The neuronal mechanism of reward timing in the primary visual cortex

描述（由申请人提供）：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层中出现奖励计时活动。因此，初级视皮层的神经活动不仅仅是对视觉线索的再呈现，而是与其行为意义的处理有关。这些发现对于理解我们的大脑如何将行为意义注入感官体验具有重要意义，并形成了我的长期职业目标的基础：在一所领先的研究型大学调查感官和奖励系统之间的相互作用，以形成适应性行为。初级视觉皮层中这种奖励计时活动的特性表明，它是局部产生的。如果是这样的话，V1参与了动物获得奖励的过程。由于V1具有理想的介导可塑性的属性，胆碱能系统是最有可能传达这种奖励信号的系统。因此，建议的研究是针对测试的假设，奖励时间活动产生的视觉皮层内的相互作用的胆碱能输入表示奖励和丘脑输入表示的刺激，预测奖励。为了解决这个问题，提出的研究计划包括多位点细胞外记录，结合1）通过体内光解未包裹的乙酰胆碱激动剂的新应用来模拟胆碱能系统在奖励时间形成中的作用，2）局部药理学阻断以确定乙酰胆碱对视觉皮层中奖励时间形成的影响，3）劫持V1区的胆碱能轴突终末，以证明它们的活动与习得性奖赏时间出现之间的因果关系。模仿，阻断和劫持胆碱能系统的奖励计时活动的出现在V1的后果将被比较，出现在正常大鼠。如果这个假设是正确的，初级视觉皮层可能是一个强大的模型系统解剖奖励为基础的学习机制。从这些实验中获得的洞察力将告知大脑奖励系统在塑造感觉系统方面的作用，其中知之甚少，但直接影响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学的理解。公共卫生相关性大脑将行为意义归因于环境刺激的机制尚不清楚，尽管有人假设神经调节“奖赏”系统将行为的结果与先前的神经活动联系起来。在这里，我测试的假设，一个这样的系统介导的学习行为的意义在初级视觉皮层模仿，阻断和劫持大脑的胆碱能神经调节系统。这项研究的成功将为强化学习理论建立实验证据，促进我们对学习和记忆的神经机制以及疾病和衰老引起的认知障碍的理解。

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.