The neuronal mechanism of reward timing in the primary visual cortex

初级视觉皮层奖励计时的神经机制

• 批准号: 8204486
• 负责人: Marshall Gilmer Shuler
• 金额: $ 40.59万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-23 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204486
• 关键词: Acetylcholine; Adaptive Behaviors; Address; Aging; Agonist; Alzheimer' s Disease; Animals; Association Learning; Behavior; Behavioral; Biological Models; Brain; Cell Nucleus; Cholinergic Agonists; Cues; Disease; Drug abuse; Etiology; Goals; Human Pathology; Impaired cognition; Impairment; Infection; Learning; Mediating; Memory; Neurons; Outcome; Photic Stimulation; Process; Property; Psychological reinforcement; Publishing; Rattus; Research; Rewards; Role; Schizophrenia; Sensory; Shapes; Signal Transduction; Site; Stimulus; Synapses; System; Testing; Thalamic structure; Time; Universities; Visual; Visual Cortex; Water; area striata; awake; base; career; cholinergic; experience; extracellular; in vivo; insight; neuromechanism; neurotensin mimic 1; novel; photoactivation; programs; relating to nervous system; research study; response; sensory cortex; sensory system; success; theories; visual stimulus

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. 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.

在最近发表的发现中，我提供了证据表明将视觉刺激与 随后的奖励会导致主要视觉奖励活动的出现 皮质。因此，初级视觉皮层中的神经活动不仅是一种 视觉提示的呈现，而是将其行为的处理联系起来 意义。这些发现对了解我们的大脑如何浸润具有影响 具有行为意义的感官体验，并构成了我的长期基础 职业目标：在一所领先的研究大学中调查 自适应行为形成的感觉和奖励系统。 在主要视觉皮层中，此奖励计时活动的特性表明 它是在本地生成的。如果是这样，V1不愿意从动物那里获得奖励。 具有介导V1中可塑性的理想属性，胆碱能系统最多 可能传达这样的奖励信号的系统。因此，拟议的研究是 致力于测试奖励定时活动的假设 视觉皮层通过胆碱能输入的相互作用表示奖励和丘脑输入 表示预测奖励的刺激。 为了解决这个问题，提出的研究计划由多站点组成 细胞外记录与1）模仿胆碱能系统的作用 通过新颖的光解未散布的新应用形成奖励时间 体内乙酰胆碱激动剂，2）局部药理阻滞以建立影响 乙酰胆碱在视觉皮层中形成奖励时机的形成和3）劫持 V1内的胆碱能轴突末端，以证明其因果关系 活动和学习的奖励时机的出现。 模仿，阻塞和劫持胆碱能系统的后果 将V1中的奖励计时活动的出现与出现 在正常大鼠中。如果假设正确，则主要视觉皮层可能是强大的 用于解剖基于奖励的学习机制的模型系统。洞察力获得了 从这些实验中，将告知大脑奖励系统在塑造的角色 感觉系统几乎没有知名度，但直接影响了我们的 了解人类病理，例如阿尔茨海默氏症，精神分裂症和药物 虐待。大脑将行为含义的机制归因于 环境刺激是未知的，尽管假设神经调节性 “奖励”系统将行为的结果与先前的神经活动联系起来。 在这里，我检验了这样一个系统介导行为学习的假设 通过模仿，封锁和劫持大脑的含义在主要视觉皮层中 胆碱能神经调节系统。这项研究的成功将建立 强化学习理论的实验证据，进一步发展 了解学习和记忆的神经机制以及认知的理解 疾病和衰老引起的损害。