Goldfish retina: organization for simultaneous color contrast.

The majority of ganglion cells in the retina of goldfish have receptive fields organized so that the cells respond particularly to simultaneous contrasts of color. The receptive fields are concentrically arranged. If the cell is excited by red light in the center, then it will also be excited by green light in the periphery, and inhibited by green light in the center or red light in the periphery. The occurrence of this arrangement and the reverse is about equal. The receptive field is much larger than had previously been thought.

Interaction of critical periods in the visual cortex of kittens.

The critical period for modifying the preferred direction in cat cortical units occurs earlier than that for monocular deprivation. The independence of the effects of these two types of deprivation from each other was tested by rearing six kittens with both reverse suture and reversed directional deprivation. The kittens were placed in a drum rotating in one direction with one eye open at ages 2 1/2 to 5 weeks; the drum rotation was reversed and the other eye opened when they were 5 to 12 weeks old. Recordings were then made in the visual cortex. The results were the sum of the effects of reverse suture and reversal of directional deprivation: most cells were driven by the eye that was open second, and most unidirectional cells preferred the direction to which the animals were exposed first. Consequently, many unidirectional cells preferred the first direction but were driven by the eye open second--a combination that the animal never saw during rearing. There was also an effect of ocular deprivation on directional properties and vice versa: reverse suture reduced the overall percentage of unidirectional cells, just as directional deprivation has been shown to affect the ocular dominance histogram. This result suggests that the same cells may be affected by both forms of deprivation.

Opponent color cells in the cat lateral geniculate nucleus.

A microelectrode survey of the cat lateral geniculate has uncovered an infrequent new type of lateral geniculate cell in layer B with "on" center responses to short wavelengths and "off" center responses to long wavelengths. The short wavelength responses are mediated by cones with peak sensitivity at about 450 nanometers, and the long wavelength responses by cones with peak sensitivity at 556 nanometers. Two of double opponent color cells also had double opponent features.

Cyclic AMP-dependent protein kinase mediates ocular dominance shifts in cat visual cortex.

Visual experience during a critical period early in postnatal development can change connections within mammalian visual cortex. In a kitten at the peak of the critical period (approximately P28-42), brief monocular deprivation can lead to complete dominance by the open eye, an ocular dominance shift. This process is driven by activity from the eyes, and depends on N-methyl-D-aspartate (NMDA) receptor activation. The components of the intracellular signaling cascade underlying these changes have not all been identified. Here we show that inhibition of protein kinase A (PKA) by Rp-8-Cl-cAMPS blocks ocular dominance shifts that occur following monocular deprivation early in the critical period. Inhibition of protein kinase G by Rp-8-Br-PET-cGMPS had no effect, indicating a specificity for the PKA pathway. Enhancement of PKA activity late in the critical period with Sp-8-Cl-cAMPS did not increase plasticity. PKA is a necessary component of the pathway leading to cortical plasticity during the critical period.

Do NMDA receptors have a critical function in visual cortical plasticity?

The theoretical framework, by which we understand the function of NMDA receptors, is derived, in large part, from work conducted on the hippocampal slice preparation, where NMDA receptors are crucial for a form of synaptic plasticity known as long-term potentiation (LTP). Establishing their role in plasticity mechanisms in the neocortex is proving to be far more difficult than originally envisaged, in part due to the fact that the operation of NMDA receptors is different in the intact animal than in vitro. For example, NMDA receptors are activated at low levels of sensory input in intact animals but only by high levels of input in slice preparations. Recent results suggest that a re-evaluation of the role of NMDA receptors in neocortical plasticity is required. Here we discuss some of the issues and introduce four criteria by which any factor supposedly involved in plasticity can be judged. NMDA receptors fulfill more of these criteria than any of the other factors so far investigated in the visual cortex, but maybe this is because they have been studied more intensively.

Rod pathways in mammalian retinae.

A variety of recent experiments has resolved the way in which signals are transmitted from rod photoreceptors to ganglion cells in the mammalian retina. Rods connect to a single class of rod bipolar cell, which depolarize in response to light. Rod bipolar cells are not connected directly to ganglion cells: they synapse onto rod amacrine cells, which excite ON-centre ganglion cells via gap junctions, and inhibit OFF-centre ganglion cells via inhibitory glycine synapses. Monoamines have particular influences on the rod system, through synapses with rod amacrine and rod bipolar cells, and a function for dopamine and indoleamines within this system can be hypothesized from recent experiments. There is evidence to suggest that dopaminergic amacrine cells bring the surround response into the rod system through synapses with the rod amacrine cell, and that an indoleamine, probably serotonin, increases the signal in the ON pathway through a feedback synapse onto the rod bipolar terminal.

Pigment migration and adaptation in the eye of the squid, Loligo pealei.

The migration of the screening pigment was investigated in the retina of the intact squid. The action spectrum of pigment migration corresponds to the action spectrum of the visual pigment, rhodopsin, rather than to the absorption spectrum of the screening pigment. The total number of quanta required for a fixed criterion of pigment migration is the same, when the quanta are delivered over any period of time from 6 s to an hour or more. When less than 3-10% of the rhodopsin is isomerized, the screening pigment migrates out to the tips of the receptors with a time-course of 5-15 min, and back again over the same period of time. When rather more than 10% is isomerized, the outward migration takes 5-15 min, but the screening pigment does not migrate inwards, even after several hours in the dark. Indirect evidence suggests that the band of screening pigment, when it reaches the tips of the receptors, is approximately equivalent to a filter of 0.6 log units. The spectral sensitivity of the optic nerve response was measured, and was found to be broader than the absorption spectrum of squid rhodopsin in vitro; the broadness could be explained by self-screening, assuming a density of rhodopsin of 0.6 log units at 500 nm.

Dark-rearing changes dendritic microtubule-associated protein 2 (MAP2) but not subplate neurons in cat visual cortex.

Sensory-dependent modification of cortical morphology is one component of the cortical plasticity that occurs during the critical period for ocular dominance changes. In this study, we used dark-rearing to examine the sensory dependency of subplate neuron death and the quantity of microtubule-associate protein 2 (MAP2)-positive dendrites. Kittens reared in total darkness until the peak of the critical period had fewer laterally extended MAP2-positive dendrites than age-matched normal kittens. This reduction was found in layer IV but not in layer V. Subsequent exposure to light for 10 days after dark-rearing was sufficient to bring the number of MAP2-positive dendrites to the normal level. Contrarily, dark-rearing did not prevent subplate neurons from dying. Exposure to light after dark-rearing did not increase the number of potential dying neurons. These results show that the quantity of MAP2-positive dendrites is sensory-dependent; however, the death of the subplate neurons is not. Therefore, the death of subplate neurons is probably not directly involved in sensory-dependent modifications of synaptic connections. The possible involvement of laterally extended MAP2-dendrites in visual plasticity is discussed.

Developmental and sensory-dependent changes of phosphoinositide-linked metabotropic glutamate receptors.

Metabotropic glutamate receptors (mGluRs) can modulate synaptic transmission, and there is evidence that phosphoinositide (PI)-linked mGluRs may be involved in sensory-dependent plasticity during the development of cat visual cortex. Consequently, we asked the questions: Where are the PI-linked mGluRs (mGluR1alpha and mGluR5) in the visual cortex? Does the quantity and distribution of these receptors change in the cat visual cortex during postnatal development, and are these features sensory-dependent? We found that the quantity of mGluR1alpha decreases with age, whereas the laminar distribution of mGluR1alpha remains the same. Quantity of mGluR5 also decreases, but the laminar distribution of mGluR5 changes during development. The pattern and timing of the mGluR5 change in distribution follow the development of geniculocortical afferents. Immunostaining indicates that reduction of receptor occurs mainly in layers V-VI for mGluR1alpha and outside layer IV for mGluR5. Dark-rearing postpones the laminar change of mGluR5 and produces an increased level of mGluR5 between postnatal 1.5-6 weeks of age but has no significant effect on the mGluR1alpha distribution or the mGluR1alpha quantity. These results suggest that mGluR1alpha and mGluR5 are involved in different aspects of cortical development. The mGluR5 is more likely to be involved in sensory-dependent events than mGluR1alpha. The lack of developmental correlation between mGluR quantities and the critical period for ocular dominance plasticity also suggests that other factors besides mGluR quantities are important for ocular dominance plasticity.

Immunohistochemical study of two phosphoinositide-linked metabotropic glutamate receptors (mGluR1 alpha and mGluR5) in the cat visual cortex before, during, and after the peak of the critical period for eye-specific connections.

The distribution of two phosphoinositide-linked metabotropic glutamate receptors (mGluR1 alpha and mGluR5) was studied immunohistochemically in area 17 before, during and after the peak of use-dependent modification of eye-specific connections. In the adult, mGluR1 alpha immunoreactivity is high in all layers except layer IV, where mGluR5 immunoreactivity is concentrated. This difference in distribution indicates different functions for these two receptor subtypes. The laminar pattern of mGluR1 alpha immunoreactivity is similar in all three ages, but the overall labeling intensity decreases after the peak (6 weeks of age) of the critical period. The laminar pattern of mGluR5 immunoreactivity changes with age. It is expressed in most layers at 2 days of age and is found mainly in layer IV in the adult. This laminar distribution and developmental pattern match the distribution and the development of the geniculocortical terminals. The change in mGluR1 alpha labeling intensity and mGluR5 laminar distribution over time is consistent with both of these mGluRs being involved in sensory-dependent plasticity for eye-specific connections in the visual cortex.

Effects of dopamine and its agonists and antagonists on the receptive field properties of ganglion cells in the rabbit retina.

We investigated the effects of dopamine and its agonists and antagonists on the receptive field properties of ganglion cells in the isolated eyecup preparation of the rabbit. In general, dopamine (20-250 microM) reduced the overall sensitivity of ganglion cells to light stimuli while increasing the spontaneous activity of off-center cells and decreasing the spontaneous activity of on-center cells and on-off directionally selective cells. Neither(-)-apomorphine (8-82 microM) nor the selective D-2 agonist LY 141865 (7-85 microM) mimicked the effects of exogenous dopamine. Instead, both drugs altered the responses of ganglion cells in a manner similar to that of the selective D-1 antagonist SCH 23390. The latter at 4-41 microM: (1) selectively reduced the antagonistic surround responses of off-center cells; (2) changed the sustained excitatory responses of on-center sustained cells to spots of light into sustained inhibitory responses; (3) selectively reduced the leading edge responses of on-off directionally selective cells to moving light stimuli, and (4) decreased the spontaneous activity of off-center cells while increasing the spontaneous activity of on-center cells. The effects of the selective D-2 antagonist S-sulpiride (37-116 microM) on the responses of on-center cells resembled those of exogenous dopamine, while for off-center cells the effects of S-sulpiride were similar to those of (-)-apomorphine and LY 141865. Results were compared with those obtained previously with dopamine antagonists haloperidol, fluphenazine and cis-flupenthixol on ganglion cell responses in the intact rabbit eye. These three drugs were clearly acting at D-1 receptors. The present findings support a physiological role for D-2 receptors in visual processing in the rabbit retina, in particular the hypothesis that endogenous dopamine release is modulated by inhibitory D-2 autoreceptors. They also suggest that one function of dopaminergic neurons may be to modulate the sensitivity of ganglion cells to light stimuli.

Developmental changes and ocular dominance plasticity in the visual cortex.

There is a shift in ocular dominance of cells recorded in the visual cortex which occurs after closure of one eye during a critical period lasting from eye opening to puberty. Three criteria distinguish factors that are crucially related to ocular dominance plasticity: 1) the factor should be more concentrated or active at the peak of the critical period; 2) dark rearing, which makes the cortex less plastic early in the critical period and more plastic late in the critical period, should have a similar effect on the factor, and 3) antagonists or inhibitors of the factor should block ocular dominance plasticity. The second criterion can be used to distinguish activity-related factors that may simply increase or decrease with development from factors that are more specifically related to plasticity. Two factors currently fulfill these criteria, namely N-methyl-D-asparate (NMDA) receptors and protein kinase A (PKA). PKA and NMDA receptors are linked through calcium, since calcium influx through the NMDA receptor increases the production of cyclic AMP by calcium-sensitive adenylate cyclase, which in turn activates PKA. PKA is specifically involved, since protein kinase G and protein kinase C antagonists do not inhibit ocular dominance plasticity. However, NMDA agonists and PKA activators by themselves are not known to bring back plasticity. Thus there may be two or more pathways for ocular dominance plasticity acting in parallel with each other: for example, metabotropic glutamate receptors may act in parallel with NMDA receptors to change calcium levels within the cell.

Glutamate receptors and development of the visual cortex: effect of metabotropic agonists on cAMP.

Glutamate receptors are more active in several respects in young animals than in adults. Here we examine the effect of metabotropic glutamate agonists on rat cortical cAMP during and after the critical period for visual cortex plasticity. Quisqualate produced a substantial increase in cAMP, which was larger during the critical period than in the adult. The increase was not affected by CNQX or APV, showing that it was not due to the action of quisqualate on ionotropic glutamate receptors. Both Type I mGluRs (mGluRs 1 and/or 5) and Type II mGluRs (mGluRs 2 and/or 3) probably contributed to the cAMP increase because (i) ACPD and L-CCG-I, which are more active on Type II mGluRs, were more effective than DHPG, which is more active on Type I mGluRs; and (ii) there was a significant difference in the effect of ACPD on the increase in cAMP, comparing mGluR1 knockout mice with control mice. Agonists which produce large stimulation of cAMP production (ACPD, L-CCG-I), as well as L-AP4, also produced small attenuations of forskolin-stimulated cAMP, but only at high concentrations. Thus, we conclude that it is the stimulation and/or potentiation of cAMP production that is significant, rather than the attenuation of forskolin-stimulated cAMP. Since this stimulation and/or potentiation is higher during the critical period than in the adult, and the cAMP second messenger system has been implicated in hippocampal plasticity, it may also play a role in visual cortex plasticity.

Critical periods and amblyopia.

During the past 20 years, basic science has shown that there are different critical periods for different visual functions during the development of the visual system. Visual functions processed at higher anatomical levels within the system have a later critical period than functions processed at lower levels. This general principle suggests that treatments for amblyopia should be followed in a logical sequence, with treatment for each visual function to be started before its critical period is over. However, critical periods for some visual functions, such as stereopsis, are not yet fully determined, and the optimal treatment is, therefore, unknown. This article summarizes the current extent of our knowledge and points to the gaps that need to be filled.

Role of metabotropic glutamate receptors in the cat's visual cortex during development.

We have studied the effect of metabotropic glutamate receptors on the second messenger cAMP, and how it varies with age in light- and dark-reared cats; the overall level of the metabotropic glutamate receptors mGluR1, 2/3, and 5 during development; the laminar distribution of these receptors; and how the physiological effect of the metabotropic glutamate receptor agonist ACPD varies with layer. The increase in cAMP produced by ACPD correlates well with the critical period for ocular dominance plasticity in both light- and dark-reared animals. Basal levels of cAMP also correlate well, but overall levels of mGluRs do not. Thus, the second messenger is likely to be the critical factor in plasticity, rather than the mGluRs. Both group I mGluRs (1 and 5) and group II mGluRs (2 and 3) contribute to the increase in cAMP. However, mGluR5 is affected by rearing in the dark, while mGluR1 is not. Moreover, the laminar distribution of mGluRs 2/3 and 5 changes with age, while mGluR1 does not. The laminar distribution is correlated with the functional effect of ACPD, which varies with layer. In upper layers, ACPD has a depressive effect on both visual response and spontaneous activity, while in lower layers it has a depressive effect on visual response and a facilitatory effect on spontaneous activity. These variations in functional effect with layer need to be taken into account before the role of metabotropic glutamate receptors in development will be fully understood.

The group III metabotropic glutamate receptor agonist, l-AP4, reduces EPSPs in some layers of rat visual cortex.

The action of the specific Group III metabotropic glutamate receptor, l-2-amino-4-phosphonobutanoic acid (l-AP4) was tested in slices of rat visual cortex. When the predominant input to the cell was stimulated, l-AP4 generally reduced the EPSP that was produced. This result was specific to the layer: it was found when recording cells in layers II/III, V and VI, but not when recording cells in layer IV. The effect was the same when G-proteins in the cell recorded were inactivated. Also, l-AP4 had little effect on membrane potential and input impedance of the cell recorded, and little effect on the response to NMDA in that cell. Thus, Group III metabotropic glutamate receptors act presynaptically to reduce the release of glutamate onto cells in layers II/III, V and VI in visual cortex, but not cells in layer IV.

5-HT2 antagonists reduce ON responses in the rabbit retina.

We have investigated the effects of serotonin (5-HT2) antagonists in the rabbit retina. These antagonists reduce the ON responses of ON-center cells as well as the surround (ON) responses of OFF-center cells, and enhance the center (OFF) responses of the latter cells. The result is consistent with the anatomy of the indoleamine-accumulating cells in the rabbit retina, which ramify in sublamina b (ON) of the inner plexiform layer and contact primarily bipolar cells that are depolarizing in the rabbit. This suggests that at least part of the surround (ON) responses to OFF-center cells is generated in the inner plexiform layer.

The contribution of NMDA receptors to the visual response in animals that have been partially monocularly deprived.

Kittens were monocularly deprived to give a partial shift in the ocular dominance histograms from their visual cortices. Responses were measured for the normal and deprived eyes at a variety of contrasts, and curves fitted to give measurements of background activity and peak visual response. The N-methyl-D-aspartate (NMDA) antagonist D-2-amino-5-phosphonovalerate (APV) was then applied, and the effect on the contrast-response curves was measured, and compared in the two eyes. In normal animals, the effect of APV on the contrast-response curve was similar in the two eyes. In monocularly deprived animals, on average, peak visual response was affected similarly in the two eyes, although there was wide variability from cell to cell. When the effect of APV on background activity was measured, there was difference between the normal and deprived eyes. APV reduced background activity in the normal eye more than it reduced background activity in the deprived eye. In other words, the NMDA contribution to background activity in the deprived eye was reduced compared to the NMDA contribution to background activity in the normal eye. This could represent a reduction of NMDA receptors in the pathway from the deprived eye, like the reduction of acetylcholine receptors associated with the losing input at the neuromuscular junction before the nerve is eliminated.

Long term potentiation varies with layer in rat visual cortex.

Long term potentiation (LTP) in various layers of rat visual cortex was studied in 90 cells with visually identified, whole-cell recordings. LTP was induced in layer II/III, layer V or layer VI with theta burst stimulation (TBS), but was not observed in layer IV. In the presence of a NMDA antagonist, D-AP5, in the bath solution, potentiation was blocked in layer II/III, some depression was seen in layer V, and potentiation still remained in layer VI. After addition of a specific mGluR1 antagonist, LY367385, to the bath solution, LTP was reduced in layer II/III and layer V, and was blocked in layer VI. After a specific mGluR5 antagonist, MPEP was applied in the bath solution, LTP was enhanced in layer VI, and blocked in layer V. We conclude that: (1) LTP in layer VI is different from other layers, depending on mGluR1, but not NMDA receptors. (2) In layer II/III, LTP is NMDA-dependent and is not blocked by group I mGluR antagonists. (3) LTP in layer V is both NMDA receptor and mGluR5 receptor-dependent. (4) LTP was not induced in layer IV with TBS.

Identification and localization of adrenergic receptors in cat visual cortex.

The concentration and location of adrenergic receptors in cat visual cortex have been determined by radioligand binding techniques using [3H]prazosin (alpha 1-adrenergic receptors), [3H]yohimbine (alpha 2-adrenergic receptors) and [3H]dihydroalprenolol (beta-adrenergic receptors). Saturable high affinity binding sites for all of these ligands were found. The beta-adrenergic receptor population was resolved into beta 1- and beta 2-sites that were present in the ratio 35:65. The laminar distributions of the alpha 1-, alpha 2- and beta-adrenergic receptors were different. The alpha 1- and beta-adrenergic receptors were very similarly localized, being seen in upper layers (I, II and III) and lower layers (layers V and VI). The labelling in upper layers was greater than that in lower layers, more so for alpha 1-adrenergic receptors than beta-adrenergic receptors. alpha 2-Adrenergic receptors were seen in a single band that occupied layer II and III but did extend to the pial surface. These results indicate that the effect of norepinephrine on neuronal activity in cat visual cortex will depend upon the layer in which it is released. Our results provide a basis for further physiological studies of the role of norepinephrine in the processing of visual information.