Gregory D. Horwitz - US grants

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Microsaccades can elevate contrast detection thresholds of human observers and modulate the activity of neurons in monkey visual cortex. Whether microsaccades elevate contrast detection thresholds in monkey observers is not known and bears on the interpretation of neurophysiological experiments. To answer this question, we trained two monkeys to perform a 2AFC contrast detection task. Performance was worse on trials in which a microsaccade occurred during the stimulus presentation. The magnitude of the effect was modest (threshold changes of 0.2 log units) and color specific: achromatic sensitivity was impaired but red-green sensitivity was not. To explore the neural basis of this effect, we recorded the responses of individual V1 neurons to a white noise stimulus. Microsaccades produced a suppression of spiking activity followed by a excitatory rebound that was similar for L-M cone-opponent and L+M non-opponent V1 neurons. We conclude that microsaccades in the monkey increase luminance contrast detection thresholds and modulate the spiking activity of V1 neurons, but the luminance-specificity of the behavioral suppression is likely implemented downstream of V1.

DESCRIPTION (provided by applicant): The visual system has emerged as a premier model for understanding information processing by neurons. Within vision, the submodality of color provides a particularly attractive experimental platform: we know a tremendous amount about the phenomenology of color perception and can explain some aspects of color perception, quantitatively and with high precision, by well- understood physiological processes. As a result of this progress, we can quickly and accurately diagnose many distinct forms of color blindness and can build devices that render colors accurately. On the other hand, our understanding of the neurophysiology of color vision is largely restricted to the retina. The central mechanisms of color vision are largely unknown, and many aspects of color perception cannot be explained by retinal mechanisms. The proposed research is to measure the quality and behavioral relevance of the signals beyond the retina that mediate color vision. Two specific aims are planned: 1) Single neuron recording in the primary visual cortex to identify the neurons most likely to underlie color vision. 2) Single neuron recording in the primary visual cortex to study how manipulations that affect color appearance affect neuronal responses. The proposed experiments extend our knowledge of color vision toward an understanding of the principles of neuroscience that give rise to perception and its disorders. Such an understanding promises to provide the means to promote recovery of visual function following trauma or neurological disease. PUBLIC HEALTH RELEVANCE: Understanding how neurons mediate perception is an important step towards developing effective treatments for pathologies that disrupt perception. The proposed experiments exploit the model system of color vision, one of the most mature submodalities of vision, to reveal the neural events that relate activation of the peripheral receptors to perception.

DESCRIPTION (provided by applicant): The goal of this project is to use behavioral and single-unit recording techniques to understand the role of three-dimensional (3D) context in the neural processing of object size. Estimating the size of an object highlights a fundamental computational problem in vision: the inherent ambiguity in the retinal image. For any given retinal image there are an infinite number of combinations of object sizes and viewing distances that could give rise to that image. A fundamental challenge is to understand how distance information - which is not explicitly represented in the retinal image - is combined with retinal size information to achieve an accurate and stable representation of object size. The overarching framework of this proposal is that distance information is combined with retinal size information in early stages of the visual system. Convergent evidence from behavioral, fMRI, and ERP experiments in humans have shown that object size is represented in the primary visual cortex. These results are inconsistent with the primary visual cortex passively reflecting the stimulus on the retina, but rather suggest that high-level signals related to 3D scene interpretation may be fed back to primary visual cortex to adjust the amount of tissue allocated to represent visual objects. To extend these findings, our proposed experiments pursue these results in an animal model using psychophysical measurements and single-neuron electrophysiological recordings. Two specific aims are proposed: 1) single-unit recording to investigate the changes in receptive field structure of individual visual cortical neurons as a function of 3D context and 2) psychophysical measurements of size illusions in the same animal model used in specific aim 1. Together these specific aims will shed light on the processes that underlie size perception, which are critical for interacting with a 3D world, and will provide a bridge between vision studies in human and non-human subjects. PUBLIC HEALTH RELEVANCE: The relevance of this project is that we will gain further understanding into how the brain constructs visual perceptions of the environment. This process is a complex interaction between the light signal that arrives at the eye and our built- in, implicit knowledge about the structure of the environment. This understanding is essential for identifying how the visual system develops and for finding potential treatments for visual impairments in response to brain injury or disease.

DESCRIPTION (provided by applicant): The primate oculomotor system is a premier model system for understanding the production of reflexive and volitional movements. Two types of saccadic eye movements are made by humans and monkeys: regular and express saccades. Regular saccades have long latencies and are thought to involve the transfer of information from the visual cortex, to the frontal cortex, to the superior colliculus. Express saccades have shorter latencies and are thought to be mediated by a direct pathway from visual cortex to the superior colliculus, bypassing the frontal cortex. Importantly, under some conditions both express and regular saccades are made in roughly equal proportion; express saccades occur on some trials, regular saccades on other, seemingly identical, trials. If, as hypothesized, express saccades are mediated by projections from the visual cortex to the superior colliculus, the probability of express saccade occurrence should increase if these projections are stimulated under conditions in which they are not naturally strongly activated. Such a manipulation was technically impossible until recently, but optogenetics has changed this. Optogenetics is a relatively new set of tools for manipulating neural activity with light, an these tools have already been extremely valuable in the study of transgenic mice. By using these tools in the awake, behaving primate, two specific aims and one broader objective will be achieved. The first aim is to test the hypothesis that the projections from visual cortex to the superior colliculus facilitate express saccades. The second aim is to test the hypothesis that electrical activity between two usually disconnected compartments in the superior colliculus become transiently connected during express saccades. The larger objective is to catalyze progress in systems neurophysiology by refining optogenetic tools for use in the awake, behaving monkey. Widespread adoption and refinement of these techniques by the primate neurophysiology community will help to reveal how signal transmission between brain areas mediates behavior. Such an understanding will be important for the diagnosis and treatment of neurological and psychiatric diseases, whose etiology may involve aberrant communication between brain areas.

Project Summary The development of trans-synaptic viral tracers is an important component of the BRAIN Initiative. At present, the lack of viral-based anterograde monosynaptic tracing tools with high signal strength and low toxicity is a gap in neuroscience. Herpes simplex virus (HSV) type 1 strain 129 (H129) is the most promising viral tool for anterograde neuronal tracing. However, current versions of genetically modified H129 viruses are limited by high virulence and toxicity, weak label signals that require immunostaining for detection, and time-dependent spread across multiple synapses. There is also a concern of the directional specificity of anterograde propagation of H129 recombinants, as they may propagate retrogradely. Investigators in the field have been working actively to develop improved versions of anterograde viral tracers, but progress has been limited. We have formed a strong interdisciplinary collaborative team composed of virologists and systems neuroscientists to develop anterograde monosynaptic recombinant H129 tracers with high signal strength and little or no toxicity for multi-species neural circuit analysis. Our published work and preliminary data establish the feasibility and key methodologies for the proposed research. We will capitalize on our established bacterial artificial chromosome (BAC) based system for rapid generation of recombinant H129 vectors and precise control of the H129 payload. We have a sound plan to reduce viral toxicity, enhance label signals and generate variants carrying different functional payloads. Our overall goal is to create a new set of safe, effective and validated anterograde-directed viral vectors that allow efficient labeling in monosynaptic projection targets of specific neuron types. These new tools will have a broad impact by enabling optical imaging, physiological recording, and activity manipulation of defined anterograde projection networks. For rapid resource sharing, we will create a service platform through the UCI Center for Virus Research to disseminate the new molecular tools to the neuroscience community.

PROJECT SUMMARY The major objective of this research program is to understand how networks of neurons communicate to produce visual perception. This knowledge will be useful to bioengineers and clinicians in the development of new devices and treatments for patients with perceptual disorders. Understanding how vision works in rhesus monkeys, an animal whose vision is similar to humans', will bring us closer to understanding the physiology of human vision in states of health and disease. The Specific Aims of this study target three different components of how the primary visual cortex (V1) contributes to visual contrast sensitivity. All of the Aims use a similar methodology: a novel, reversible system for neuronal inactivation combined with simultaneous quantitative behavioral measurement. These measurements will reveal how signals are routed through the visual system to control behavior. The first Aim is to determine how much of the baseline noise in V1 contributes to the variability of perceptual reports. This Aim will be achieved by suppressing V1 activity in a monkey trained to report the presentation of a low-contrast visual stimulus. On some trials, no stimulus is shown and the monkey must guess whether one was. A key question is whether suppression of V1 activity prevents the monkey from guessing that a stimulus was presented when none, in fact, was. The second Aim is to determine whether the visual pathways that bypass V1 are sufficient to mediate the monkeys' behavioral reports. We will achieve this Aim by testing the monkeys' ability to detect stimuli designed to activate the neural pathways that bypass V1. If the monkey can see these stimuli when activity in V1 is suppressed, and if the predictions of control experiments are confirmed, we will know that the pathways that bypass V1 can mediate contrast detection. The third Aim is to determine whether aspects of V1 activity other than the feedforward volley are necessary for stimulus detection. We will achieve this Aim by measuring the monkeys' threshold for detecting electrical microstimulation of area V2 when activity in V1 is suppressed. Together, completion of these Aims will answer important and outstanding questions about the role of area V1 in stimulus detection. These questions cannot be adequately addressed with classical techniques, and the inactivation technique that we will use to complete these Aims is an important technical contribution of the proposed work.

Project Summary/Abstract The goal of this proposal is to develop a high-fidelity adaptive electrical interface to the retina and use it to investigate the contributions of the parallel visual pathways (M and P, ON and OFF) to the perception and behavior of macaque monkeys. The device will operate bi-directionally at the resolution of single cells and single spikes, and will adapt itself to the diversity of cell types and locations in the host neural circuitry. We build on our extensive work in isolated primate retina, which demonstrates the ability to electrically stimulate and record nearly complete populations of retinal ganglion cells at single-cell, single-spike resolution. We will develop the technologies needed to take this approach to the in vivo setting, and then use them to probe visual function in behaving macaques, by pursuing three aims: (1) develop and test a high-density, large-scale electrical recording and stimulation device, (2) develop surgical techniques, test biocompatibility, and test functionality in anesthetized animals, and (3) probe the computations within and between the M and P pathways and their role in motion vision. Our unique approach to these problems relies on a team with extensive experience in neurophysiology, visual behavior, integrated circuits, materials science, surgery, and signal processing. In addition to testing fundamental aspects of visual function in novel ways, this work will produce a platform technology for other neural interfaces and a functional prototype for a future retinal implant to treat incurable blindness.