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出现奖励计时活动。因此，初级视觉皮层的神经活动不仅仅是对视觉线索的再现，而是与对其行为意义的处理有关。这些发现对理解我们的大脑如何将感官体验灌输给行为意义具有重要意义，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适应性行为形成过程中感官系统和奖励系统之间的相互作用。初级视觉皮层中奖励计时活动的特性表明它是局部产生的。如果是这样，V1对动物获得奖励是知情的。由于具有调节V1可塑性的理想属性，胆碱能系统是最有可能传递这种奖励信号的系统。因此，本研究旨在验证这样一种假设，即奖励计时活动是在视觉皮层内通过表示奖励的胆碱能输入和表示预测奖励的刺激的丘脑输入的相互作用产生的。为了解决这个问题，我们提出的研究计划包括多位点细胞外记录，并结合以下方法：1)通过在体内新应用光解释放的乙酰胆碱激动剂来模拟胆碱能系统在奖励时间形成中的作用，2)局部药物阻断以确定乙酰胆碱对视觉皮层奖励时间形成的影响，以及3)劫持V1内的胆碱能轴突终端。为了证明他们的活动和习得奖励时间的出现之间的因果关系。模仿、阻断和劫持胆碱能系统对V1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，用于剖析基于奖励的学习机制。从这些实验中获得的见解将告诉我们大脑奖励系统在塑造感觉系统方面的作用，这方面我们知之甚少，但它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疾病的理解。尽管假设神经调节“奖励”系统将行为结果与之前的神经活动联系起来，但大脑将行为意义归因于环境刺激的机制尚不清楚。在这里，我测试了这样一个假设，即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层中行为意义的学习。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以及因疾病和衰老引起的认知障碍的神经机制的理解。

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.