Visual cortex circuits mediating arousal and visual discrimination

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Project Summary: Arousal state transitions are evoked by unexpected or aversive stimuli that change the context of the environment. These transitions prime the brain to be more alert to sensory input and optimize sensory processing for goal-directed behavior. VIP neurons disinhibit excitatory neurons and are known to alter excitatory sensory processing in response to top-down or neuromodulatory input. VIP neurons activate in response to contextual changes and their activity increases during periods of increased arousal. However, it is unclear how changes in arousal lead to VIP activation, or indeed if VIP neurons modulate sensory processing in an arousal-state-dependent manner. Arousal state is controlled by norepinephrine (NE) release from the locus coeruleus (LC), which fires in response to contextual change and projects to the cortex. LC-NE signaling is a putative mediator of VIP activation following arousal state transitions, but this mechanism has never been experimentally addressed. In this proposal, I will use the visual cortex as a model to test the hypothesis that arousal state transitions modify cortical sensory processing through LC-NE mediated VIP activation to optimize context-dependent goal-directed behavior. Excitatory neurons in the visual cortex become more selective and reliable during increased arousal states. In Aim 1, I will examine the role of VIP neurons in mediating these and other changes in visual processing by using dual-wavelength two-photon calcium imaging to simultaneously record excitatory and VIP neurons during different arousal states. I will then use optotagging to examine the temporal pattern of VIP activity as it relates to changes in visual processing. I will then test if VIP-driven changes in visual processing mirror the effects of arousal states on visual processing using optogenetic VIP stimulation. In Aim 2, I will examine the relationship between LC-NE and VIP activity using optotagging, LC axonal imaging, and NE imaging. I will then test if LC- NE stimulation drives VIP activation and alters visual processing using LC axonal optogenetics in V1. In Aim 3, I will relate these findings to goal-directed behavior using a learned visual discrimination task. I will determine if LC axonal and VIP neuronal activity are predictive of discrimination accuracy and improved excitatory encoding. Finally, I will optogenetically activate or inhibit VIP neurons during the task to directly measure their contribution to arousal-driven changes in discrimination accuracy. The Sur research group at MIT is an ideal environment to pursue the research outlined in this proposal and to receive training that will prepare me for a career as an independent investigator. I will have the opportunity to master technologies pioneered in the Sur research group, including next-generation dual-wavelength two-photon imaging, optotagging, quantitative analyses of behavior and its neuronal correlates, optogenetic manipulations, and computational analysis of neuronal populations to examine changes in sensory processing and encoding. Taken together, the research project, training plan, and research environment create a path to future independence well suited to my career goals.