The neuronal mechanism of reward timing in the primary visual cortex

描述(申请人提供)：在最近发表的研究结果中，我提供了证据，证明将视觉刺激与随后的奖励配对会导致初级视觉皮质出现奖励计时活动。因此，初级视觉皮质中的神经活动不是简单地再现视觉线索，而是与其行为意义的处理有关。这些发现有助于理解我们的大脑如何赋予感觉体验以行为意义，并构成我长期职业目标的基础：在一所领先的研究型大学研究感觉和奖励系统之间的相互作用，以形成适应行为。初级视觉皮质中这种奖励计时活动的特性表明，它是在局部产生的。如果是这样的话，V1就参与了动物获得奖励的过程。胆碱能系统具有调节V1可塑性的理想属性，是最有可能传递这种奖励信号的系统。因此，本研究旨在验证这一假说，即在视觉皮质内，通过代表奖赏的胆碱能输入和代表预测奖赏的刺激的丘脑输入的相互作用，产生奖赏计时活动。为了解决这个问题，建议的研究计划包括：多点细胞外记录和1)通过在体内应用光解未拆分的乙酰胆碱激动剂来模拟胆碱能系统在奖赏计时形成中的作用，2)局部药物阻断以确定乙酰胆碱对视觉皮质奖赏计时形成的影响，以及3)劫持V1内的胆碱能轴突终末，以证明它们的活动与习得奖赏计时的出现之间的因果关系。模拟、阻断和劫持胆碱能系统对V1中出现的奖赏计时活动的影响将与正常大鼠的结果进行比较。如果这一假设是正确的，初级视觉皮质可能是剖析基于奖励的学习机制的一个强大的模型系统。从这些实验中获得的洞察力将有助于了解大脑奖励系统在塑造感觉系统方面的作用，目前人们对此知之甚少，但这些作用直接影响了我们对阿尔茨海默氏症、精神分裂症和药物滥用等人类病理的理解。公共健康相关性大脑将行为意义归因于环境刺激的机制尚不清楚，尽管人们假设神经调节“奖励”系统将行为的结果与之前的神经活动联系起来。在这里，我测试了这样一个假设，即其中一个这样的系统通过模仿、阻断和劫持大脑的胆碱能神经调节系统来调节初级视觉皮质的行为意义的学习。这项研究的成功将为强化学习理论建立实验证据，进一步加深我们对学习和记忆的神经机制以及疾病和衰老造成的认知障碍的理解。

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.