Adam M. Sillito

Cholinergic modulation of the functional organization of the cat visual cortex

The cortex receives a cholinergic input which is considered to be involved in mediating the effects of arousal. The experiments reported here have examined the nature of the cholinergic influence on the neuronal organization of the cat visual cortex. Out of 83 cells studied, 92% exhibited a modification in their visual response properties during the iontophoretic application of ACh. These comprised 61% in which responses were facilitated and 31% in which responses were depressed. The facilitatory effects were associated with a striking increase in stimulus specific responses without any concomitant loss in the selectivity. This comment applied equally to orientation and direction selectivity. It is argued that the facilitatory action of ACh on stimulus specific responses is consistent with a modulation of potassium conductance and most probably the conductance associated with a voltage dependent channel. We found no evidence to support the view that the facilitatory action involved disinhibition; the action of bicuculline, which blocks inhibitory influences in the visual cortex, was quite distinct to that of ACh. The facilitatory and depressive effects of ACh did not show any correlation with the simple-complex classification of cells or any other obvious parameter of receptive field organization, but there was a correlation with cortical lamination. Cells facilitated by ACh were found in all cortical laminae, but those depressed by ACh were found in laminae III and IV.

A re-evaluation of the mechanisms underlying simple cell orientation selectivity

Following from evidence supporting GABA as a putative inhibitory transmitter in the visual cortex, we have iontophoretically applied the GABA antagonist N-methyl bicuculline (Nmb) to simple cells in order to block the inhibitory inputs acting on them. We found that under these conditions previously sharply-tuned simple cells responded equally to all orientations. Moreover receptive field dimensions, judged by the response to stimuli at the optimal and orthogonal orientations, equated best with that expected from a single dLGN cell input. It seems thus, that asymmetries in the excitatory input are not a significant factor in the generation of simple cell orientation selectivity. The asymmetry underlying orientation selectivity rather originates from the operation of an intracortical inhibitory mechanism.

The cholinergic influence on the function of the cat dorsal lateral geniculate nucleus (dLGN).

The functional influence of the cholinergic input to cat dLGN has been examined by assessing the action of iontophoretically applied acetylcholine (ACh) on the visual responses of cells in layers A and A1. Iontophoretically applied pulses of ACh exerted a strong excitatory action on all 113 cells studied within these layers. In the presence of a sustained application of ACh, the excitatory responses to an optimal stimulus such as a spot of light located within the receptive field centre were greatly facilitated, but at the same time stimulus-specific inhibitory influences were also enhanced. The action of ACh on the stimulus-specific inhibitory influences had the consequence that the responses to non-optimal stimuli were not facilitated to the same extent as those to optimal stimuli and in some cases even diminished. The stimulus-specific inhibitory effects seen in the presence of ACh were very powerful and frequently resulted in complete suppression of the elevated background discharge. We suggest that the ACh directly excites both the relay cells and the Golgi type II inhibitory interneurones within the dLGN. The facilitation of the stimulus-specific inhibition may follow from a direct action on the presynaptic dendrites of the Golgi type II cells which arborize within the dendritic field of the relay cell. Supplementary observations on cells in the perigeniculate nucleus confirm previous findings showing that ACh has an inhibitory effect on these cells. We suggest a tripartite action for the cholinergic influence on the dLGN, involving direct facilitation of relay cells, enhancement of stimulus-specific inhibition via the Golgi type II cells, and disinhibition of the non-specific inhibitory influence form the perigeniculate nucleus.

Corticothalamic feedback enhances stimulus response precision in the visual system

There is a tightly coupled bidirectional interaction between visual cortex and visual thalamus [lateral geniculate nucleus (LGN)]. Using drifting sinusoidal grating stimuli, we compared the response of cells in the LGN with and without feedback from the visual cortex. Raster plots revealed a striking difference in the response pattern of cells with and without feedback. This difference was reflected in the results from computing vector sum plots and the ratio of zero harmonic to the fundamental harmonic of the fast Fourier transform (FFT) for these responses. The variability of responses assessed by using the Fano factor was also different for the two groups, with the cells without feedback showing higher variability. We examined the covariance of these measures between pairs of simultaneously recorded cells with and without feedback, and they were much more strongly positively correlated with feedback. We constructed orientation tuning curves from the central 5 ms in the raw cross-correlograms of the outputs of pairs of LGN cells, and these curves revealed much sharper tuning with feedback. We discuss the significance of these data for cortical function and suggest that the precision in stimulus-linked firing in the LGN appears as an emergent factor from the corticothalamic interaction.

The Cholinergic Modulation of Cortical Function

The cholinergic input to neocortex has long been considered to mediate a non-specific influence over its function (Hebb, 1957; Shute and Lewis, 1967, Szerb, 1967, Spehlmann, 1971) rather than convey specific thalamic inputs (Spehlmann et al. 1971). The general view has been that it produces the changes in cortical function that are normally associated with arousal (Singer, 1979). However, not only does the situation appear to be more complex than earlier work suggested, but we now have a much greater insight into the mechanisms of action of acetylcholine (ACh) at pre- and postsynaptic levels. In this account I shall attempt to bring together a summary of the various components of our knowledge regarding the cholinergic innervation of neocortex together with its possible function, and then discuss the ways in which the cholinergic system may interact with the other nonspecific inputs to neocortex. Some sections will draw heavily on information available for visual cortex because this is to date one of the best models of cortical function that we have. While there has been a tendency to regard the nonspecific inputs as simply shifting the cortex backwards and forwards between the sleeping and waking states, what now emerges is a much more complex picture. The interplay between the nonspecific systems and the cortex appears to be very subtle; it suggests roles in selective attention and interactions that influence the control of cortical blood flow, metabolism, and brain plasticity.

GABAergic Processes in the Central Visual System

There is now persuasive evidence that GABA is a primary inhibitory transmitter in the visual cortex and we have a reasonable knowledge of the morphological characteristics of the GABAergic cells (Iversen et al., 1971; Sillito, 1975a, 1984; Ribak, 1978; Peters and Fairen, 1978; Peters and Regidor, 1981; Somogyi et al., 1981, 1984; Freund et al., 1983). My purpose in this account is to provide an overview of the range and types of contributions that GABAergic inhibitory processes make to the functional organization of the primary visual cortex. In so doing it will be necessary to place the comments in the context of our radically changing perspective on many aspects of the synaptic organization of the visual cortex and to consider interactions at the thalamic level. The discussion will be largely based on observations made in the feline visual cortex, which is a primary model for work of this type, and will center around a consideration of those processes involved in the generation of orientation and directional selectivity, ocular dominance, and length preference.