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.

在最近发表的研究结果中，我提供了将视觉刺激与 随后的奖赏导致初级视觉中出现奖赏-计时活动 大脑皮层。因此，初级视皮层的神经活动不是简单的反应。 视觉提示的呈现，但更多地涉及对其行为的处理 意义。这些发现对理解我们的大脑如何灌输 具有行为意义的感官体验，并构成我长期的基础 职业目标：在一所领先的研究型大学研究 感觉和奖赏系统在适应行为形成中的作用。 初级视觉皮质中这种奖赏计时活动的特性表明 它是在当地产生的。如果是这样的话，V1就参与了动物获得奖励的过程。 在V1中，胆碱能系统是调节可塑性的理想属性 可能的系统来传递这样的奖励信号。因此，拟议的研究是 旨在测试奖励计时活动是在 表示奖赏的胆碱能输入与丘脑输入相互作用的视觉皮质 表示预测奖赏的刺激。 为了解决这一问题，提出的研究计划由多个站点组成 结合1)模拟胆碱能系统的活动的细胞外记录 在通过光解未老化的新应用形成奖励计时中 体内乙酰胆碱激动剂，2)局部药理阻断建立影响 乙酰胆碱对视觉皮层奖赏计时形成的影响以及3)劫持 V1内的胆碱能轴突终末，以证明它们之间的因果关系 活跃性和习得性奖励时机的出现。 模仿、阻断和劫持胆碱能系统的后果 关于V1中出现的奖励计时活动将与出现的活动进行比较 在正常大鼠身上。如果假设是正确的，初级视觉皮质可能是一个强大的 基于奖励的学习机制剖析模型系统。获得的洞察力 这些实验将揭示大脑奖励系统在塑造 感官系统，其中知之甚少，但直接影响我们的 了解人类的病理，如阿尔茨海默氏症、精神分裂症和药物 虐待。大脑将行为意义归因于 环境刺激是未知的，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，即一个这样的系统中介了行为学习 通过模仿、阻断和劫持大脑的 胆碱能神经调节系统。这项研究的成功将确立 强化学习理论的实验证据，进一步推动了我们的 对学习记忆和认知的神经机制的理解 因疾病和衰老造成的损害。