Epigenetic Regulation Of Striatal Circuit Function For Action And Habit Learning

项目摘要 越来越多的证据表明，成瘾和其他行为控制疾病是由 不良习惯事实上，对习惯的过度依赖与强迫性表型有关， 被诊断为成瘾和酗酒的患者，以及合并症，包括强迫症 精神障碍和精神分裂症。成瘾物质和压力被认为会劫持大脑系统， 通常支持习惯学习，导致习惯形成更快，比正常情况下更强烈地影响行为。 这导致了对后果不敏感的行为，即使这些后果是负面的。 我们的最终目标是揭示表观遗传-基因组-生理-功能管道， 暴露于成瘾物质，以促进这些适应不良的习惯。为了实现这一目标，我们的具体目标是 是揭示多层次的生物结构所需的机械理解的适应性和 不良习惯因此，这项工作将提供洞察病理状态如何产生和可以做什么 来对抗他们 长期以来，人们都知道纹状体在习惯学习中起作用。缺乏信息的地方是， 纹状体投射通路，基底神经节输出核的直接和间接投射， 它们的功能可能不同，这取决于解剖学和功能上不同的内侧和外侧纹状体 细分。我们将使用多方面和综合的方法来揭示生理和分子 在目标导向和习惯学习过程中每个纹状体子回路发生的变化。我们的初步 研究表明，一种主要的表观遗传阻遏物HDAC 3在纹状体中起负调控作用， 习惯形成的调节器。我们的假设是背侧纹状体HDAC 3作为一个分子门， 习惯，参与关键神经元活动基因的启动子，以减缓向习惯的转变， 当习惯占主导地位的条件成熟时，就把它去掉。因此，长期的压力和接触成瘾 物质可能会打开这扇门，创造一个表观遗传景观，使未来的行为策略偏向于 习惯，即使是这样，也不是适应性的，产生了许多精神疾病的强迫性。我们提出的 研究开始通过研究允许HDAC 3 规范习惯。这将使未来的调查如何中断这些机制促进 适应不良的行为

PROJECT SUMMARY Growing evidence suggests addiction and other diseases of behavioral control result from the development of maladaptive habits. Indeed, an overreliance on habit is associated with the compulsive phenotype found in patients diagnosed with addiction and alcoholism, and comorbid conditions including obsessive-compulsive disorder and schizophrenia. Addictive substances and stress are thought to hijack the brain systems that normally support habit learning, causing habits to form faster and more strongly influence behavior than normal. This results in behavior that is insensitive to its consequences, even when those consequences are negative. Our ultimate goal is to expose the epigenetic-genomic-physiological-functional conduit that allows stress and exposure to addictive substances to promote these maladaptive habits. To achieve this, our specific goal here is to expose the multi-layered biological architecture required for mechanistic understanding of adaptive and maladaptive habits. Thus, this work will provide insight into how pathological states arise and what can be done to combat them. The striatum has long been known to function in habit learning. Where information is lacking is on how each striatal projection pathway, the direct- and indirect-projections to basal ganglia output nuclei, contribute and how their function might differ depending on the anatomically and functionally distinct medial and lateral striatal subdivisions. We will use a multi-faceted and integrative approach to expose the physiological and molecular changes that occur in each striatal subcircuit during goal-directed and habit learning. Our preliminary investigations have indicated that one major epigenetic repressor, HDAC3, functions in the striatum as a negative regulator of habit formation. Our hypothesis is that dorsal striatal HDAC3 functions as a molecular gate over habit, being engaged at the promoters of key neuronal activity genes to slow the transition to habit and being removed when conditions are ripe for habits to dominate. Thus, chronic stress and exposure to addictive substances might open this gate, creating an epigenetic landscape that biases future behavioral strategy towards habit, even with this is not adaptive, producing the compulsivity that marks many mental illnesses. Our proposed research begins to test this by investigating the molecular and cellular mechanisms that allows HDAC3 to regulate habit. This will enable future investigations into how disruptions in these mechanisms promote maladaptive behavior.