Traumatic brain injury to primary visual cortex produces long-lasting circuit dysfunction

Primary sensory areas of the mammalian neocortex have a remarkable degree of plasticity, allowing neural circuits to adapt to dynamic environments. However, little is known about the effects of traumatic brain injury on visual circuit function. Here we used anatomy and in vivo electrophysiological recordings in adult mice to quantify neuron responses to visual stimuli two weeks and three months after mild controlled cortical impact injury to primary visual cortex (V1). We found that, although V1 remained largely intact in brain-injured mice, there was ~35% reduction in the number of neurons that affected inhibitory cells more broadly than excitatory neurons. V1 neurons showed dramatically reduced activity, impaired responses to visual stimuli and weaker size selectivity and orientation tuning in vivo. Our results show a single, mild contusion injury produces profound and long-lasting impairments in the way V1 neurons encode visual input. These findings provide initial insight into cortical circuit dysfunction following central visual system neurotrauma.

Sub-Optimality of the Early Visual System Explained Through Biologically Plausible Plasticity

The early visual cortex is the site of crucial pre-processing for more complex, biologically relevant computations that drive perception and, ultimately, behaviour. This pre-processing is often studied under the assumption that neural populations are optimised for the most efficient (in terms of energy, information, spikes, etc.) representation of natural statistics. Normative models such as Independent Component Analysis (ICA) and Sparse Coding (SC) consider the phenomenon as a generative, minimisation problem which they assume the early cortical populations have evolved to solve. However, measurements in monkey and cat suggest that receptive fields (RFs) in the primary visual cortex are often noisy, blobby, and symmetrical, making them sub-optimal for operations such as edge-detection. We propose that this suboptimality occurs because the RFs do not emerge through a global minimisation of generative error, but through locally operating biological mechanisms such as spike-timing dependent plasticity (STDP). Using a network endowed with an abstract, rank-based STDP rule, we show that the shape and orientation tuning of the converged units are remarkably close to single-cell measurements in the macaque primary visual cortex. We quantify this similarity using physiological parameters (frequency-normalised spread vectors), information theoretic measures [Kullback–Leibler (KL) divergence and Gini index], as well as simulations of a typical electrophysiology experiment designed to estimate orientation tuning curves. Taken together, our results suggest that compared to purely generative schemes, process-based biophysical models may offer a better description of the suboptimality observed in the early visual cortex.

ON/OFF domains shape receptive fields in mouse visual cortex

In higher mammals, thalamic afferents to primary visual cortex (area V1) segregate according to their responses to increases (ON) or decreases (OFF) in luminance1–4. This organization induces columnar, ON/OFF domains postulated to provide a scaffold for the emergence of orientation tuning2,5–15. To further test this idea, we asked whether ON/OFF domains exist in mouse V1 – a species containing orientation tuned, simple cells, like those found in other mammals16–19. Here we show that mouse V1 is indeed parceled into ON/OFF domains. Revealingly, fluctuations in the relative density ON/OFF neurons on the cortical surface mirror fluctuations in the relative density of ON/OFF receptive field centers on the visual field. In each cortical volume examined, the average of simple-cell receptive fields correlates with the difference between the average of ON and OFF receptive fields7. Moreover, the local diversity of simple-cell receptive fields is explained by a model in which neurons linearly combine a small number of ON and OFF signals available in their cortical neighborhoods15,20. Altogether, these findings indicate that ON/OFF domains originate in fluctuations of the spatial density of ON/OFF inputs on the visual field which, in turn, shapes the structure of receptive fields10–13,21–23.

Microendoscopic calcium imaging of the primary visual cortex of behaving macaques

In vivo calcium imaging with genetically encoded indicators has recently been applied to macaque brains to monitor neural activities from a large population of cells simultaneously. Microendoscopic calcium imaging combined with implantable gradient index lenses captures neural activities from deep brain areas with a compact and convenient setup; however, this has been limited to rodents and marmosets. Here, we developed miniature fluorescent microscopy to image neural activities from the primary visual cortex of behaving macaques. We found tens of clear fluorescent signals from three of the six brain hemispheres. A subset of these neurons showed clear retinotopy and orientation tuning. Moreover, we successfully decoded the stimulus orientation and tracked the cells across days. These results indicate that microendoscopic calcium imaging is feasible and reasonable for investigating neural circuits in the macaque brain by monitoring fluorescent signals from a large number of neurons.

The development of active binocular vision under normal and alternate rearing conditions

The development of binocular vision is an active learning process comprising the development of disparity tuned neurons in visual cortex and the establishment of precise vergence control of the eyes. We present a computational model for the learning and self-calibration of active binocular vision based on the Active Efficient Coding framework, an extension of classic efficient coding ideas to active perception. Under normal rearing conditions with naturalistic input, the model develops disparity tuned neurons and precise vergence control, allowing it to correctly interpret random dot stereograms. Under altered rearing conditions modeled after neurophysiological experiments, the model qualitatively reproduces key experimental findings on changes in binocularity and disparity tuning. Furthermore, the model makes testable predictions regarding how altered rearing conditions impede the learning of precise vergence control. Finally, the model predicts a surprising new effect that impaired vergence control affects the statistics of orientation tuning in visual cortical neurons.

Inhibiting retinoic acid mitigates vision loss in a mouse model of retinal degeneration

In degenerative retinal disorders, rod and cone photoreceptors die, causing vision impairment and blindness. Downstream neurons survive but undergo morphological and physiological remodeling, with some retinal ganglion cells (RGC) exhibiting heightened spontaneous firing. Retinoic acid (RA) has been implicated as the key signaling molecule that induces RGC hyperactivity, obscuring RGC light responses and reducing light avoidance behaviors triggered by residual rods and cones. However, evidence that RA-dependent remodeling corrupts image-forming vision has been lacking. Here we show that disulfiram, an FDA-approved drug that inhibits RA synthesis, and BMS 493, an RA receptor (RAR) inhibitor, reduce RGC hyperactivity and augment image detection in visually impaired mice. Functional imaging of visual cortical neurons shows that disulfiram and BMS 493 sharpen orientation-tuning and strengthen response fidelity to naturalistic scenes. These findings establish a causal link between RA-induced retinal hyperactivity and vision impairment and define molecular targets and candidate drugs for boosting image-forming vision in retinal degeneration.

Development of visual response selectivity in cortical GABAergic interneurons

The visual cortex of carnivores and primates displays a high degree of modular network organization characterized by local clustering and structured long-range correlations of activity and functional properties. Excitatory networks display modular organization before the onset of sensory experience, but the developmental timeline for modular networks of GABAergic interneurons, remains under-explored. Using in vivo calcium imaging of the ferret visual cortex, we find evidence that before visual experience, interneurons display weak orientation tuning and widespread non-specific activation in response to visual stimuli. Modular organization and orientation tuning are evident with as little as one week of visual experience. Furthermore, we find that the development of orientation tuning requires visual experience, while the reduction in widespread network activity does not. Thus, the maturation of inhibitory cortical networks occurs in a delayed, parallel process relative to excitatory neurons.

Population Models, Not Analyses, of Human Neuroscience Measurements

Selectivity for many basic properties of visual stimuli, such as orientation, is thought to be organized at the scale of cortical columns, making it difficult or impossible to measure directly with noninvasive human neuroscience measurement. However, computational analyses of neuroimaging data have shown that selectivity for orientation can be recovered by considering the pattern of response across a region of cortex. This suggests that computational analyses can reveal representation encoded at a finer spatial scale than is implied by the spatial resolution limits of measurement techniques. This potentially opens up the possibility to study a much wider range of neural phenomena that are otherwise inaccessible through noninvasive measurement. However, as we review in this article, a large body of evidence suggests an alternative hypothesis to this superresolution account: that orientation information is available at the spatial scale of cortical maps and thus easily measurable at the spatial resolution of standard techniques. In fact, a population model shows that this orientation information need not even come from single-unit selectivity for orientation tuning, but instead can result from population selectivity for spatial frequency. Thus, a categorical error of interpretation can result whereby orientation selectivity can be confused with spatial frequency selectivity. This is similarly problematic for the interpretation of results from numerous studies of more complex representations and cognitive functions that have built upon the computational techniques used to reveal stimulus orientation. We suggest in this review that these interpretational ambiguities can be avoided by treating computational analyses as models of the neural processes that give rise to measurement. Building upon the modeling tradition in vision science using considerations of whether population models meet a set of core criteria is important for creating the foundation for a cumulative and replicable approach to making valid inferences from human neuroscience measurements. Expected final online publication date for the Annual Review of Vision Science, Volume 7 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Serotonergic Modulation of Orientation Tuning of Neurons in Primary Visual Cortex of Anesthetized Mice

Introduction: Sensory processing is profoundly regulated by brain neuromodulatory systems. One of the main neuromodulators is serotonin which influences higher cognitive functions such as different aspects of perceptual processing. So, malfunction in the serotonergic system may lead to visual illusion in psychiatric disorders such as autism and schizophrenia. In this work, we examined the serotonergic modulation of visual responses of neurons to stimulus orientation in the primary visual cortex. Methods: Eight-weeks old naive mice were anesthetized and craniotomy was done on the region of interest in primary visual cortex. Spontaneous and visual-evoked activities of neurons were recorded before and during the electrical stimulation of dorsal raphe nucleus using in vivo whole-cell patch-clamp recording. Square-wave grating of 12 orientations was presented. Data was analyzed and Wilcoxon signed-rank test, used in order to compare the data of two conditions that belong to the same neurons, with or without electrical stimulation. Results: The serotonergic system changed orientation tuning of about 60 % recorded neurons by decreasing the mean firing rate in two independent visual response components: gain and baseline response. It also increased mean firing rate in a small number of neurons (about 20%). Beyond that, it left the preferred orientation and sensitivity of neurons unchanged. Conclusion: However, serotonergic modulation showed a bi-directional effect; it seems to cause predominately divisive and subtractive decreases in the visual responses of the neurons in the primary visual cortex that can modify the balance between internal and external sensory signals and result in disorders.

A binocular synaptic network supports interocular response alignment in visual cortical neurons

In the visual system, signals from the two eyes are combined to form a coherent representation through the convergence of synaptic input populations onto individual cortical neurons. As individual synapses originate from either monocular (representing one eye) or binocular (representing both eyes) cortical networks, it has been unclear how these inputs are integrated coherently. Here, we imaged dendritic spines on layer 2/3 binocular cells in ferret visual cortex with in vivo two-photon microscopy to examine how monocular and binocular synaptic networks contribute to the interocular alignment of orientation tuning. We found that binocular synapses varied in degree of "congruency", namely response correlation between left and right eye visual stimulation. Binocular congruent inputs were functionally distinct from binocular noncongruent and monocular inputs, exhibiting greater tuning selectivity and connection specificity. Using correlative light and electron microscopy, we found no difference in ultrastructural anatomy and instead, observed strength in numbers using a simple model simulating aggregate synaptic input. This model demonstrated a predominate contribution of binocular congruent inputs in sculpting somatic orientation preference and interocular response alignment. Our study suggests that, in layer 2/3 cortical neurons, a binocular network is responsible for forming a coherent representation in individual neurons through recurrent intracortical interactions.