Jianhua Cang - US grants

DESCRIPTION (provided by applicant): Retinotopic representation of visual space is a general feature of mammalian visual cortex. Experiments in this proposal will study whether the retinotopic map is required for the physiological processing of sensory information. Specifically, the proposed work will study the consequences that genetically disrupted retinotopic maps have for receptive field properties, cortical circuits and visual behaviors. Several lines of mutant mice that display mapping errors in their visual cortex will be used, including the mice deficient in the molecular guidance cues ephrin-As, the mice that have disrupted patterns of spontaneous activity in the developing retina, and the mice in which these two disruptive interventions are combined. In addition, retinotopic maps will also be disrupted in wild type mice by misexpressing ephrin-As in the developing visual cortex. Using these mice, the investigators will first determine whether cortical receptive fields are abnormal when retinotopic maps are disrupted. Single-unit recordings will be performed to measure the size, orientation selectivity and spatial tuning of individual cortical neurons. By comparing the receptive field properties of mice that have different degrees of mapping errors, the contribution of topographic maps in shaping receptive fields in the visual cortex will be determined. Second, intracellular whole cell recording will be performed in the intact brain to study the pattern of intracortical synaptic inhibition in the absence of a precise retinotopic map. Finally, using a swimming test of visual discrimination and a test of optomotor response, the investigators will determine whether disruption of retinotopic maps affects visual behaviors. Together, these studies will elucidate the role of retinotopic maps in visual processing and will also help define how precise patterns of synaptic connections contribute to the normal behavioral output of the nervous system in general. Importantly, these experiments will reveal how mis-wired visual systems function at cellular, circuit and behavioral levels. Such knowledge will be useful for the understanding and treatment of disorders resulting from brain injury and from aberrant neuronal connections.

DESCRIPTION (provided by applicant): Optimal functioning of the nervous system requires selective wiring of neural circuits, the precision of which is achieved through experience-dependent refinement after birth. A classical model system of the experience-dependent development is the ocular dominance plasticity in the visual system, where monocular eyelid closure in a critical period of early life leads to a shift of cortical responses towards the non-deprived eye. Despite decades of work, it is still unknown what purpose the critical period serves during normal development, when the inputs from the two eyes are intact. In this grant, the proposed work aims to determine what cortical function is shaped by normal vision-induced plasticity during the critical period and to reveal its underlying molecular and synaptic mechanisms. First, the investigators will test whether the critical period plasticity drives the matching of binocular orientation preference during normal development. Both single unit recording and two-photon calcium imaging will be performed in the mouse visual cortex to determine the time course of binocular matching of orientation preference and its requirement of normal visual experience in the critical period. Second, with genetically or pharmacologically altered level of inhibition, which is known to shift the timing of the critical period of ocular dominance plasticity, the investigators will determine whether intracortical inhibition controls the timing of binocular matching by regulating the maturation of orientation selectivity. Intracellular whole cell recording will also be performed in vivo to reveal the spatiotemporal patterns of synaptic inhibition in mediating the binocular matching of orientation preference and in regulating the critical period timing. Finally, the receptive field structure of individual cortical neurons will be studied separately to the two eyes at different developmental stages to reveal how receptive fields change monocularly during the critical period to mediate binocular matching of orientation preference. Pharmacological experiments will also be carried out to determine if cortical activity and NMDA receptor activation are required for the binocular matching process. Together, these studies will reveal a physiological role for the critical period in normal development. Because ocular dominance plasticity and its critical period is a model system for human amblyopia and strabismus, a full understanding of cortical changes that normally take place during development will have important implications for the understanding and treatment of these diseases.

Project Summary/Abstract The mammalian superior colliculus (SC) is a subcortical structure that integrates visual and other sensory information to initiate orienting movements of the eyes and head. A fundamental feature of SC organization is that the representations of sensory inputs and motor outputs are topographically arranged and aligned. While great progress has been made in understanding the development of the visual representation in the SC, how the motor maps are formed and aligned with the visual map remains unknown. In order to take advantage of the available genetic tools in mice, the investigators propose to perform a comprehensive investigation of the organization and development of motor maps in the mouse SC. First, electrical microstimulation will be conducted in the deep layers of the SC to evoke saccade-like rapid eye movements in mice. The topographic organization of the eye movement map will be revealed by systematically varying the stimulation sites in the SC and determining the amplitude and direction of the evoked movements. Single-unit recording will also be performed in the deep layers to determine how individual neurons encode eye movement direction and amplitude, and how such movement fields are mapped in the mouse SC. Second, the same experiments will be performed in mice deprived of visual experience from birth and in an existing transgenic mouse line that have altered visual maps in the SC. These experiments will determine whether visual inputs provide an instructive signal for motor map development and visuomotor alignment. Together, the proposed experiments will provide the first systematic mapping of the deep layers of the mouse SC and initiate studies on factors influencing sensorimotor development. These studies will have important implications for the understanding and potential treatment of human eye movement disorders and other diseases that result from miswiring of neuronal connections. 6

DESCRIPTION (provided by applicant): The mammalian superior colliculus (SC) is a subcortical structure that integrates visual and other sensory information to initiate orienting movements of the eyes and head. A fundamental feature of SC organization is that the representations of sensory inputs and motor outputs are topographically arranged and aligned. While great progress has been made in understanding the development of the visual representation in the SC, how the motor maps are formed and aligned with the visual map remains unknown. In order to take advantage of the available genetic tools in mice, the investigators propose to perform a comprehensive investigation of the organization and development of motor maps in the mouse SC. First, electrical microstimulation will be conducted in the deep layers of the SC to evoke saccade-like rapid eye movements in mice. The topographic organization of the eye movement map will be revealed by systematically varying the stimulation sites in the SC and determining the amplitude and direction of the evoked movements. Single-unit recording will also be performed in the deep layers to determine how individual neurons encode eye movement direction and amplitude, and how such movement fields are mapped in the mouse SC. Second, the same experiments will be performed in mice deprived of visual experience from birth and in an existing transgenic mouse line that have altered visual maps in the SC. These experiments will determine whether visual inputs provide an instructive signal for motor map development and visuomotor alignment. Together, the proposed experiments will provide the first systematic mapping of the deep layers of the mouse SC and initiate studies on factors influencing sensorimotor development. These studies will have important implications for the understanding and potential treatment of human eye movement disorders and other diseases that result from miswiring of neuronal connections. 6

? DESCRIPTION (provided by applicant): How visual information is processed and transformed in the nervous system is a fundamental question in vision research. Given its clear importance in visually-guided behaviors and the available genetic tools, the mouse superior colliculus (SC) holds great promise for understanding visual signal transformation and its mechanisms. The SC is a layered structure important for multimodal integration and sensorimotor transformation, and its superficial layers are purely visual and receive direct retinotopic inputs from the retina. In his proposal, the investigators will study the brain circuitry and synaptic mechanisms underlying the important transformations that take place in the retinocollicular pathway, especially the processing of motion direction. First, 2-photon calcium imaging will be performed to determine the direction selectivity of individual SC neurons and their spatial organization. These experiments will establish whether there is a depth-, region-, and/or cell type-specific organization of direction selectivity in the superficial SC, thereby forming a foundation for the following aims. Second, the investigators will determine the response properties of the retinal input that project to the SC. Genetically-encoded calcium indicators will be expressed in retinal ganglion cells and 2- photon imaging will be performed to visualize their axonal terminals in the colliculus. Third, the methods of imaging retinal terminals and collicular neurons will be used in a line of transgenic mice where retinocollicular projections are spatially altered, in order to determine whether direction selective retinal input is required for the direction selectivity in th SC. Finally, the investigator will perform in vivo whole cell recording to study visually-evoked responses in the SC. These experiments will be performed in transgenic mice where excitatory SC neurons can be silenced by optogenetic stimulation, thereby exposing the retinal input to the recorded cells. By comparing the selectivity of the total and retinal input to individual SC neurons, these experiments will start to reveal the synaptic mechanisms underlying the processing and transformation of direction selectivity in the retinocollicular pathway. Together, these experiments will generate important data needed for a complete understanding of visual processing in the brain. Because normal visual processing is compromised in a number of neurological and psychiatric disorders, such as dyslexia, schizophrenia and autism spectrum disorders, these studies will provide insights for the understanding and treatment of these disorders.

Project Summary/Abstract How visual information is processed and transformed in the nervous system is a fundamental question in vision research. Given its clear importance in visually-guided behaviors and the available genetic tools, the mouse superior colliculus (SC) holds great promise for understanding visual processing and its neural mechanisms. The SC is a midbrain structure important for multimodal integration and sensorimotor transformation. Its superficial layers are purely visual and receive direct inputs from the retina. In this proposal, the investigators will study motion processing in a visual layer of the SC, the SGS, with a particular focus on its modulation by stimulus context, locomotion state, and self-generated visual flow. First, in vivo whole cell recording will be performed to determine the synaptic inputs that individual SGS neurons receive from the region surrounding their receptive fields. These experiments will reveal the local connectivity of excitatory and inhibitory neurons that mediates the bidirectional encoding of motion contrast between the visual stimulus and its context. Second, two-photon calcium imaging will be performed in awake mice to determine whether and how locomotion affects visual responses in the SGS. These experiments will be done across the depth of the SGS and in a cell- type-specific manner. Finally, the investigators will study whether and how self-generated visual flow affects the responses of SGS neurons. Two-photon imaging and physiological recording will be performed in head- restrained mice running in a virtual reality system. These experiments will be conducted across different retinotopic locations in the SGS, in order to reveal whether a region-specific organization exists in the SGS in the context of encoding self-generated motion. Together, these experiments will generate important data needed for a complete understanding of visual processing in the brain. Because normal visual processing is compromised in a number of neurological and psychiatric disorders, such as dyslexia, schizophrenia, and autism spectrum disorders, these studies will provide novel insights for the understanding and treatment of these disorders.

ABSTRACT Perceptual decision-making is a fundamental cognitive ability that is vital to healthy, daily functioning and is impaired in many diseases. Although many brain regions are known to be involved, there is no clear brain-wide model of how perceptual decisions are formed and executed and the underlying circuit mechanisms are still largely unknown. Here, a team of investigators propose a series of experiments that will use behavioral measures, imaging, physiology, circuit dissection, and computational modeling to study how the midbrain superior colliculus (SC) participates in visual decision-making. Specifically, this new team of investigators will probe the contribution of two SC neuronal cell types, wide field vertical (WFV) cells in the visuosensory layers and predorsal bundle (PDB) cells in the motor layers. These experiments will be done in mice and tree shrews, to reveal the underlying circuits and computational principles across species and to lay the foundation for future experiments designed to dissect decision-making circuits in primates. In Aim 1, the investigators will establish and perform psychophysical experiments to assess perceptual decision-making in both species. The behavioral data will be fitted with computational models to arbitrate between different theories of decision-making. In Aim 2, two photon calcium imaging and/or physiological recording will be performed in mice and tree shrews to determine the activity of WFV and PDB neurons during the psychophysical measures established in Aim 1. In addition, WFV and PDB neurons will be silenced optogenetically during the behavioral tasks to reveal their specific roles in decision-making. In Aim 3, the investigators will use intersectional monosynaptic viral tracing techniques, multiplexed peroxidase labeling for confocal and ultrastructural analysis of synaptic connections and and optogenetics-assisted brain slice recording to investigate the intrinsic and extrinsic circuits that link WFV and PDB cells. Together, these experiments will generate novel knowledge of the synapse to circuit mechanisms underlying perceptual decision-making, and provide technical and theoretical foundations for future mechanistic studies of cognitive function in higher mammalian species directly relevant to humans.