell's
nonlinear receptive field.
Demb JB. Haarsma L. Freed MA. Sterling P.
Neurosci. Res. Suppl (1991) strong>15: S185-S198
Spatial summation by ganglion cells: Some consequences for
the efficient encoding of natural scenes.
Tsukamoto Y, Sterling P
Prog. Brain Res 1992 90: 107-131.
GABAergic circuits in the mammalian retina
Freed MA
Cost of cone coupling to trichromacy in primate fovea.
Hsu A, Smith RG, Buchsbaum G, Sterling P
J Neurophysiol. 2000 In Press
Rate of quantal excitation to a retinal ganglion
cell evoked by sensory input.
Freed MA
J Neurosci. (2000) In Press.
Freed MA (2000)
In: Analysis and Modeling of Neural Systems, Ed. by Frank H.
Eeckman. Kluwer Academic Publishers.
Retinal circuits for daylight: why ballplayers don't wear
shades.
Sterling, P., Cohen, E., Smith, R.G., and Tsukamoto, Y. (1992)
Functional architecture of primate cone and rod axons
Hsu, A., Tsukamoto, Y., Smith, R.G., and Sterling, P.
Nature 1995 377:676-677.
Tuning retinal circuits.
Sterling P
Effects of Noise on the Spike Timing Precision of Retinal
Ganglion Cells.
In: Computation in Neurons and Neural Systems" (1994) Ed. by Frank
H. Eekman. Kluwer Academic Publishers, Boston.Simulating the foveal cone receptive field
Hsu A and Smith RG
Electrical coupling between mammalian cones
DeVries S; Qi X; Smith R; Makous W; Sterling P
Current Biology 2002 12:1900-1907.
Contrast Threshold of a Brisk-Transient ganglion cell
Dhingra NK, Kao YH, Sterling P, Smith RG
J. Neurophysiol. 2003 89: 2360-2369.
Timing of quantal release from the retinal bipolar terminal is
regulated by a feedback circuit
Michael A. Freed, Robert G. Smith, and Peter Sterling
Neuron 2003 38: 89-101.
Spike generator limits efficiency of information transfer in a retinal
ganglion cell
Dhingra NK and Smith RG
J. Neurosci. 2004 24: 2914-2922.
How efficiently a ganglion cell codes the visual signal
Smith RG, Dhingra NK, Kao YH, Sterling P
Proc. IEEE Eng. Med. Biol. Soc. (2001) IEEE, Piscataway, NJ,
1: 663-665
Psychophysics to biophysics: how a perception depends on
circuits, synapses, and vesicles.
Dhingra NK, Smith RG, and Sterling P
In: A. Kaneko (Ed) The Neural Basis of Early Vision.
(2003) Keio University International symposia for Life Sciences and
Medicine, Springer-Verlag, Tokyo, Vol. 11.
Direction selectivity in a model of the starburst amacrine cell
Tukker JJ Taylor WR, and Smith RG
Visual Neuroscience (2004) 21: 611-625.
Transmission of scotopic signals from the rod to rod-bipolar cell
in the mammalian retina.
Taylor WR, and Smith RG
Vision Research (2004) 44: 3269-3276.
Transmission of single photon signals through a binary synapse in
the mammalian retina
Berntson A, Smith RG, and Taylor WR
Visual Neurosci. (2004) 21:693-702
Postsynaptic calcium feedback between rods and rod bipolar
cells in the mouse retina
Berntson A, Smith RG, and Taylor WR
Visual Neurosci. (2004) 21:913-924
Sluggish and brisk ganglion cells detect contrast with similar
sensitivity
Xu Y, Dhingra NK, Smith RG, Sterling P
J. Neurophysiol. (2005) 93:2388-2395
Voltage-gated sodium channels improve contrast sensitivity of a
retinal ganglion cell.
Dhingra NK, Freed, MA, Smith RG
J. Neurosci. (2005) 25:8097-8103
Chromatic properties of horizontal and ganglion cell responses follow a dual
gradient in cone opsin expression.
Yin L, Smith RG, Sterling P, Brainard DH
J. Neurosci. (2006) 26:12351-12361
Design of a Neuronal Array
Borghuis BG, Ratliff CP, Smith RG, Sterling P, Balasubramanian V.
J. Neurosci. (2008) 28:3178-3189.
Contributions of Horizontal Cells
Smith RG
In: Allan I. Basbaum, Akimichi Kaneko,
Gordon M. Shepherd, and Gerald Westheimer (Editors) The Senses: A
Comprehensive Reference, Vol 1, Vision I, Richard Masland, and
Thomas D Albright, Eds. San Diego, Academic Press, p 348-350.
Retinal On- bipolar cells express a new PCP-2 splice variant that accelerates the light response.
Download pdf file of this article
Xu, Y, Sulaiman, P, Fedderson, R., Liu, J., Smith, R.G. and Vardi, N.
J. Neurosci. (2008) 28:8873-8884.
Physiology and morphology of color-opponent ganglion cells in a retina expressing a dual gradient of S and M opsins
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Yin L, Smith, R.G., Sterling, P. and Brainard D.H
J. Neurosci. (2008) 29:2706-2724.
Loss of sensitivity in an analog neural circuit
Download pdf file of this article
Borghuis, B.G., Sterling, P. and Smith, R.G.
J. Neurosci. (2009) 29:3045-3058.
Cone photoreceptor cells: soma and synapse
Smith, R.G.
Published online (Elsevier) :In press
Rod photoreceptor cells: soma and synapse
Smith, R.G.
Published online (Elsevier) :In press
Ideal observer analysis of signal quality in retinal circuits
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PMID: 19446034
Smith, R.G. and Dhingra, N.K.
Progress in Retinal and Eye Research
Maximizing contrast resolution in the outer retina of mammals.
[PMID: 20361204]
Lipin MK, Smith RG, Taylor WR (2010)
Biological Cybernetics, Biol Cybern. 103:57-77
Dendritic Spikes Amplify the Synaptic Signal to Enhance Detection of Motion in a Simulation of the Direction-Selective Ganglion Cell.
Download pdf file of this article
Schachter MJ, Oesch N, Smith RG, Taylor WR
PLoS Comput Biol 6(8): e1000899. doi:10.1371/journal.pcbi.1000899.
Trigger features and excitation in the retina
Download pdf file of this article
Taylor WR, Smith RG.
Curr Opin Neurobiol, doi:10.1016/j.conb.2011.07.001
Parallel Mechanisms Encode Direction in the Retina
Download pdf file of this article
[PMID: 21867884]
Trenholm S, Johnson K, Li X,Smith RG, Awatramani GB (2011)
Neuron, doi 10.1016/j.neuron.2011.06.020
The role of starburst amacrine cells in visual signal processing.
Download pdf file of this article
[PMID: 22310373]
Taylor WR, Smith RG. (2012)
Visual Neuroscience 29:73-81.
Cones Respond to Light in the Absence of Beta Transducin Subunit
Download pdf file of this article
[PMID: 23516284]
Nikonov SS, Lyubarsky A, Fina ME, Nikonova ES, Sengupta A, Chinniah C, Ding X-Q, Smith RG, Pugh EN Jr, Vardi N, Dhingra A.
J Neurosci 2013 33:5182-5194
Directional Summation in non-Direction Selective Retinal Ganglion Cells.
Download pdf file of this article
[PMID: 23516351] Abbas SY, Hamade KC, Yang EJ, Nawy S, Smith RG, Pettit DL
PLoS Comput Biol (2013) e1002969 doi:10.1371/journal.pcbi.1002969
NaV1.1 Channels in axon initial segments of retinal bipolar cells augment input to magnocellular visual pathways
[PMID: 24107939]
Puthussery T, Venkataramani S, Gayet-Primo J, Smith RG, Taylor WR
J Neurosci (2013) 33(41): 16045-16059, doi: 10.1523/JNEUROSCI.1249-13.2013
Dendritic Computation of Direction in Retinal Neurons.
Smith RG, Taylor WR
In Eds: Cuntz H, Remme MWH, Torben-Nielsen B, "The Computing Dendrite: From Structure to Function", Springer Series in Computational Neuroscience, ISBN-13: 978-1461480938
Post-receptor adaptation: lighting up the details.
[PMID: 25004365]
Smith RG, Delaney KR, Awatramani GB
Curr Biol. (2014) July 7; 24(13):R608-10. doi: 10.1016/j.cub.2014.05.058.
Nonlinear dendritic integration of electrical and chemical synaptic inputs drives fine-scale correlations.
[PMID: 25344631]
Trenholm S, McLaughlin AJ, Schwab DJ, Turner MH, Smith RG, Rieke F, Awatramani GB. (2014)
Nat Neurosci. 17:1759-1766. doi: 10.1038/nn.3851
Inhibitory Input to the Direction Selective Ganglion Cells Is Saturated at Low Contrast
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Lipin, MY, Taylor WR, Smith RG. (2015)
J. Neurophysiology 2015 June DOI: 10.1152/jn.00413.2015
Time-course of EPSCs in On-type starburst amacrine cells in mouse retina is independent of dendritic location.
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[PMID: 27219620] Stincic T, Smith RG, Taylor WR. (2016)
Journal of Physiology 594:5685-5694 DOI: 10.1113/jp272384
Species-specific wiring for direction selectivity in the mammalian retina.
[PMID: 27350241]
Ding H, Smith RG, Poleg-Polsky A, Diamond JS, Briggman KL. (2016)
Nature 535:105-110 doi:10.1038/nature18609
Directional Excitatory Input to Direction-Selective Ganglion Cells in the Rabbit Retina
[PMID: 28295340] Percival KA, Venkataramani S, Smith RG, Taylor WR (2019)
J Comp Neurol. 2019 Jan 1;527:270-281. doi: 10.1002/cne.24207
Rod Photoreceptor Cells: Soma and Synapse
[online] Krizaj D, Smith RG (2017)
Science Direct: Reference Module in Neuroscience and Biobehavioral Psychology,
A novel mechanism of cone photoreceptor adaptation
[PMID: 28403143] Howlett MH, Smith RG, Kamermans M(2017)
PLoS Biol. 2017 Apr 12;15(4):e2001210.
Impact of light-adaptive mechanisms on mammalian retinal visual encoding at high light levels
PMID: 29357459
Borghuis BG, Ratliff CP, Smith RG (2018)
J Neurophysiol. 2018 Apr 1;119(4):1437-1449. doi: 10.1152/jn.00682.2017
Light-Evoked Glutamate Transporter EAAT5 Activation Coordinates with Conventional Feedback Inhibition to Control Rod Bipolar Cell Output
PMID: 32233906
Bligard GW, DeBrecht J, Smith RG, Lukasiewicz PD (2020)
J Neurophysiol. 2020 123(5):1828-1837. doi: 10.1152/jn.00527.2019.
Bayesian inference for biophysical neuron models enables stimulus optimization for retinal neuroprosthetics
https://elifesciences.org/articles/54997
Oesterle J, Behrens C, Schröder C, Hermann T, Euler T, Franke K, Smith RG, Zeck G, Berens P. (2020)
elife 2020;9:e54997. doi: 10.7554/eLife.54997
Preserving inhibition with a disinhibitory microcircuit in the retina
https://elifesciences.org/articles/62618
Chen Q, Smith RG, Huang X, Wei W (2020)
eLife 2020;9:e62618 doi: 10.7554/eLife.62618
Cholinergic feedback to bipolar cells contributes to motion detection in the mouse retina
https://www.sciencedirect.com/science/article/pii/S2211124721016004
Download pdf file of this article
Hellmer CB, Hall LM, Bohl JM, Sharpe ZJ, Smith RG, Ichinose T (2021)
Cell Reports 2021 37:110106 doi: 10.1016/j.celrep.2021.110106.
Retinal horizontal cells use different synaptic sites for global feedforward and local feedback signaling
https://www.sciencedirect.com/science/article/pii/S0960982221016419
Behrens C, Yadav SC, Korympidou MM, Zhang Y, Haverkamp S, Irsen S, Schaedler A, Lu X, Liu Z, Lause J, St-Pierre F, Franke K, Vlasits A, Dedek K, Smith RG, Euler T, Berens P, Schubert T (2021)
Current Biology 2021 32:545-558.e5. doi: 10.1016/j.cub.2021.11.055
Gain control by sparse, ultra-slow glycinergic synapses
https://www.sciencedirect.com/science/article/pii/S2211124722001346
Jain V, Hanson L, Sethuramanujam S, Michaels T, Gawley J, Gregg RG, Pyle I, Zhang C, Smith RG, Berson D, McCall MA, Awatramani GB (2022)
Cell Reports 38:11041. https://doi.org/10.1016/j.celrep.2022.110410
Origins of direction selectivity in the primate retina
https://www.nature.com/articles/s41467-022-30405-5.pdf
Kim YJ, Peterson BB, Crook JD, Joo HR, Wu J, Puller C, Robinson FR, Gamlin PD, Yau K-W, Viana F, Troy JB, Smith RG, Packer OS, Detwiler PB, Dacey DM (2022)
Nature Communications 13,2862 https://doi.org/10.1038/s41467-022-30405-5
Visual Stimulation Induces Distinct Forms of Sensitization of On-Off Direction-Selective Ganglion Cell Responses in the Dorsal and Ventral Retina
https://www.jneurosci.org/content/jneuro/42/22/4449.full.pdf
Huang X, Kim AJ, Ledesma HA, Ding J, Smith RG, Wei W (2022)
J Neurosci 42:4449-4469 https://doi.org/10.1523/jneurosci.1391-21.2022
Two mechanisms for direction selectivity in a model of the primate starburst amacrine cell
https://doi.org/10.1017/S0952523823000019
Wu J, Kim YJ, Dacey DM, Troy JB, Smith, RG (2023)
Vis Neurosci 40:E003
Cone Photoreceptor Cells: Soma and Synapse
[online] Smith RG (2018)
Science Direct: Reference Module in Neuroscience and Biobehavioral Psychology,