Processing of transient stimuli by the visual system of the rat

While three decades of intensive cortical electrophysiology using a variety of sustained visual stimuli has made a significant contribution to many aspects of visual function, it has not supported the existence of intracortical circuit operations in cortical processing. This study investigated cortical processing by a comparison of the response of primary visual cortical neurones to transient electrical and strobe-flash stimulation. Experiments were performed on 74 anaesthetised Long Evans rats. Standard stereotaxic and extracellular electrophysiological techniques were employed. Continuous (on-line) raster plots and peri-stimulus time histograms (PSTHs) of the extracellular spikes from 81 visual cortical and 55 lateral geniculate nucleus (LGN) neurones were compiled. The strobe-flash stimuli (0.05 ms) were applied to the contralateral eye while the monopolar or bipolar electrical stimuli (0.2 ms, 80-400 μA) were applied to the ipsilateral LGN. 60 of the 81 (74%) tested cortical units were found to be responsive to visual stimuli. A distinct and consistent difference in the cortical response to the two types of transient stimuli was found: (a) Electrical stimulation evoked a prolonged period (197 ± 61 ms) of inhibition in all cortical neurones tested (n=20). This was the case even in those cortical units that were completely unresponsive to visual stimulation. The protracted inhibition was usually followed by a 100-200 ms phase of rebound excitation. (b) Flash stimulation evoked a prominent excitatory discharge (5-30 ms duration) after a latency of 30-60 ms from the onset of the stimulus (n = 59). This was followed by either moderate inhibition or return to a firing rate similar to control activity, for a maximum of 40 ms. Thereafter, cortical neurones showed a sustained increased level of activity with superimposed secondary excitatory phases. The duration of this late re-excitatory phase was 200-300 ms. In 17 of 20 (85%) tested units, the temporal profile of the cortical response to flash stimulation was modulated by small changes in the level of background illumination. In 16 of the 17 units, this sensitivity was reflected primarily as an emergence of a brief secondary inhibitory phase at the lowest level of background illumination (0 lux). Only 1 of the 17 cortical units displayed a flash-evoked primary inhibitory phase at O lux. We explored the possibility that neurones in the lateral geniculate nucleus (LGN) of the thalamus were responsible for the late phase of cortical reexcitation. 49 of the 55 (89%) LGN neurones could be classified as either of the "ON type" i.e. excited by visual stimuli, or the "OFF type" i.e. inhibited by visual stimuli. The response of ON-like LGN neurones to strobe-flash stimulation of the contralateral eye was characterised by a primary excitatory or early discharge (ED) phase after a latency of 25-40 ms. Thereafter, a 200- 400 ms period of inhibition was observed. In 57% of the sample, a rebound excitatory or late discharge (LD) phase completed the response. OFF-like LGN neurones were inhibited by the strobe-flash stimuli after a latency of 30- 35 ms. This flash-evoked inhibition was maintained for 200-400 ms. The sensitivity of the flash-evoked LGN response to the level of background illumination was tested in 11 ON-like and 10 OFF-like neurones. No sustained secondary excitatory events, as observed in visual cortical neurones, were found in any of the ON- and OFF-like LGN neurones, irrespective of the level of background illumination. In conclusion, the data show that the late re-excitatory phase evoked in cortical neurones upon strobe-flash stimulation, is not due to sustained LGN (thalamic) input. Rather, it suggests that these re-excitatory phases are due to intracortical processing of the transient stimuli. These findings emphasize the independent role of the cortex in computing the response to visual stimuli, and cast doubt on traditional theories that have emphasised the role of the thalamus in shaping cortical responses. The difference in the flash and electrically evoked cortical response suggests that even though substantial inhibition is available to the cortex, only a small fraction of this inhibitory capacity is utilised during natural stimulation

Development and Function of Retinal Ganglion Cell Circuits

The function of our nervous system relies on specific patterns of synaptic connections between diverse neuronal cell types. My thesis research addressed how cell-type-specific patterns of connectivity emerge in the developing mouse retina and how they enable mature retinal neurons to detect specific sensory stimuli. Spike trains of the approximately 40 retinal ganglion cell (RGC) types in mammals encode specific features and events in the visual world, and are the sole source of visual information to the brain. Recent studies have begun to dissect the presynaptic circuits underlying diverse RGC light responses, but how cell-type-specific retinal circuits emerge during development is poorly understood. The first part of my dissertation explored the plasticity of the ON alpha (ONα-) RGC circuit. I found that developmental removal of the dominant excitatory input to ONα-RGCs triggers cell-type-specific rewiring, which precisely preserves ONα-RGCs’ characteristic light responses including high contrast sensitivity. Spiking neurons, including RGCs, typically encode sensory information by increasing firing rates in the presence of preferred stimuli. Suppressed-by-Contrast (SbC-) RGCs are unique in that they signal changes in luminance (i.e., contrast) by decreasing rather than increasing spiking. Taking advantages of mouse genetics, in the second part of my thesis, I characterized SbC-RGCs’ responses to complex stimuli and identified the synaptic mechanisms underlying their suppressive contrast encoding. Interestingly, I found that VGluT3-expressing amacrine cells (VG3-ACs) are dual transmitter neurons that release excitatory and inhibitory transmitters in a target-specific manner, and VG3-ACs specifically contributes to OFF inhibition to SbC-RGCs in response to small stimuli. Finally, using an intersectional transgenic approach, I preferentially labeled SbC-RGCs and mapped their central projections to explore the contribution of SbC-RGCs to vision

The context dependence of network response properties in the primary visual cortex of the primate and cat

In the mammalian visual system, stimulus context was investigated with respect to the ways it influenced neuronal mean response magnitude (the average number of spikes fired per second), response temporal structure (the timing of spikes with respect to one another), and the extent to which distributed neurones fired spikes synchronous due to synaptic interaction between them. Neurones were presented with bipartite grating stimuli, in which the spatio-temporal relationship between the grating activating the excitatory receptive field and that presented to the surrounding visual space could be varied systematically. Simultaneous extracellular recordings were made of the responses of up to four single neurones separated by 750-1000µm, in the lateral geniculate nucleus (LGN) of the thalamus in the cat, or the primary visual cortex (V1) of non-human primates or cats. Changing context systematically influenced the activity of groups of cells. The responses of 83% of primate V1 cells to discontinuous stimuli, in which the centre/surround orientation difference was greater than 45°, contained stronger oscillations at frequencies below 80Hz, than responses to continuous stimuli. Many cat and primate V1 neurones exhibited elevated response magnitudes to such stimuli. In primate V1, the strength of a cell's oscillatory discharge was dependent on stimulus configuration rather than response magnitude. In the LGN and V1, cell pairs with different orientation preferences fired synchronised responses when stimulated by specific discontinuous grating configurations. Stimulus specific synchronised LGN input, and reciprocal excitatory and inhibitory cortico-cortical connections could generate these properties of cells, and the network in which they exist. A model is proposed to account for the function significance of contour discontinuities in generating coherent neural representations of objects in the visual world. It involves response synchronisation in horizontal, feedforward and feedback interactions, within and between the LGN, V1, V2 and V4

Residual function, spontaneous reorganisation and treatment plasticity in homonymous visual field defects

This thesis will focus on the residual function and visual and attentional deficits in human patients, which accompany damage to the visual cortex or its thalamic afferents, and plastic changes, which follow it. In particular, I will focus on homonymous visual field defects, which comprise a broad set of central disorders of vision. I will present experimental evidence that when the primary visual pathway is completely damaged, the only signal that can be implicitly processed via subcortical visual networks is fear. I will also present data showing that in a patient with relative deafferentation of visual cortex, changes in the spatial tuning and response gain of the contralesional and ipsilesional cortex are observed, which are accompanied by changes in functional connectivity with regions belonging to the dorsal attentional network and the default mode network. I will also discuss how cortical plasticity might be harnessed to improve recovery through novel treatments. Moreover, I will show how treatment interventions aimed at recruiting spared subcortical pathway supporting multisensory orienting can drive network level change

A neurobiological model of visual attention and invariant pattern recognition based on dynamic routing of information

We present a biologically plausible model of an attentional mechanism for forming position- and scale-invariant representations of objects in the visual world. The model relies on a set of control neurons to dynamically modify the synaptic strengths of intracortical connections so that information from a windowed region of primary visual cortex (V1) is selectively routed to higher cortical areas. Local spatial relationships (i.e., topography) within the attentional window are preserved as information is routed through the cortex. This enables attended objects to be represented in higher cortical areas within an object-centered reference frame that is position and scale invariant. We hypothesize that the pulvinar may provide the control signals for routing information through the cortex. The dynamics of the control neurons are governed by simple differential equations that could be realized by neurobiologically plausible circuits. In preattentive mode, the control neurons receive their input from a low-level “saliency map” representing potentially interesting regions of a scene. During the pattern recognition phase, control neurons are driven by the interaction between top-down (memory) and bottom-up (retinal input) sources. The model respects key neurophysiological, neuroanatomical, and psychophysical data relating to attention, and it makes a variety of experimentally testable predictions

Local and global interneuron function in the retina

Brain regions consist of intricate neuronal circuits with diverse interneuron types. In order to gain mechanistic insights into brain function, it is essential to understand the computational purpose of the different types of interneurons. How does a single interneuron type shape the input-output transformation of a given brain region? Here I investigated how different interneuron types of the retina contribute to retinal computations. I developed approaches to systematically and quantitatively investigate the function of retinal interneurons by combining precise circuit perturbations with a system-wide read-out of activity. I studied the functional roles of a locally acting interneuron type, starburst amacrine cells, and of a globally acting type, horizontal cells. In Chapter 1, I show how a defined genetic perturbation in starburst amacrine cells, the mutation of the FRMD7 gene, leads to specific effects in the direction-selective output channels of the retina. Our findings provide a link between a specific neuronal computation and a human disease, and present an entry point for understanding the molecular pathways responsible for generating neuronal circuit asymmetries. Chapter 2 addresses how mutated FRMD7 in starburst cells and the genetic ablation of starburst cells affect the computation of visual motion in the retina and in primary visual cortex. Chapter 3 addresses how horizontal cells mediate rod depolarization under bright daylight conditions. In Chapter 4, I combined the precise, yet retina-wide, perturbation of horizontal cells with a system-level readout of the retinal output. I uncovered that horizontal cells can differentially shape the response dynamics of individual retinal output channels. Our combined experimental and theoretical work shows how the inhibitory feedback at the first visual synapse shapes functional diversity in the retina

Seeing Through the Tectal Eye: Visual Representations in the Primate Superior Colliculus With and Without Eye Movements

Vision is an important sensory modality for primates. However, because of fo-veated retinal organization, vision requires repetitive eye movements to align the fovea with new objects. This creates interesting theoretical questions about percep-tion in general, since eye movements themselves alter images on the retina even if there are no moving objects in the world. Thus, to study vision is to also study how vision operates during active behavior. In my dissertation, I have investigated the concept of “active vision” in a brainstem structure critical for eye movement gener-ation, the superior colliculus (SC). The SC is a well-studied structure, with a promi-nent role in driving eye movements. However, this structure is also ultimately a vis-ual structure, and it is the primary visual structure in lower animals. Given a rela-tively sparse interest in visual properties of the primate SC in the literature, and given the proximity of both visual and motor representations already together within the same structure, we have adopted the SC as an ideal locus for investigating active vision. We first characterized SC visual representations in the absence of eye movements. We found surprising asymmetries in visual representations between upper and lower visual fields, which have direct consequences on oculomotor be-havior. We also performed analogs of visual neurophysiology experiments in struc-tures like primary visual cortex (V1) or lateral geniculate nucleus (LGN), but this time to characterize SC spatial and temporal frequency tuning properties. We found remarkable tuning properties and response time profiles of SC neurons that we think allow this structure to be highly in-tune with the statistics of natural scenes. This in turn allows very efficient eye movement response times to spatial frequencies prominent in our environment. In the same set of studies, we also characterized cen-ter-surround interactions, orientation tuning, and temporal frequency tuning. To fur-ther explore the concept of “active vision”, we showed how visual representations in the SC are modulated around the time of eye movements. We discovered surprising and spatially far-reaching pre-movement enhancement of contrast sensitivity, which can provide a neural basis for attentional enhancements in behavior. We also found spatial-frequency-specific post-movement modulations of neural activity. The latter results are particularly interesting when related to classic perceptual phenomena of saccadic suppression, and also when considering different neuronal cell types. Fi-nally, we tested how the eyes stabilize themselves after saccadic eye movements and found an enhanced ocular drift control even for the smallest possible saccades gen-erated during fixation. The overall aggregation of our results creates several inter-esting new research avenues with important and solid foundations for future under-standing of detailed circuit-mechanisms of SC function, and also for relating such mechanisms to perception and action

A Novel Circuit Model of Contextual Modulation and Normalization in Primary Visual Cortex

The response of a neuron encoding information about a sensory stimulus is influenced by the context in which that information is presented. In the primary visual cortex (area V1), neurons respond selectively to stimuli presented to a relatively constrained region of visual space known as the classical receptive field (CRF). These responses are influenced by stimuli in a much larger region of visual space known as the extra-classical receptive field (eCRF). In that they cannot directly evoke a response from the neuron, surround stimuli in the eCRF provide the context for the input to the CRF. Though the past few decades of research have revealed many details of the complex and nuanced interactions between the CRF and eCRF, the circuit mechanisms underlying these interactions are still unknown. In this thesis, we present a simple, novel cortical circuit model that can account for a surprisingly diverse array of eCRF properties. This model relies on extensive recurrent interactions between excitatory and inhibitory neurons, connectivity that is strongest between neurons with similar stimu- lus preferences, and an expansive input-output neuronal nonlinearity. There is substantial evidence for all of these features in V1. Through analytical and computational modeling techniques, we demonstrate how and why this circuit is able to account for such a comprehensive array of contextual modulations. In a linear network model, we demonstrate how surround suppression of both excitatory and inhibitory neurons is achieved through the selective amplification of spatially-periodic pat- terns of activity. This amplification relies on the network operating as an inhibition-stabilized network, a dynamic regime previously shown to account for the paradoxical decrease in in- hibition during surround suppression (Ozeki et al., 2009). With the addition of nonlinearity, effective connectivity strength scales with firing rate, and the network can transition be- tween different dynamic regimes as a function of input strength. By moving into and out of the inhibition-stabilized state, the model can reproduce a number of contrast-dependent changes in the eCRF without requiring any asymmetry in the intrinsic contrast-response properties of the cells. This same model also provides a biologically plausible mechanism for cortical normalization, an operation that has been shown to be ubiquitous in V1. Through a winner-take-all population response, we demonstrate how this network undergoes a strong reduction in trial-to-trial variability at stimulus onset. We also propose a novel mechanism for attentional modulation in visual cortex. We then go on to test several of the critical pre- dictions of the model using single unit electrophysiology. From these experiments, we find ample evidence for the spatially-periodic patterns of activity predicted by the model. Lastly, we show how this same circuit motif may underlie behavior in a higher cortical region, the lateral intraparietal area