The neuronal mechanism of reward timing in the primary visual cortex

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Description (provided by applicant): In recently published findings, I provided evidence that pairing visual stimuli with subsequent reward leads to the emergence of reward-timing activity in the primary visual cortex. Therefore, neural activity in the primary visual cortex is not simply a re- presentation of a visual cue, but rather relates the processing of its behavioral significance. These findings have implications for understanding how our brains imbue sensory experience with behavioral meaning, and forms the basis of my long-term career goal: to investigate, at a leading research university, the interaction between sensory and reward systems in the formation of adaptive behaviors. The properties of this reward timing activity in the primary visual cortex suggest that it is generated locally. If so, V1 is privy to the acquisition of reward by the animal. With attributes ideal for mediating plasticity in V1, the cholinergic system is the most likely system to convey such a reward signal. Therefore, the proposed research is directed towards testing the hypothesis that reward timing activity is generated within the visual cortex by the interaction of cholinergic inputs signifying reward and thalamic inputs signifying the stimuli that predict reward. To address this question, the research program proposed consists of multi-site extracellular recordings combined with 1) mimicking the action of the cholinergic system in the formation of reward timing by a novel application of photolytically uncaged acetylcholine agonist in vivo, 2) local pharmacological blockade to establish the impact of acetylcholine on the formation of reward timing in the visual cortex, and 3) hijacking the cholinergic axonal terminals within V1, to demonstrate causality between their activity and the emergence of learned reward timing. The consequences of mimicking, blocking, and hijacking the cholinergic system on the emergence of reward timing activity in V1 will be compared to that which emerges in normal rats. If the hypothesis is correct, the primary visual cortex could be a powerful model system for dissecting mechanisms of reward-based learning. The insight gained from these experiments will inform upon the role brain reward systems have on shaping sensory systems, of which very little is known, yet which impact directly our understanding of human pathologies such as Alzheimer's, schizophrenia, and drug abuse. PUBLIC HEALTH RELEVANCE The mechanism by which the brain comes to attribute behavioral meaning to environmental stimuli is unknown, though it is hypothesized that neuromodulatory "reward" systems relate the outcome of behavior with preceding neural activity. Here, I test the hypothesis that one such system mediates the learning of behavioral meaning in the primary visual cortex by mimicking, blocking, and hijacking the brain's cholinergic neuromodulatory system. Success in this study would establish experimental evidence for theories of reinforcement learning, furthering our understanding of neural mechanisms of learning and memory and of cognitive impairment due to disease and aging.