Epigenetic Regulation Of Striatal Circuit Function For Action And Habit Learning

纹状体回路功能的表观遗传调节用于行动和习惯学习

• 批准号: 10343666
• 负责人: Kate M Wassum
• 金额: $ 54.6万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10343666
• 关键词: Alcoholism; Anatomy; Architecture; Attenuated; Basal Ganglia; Behavior; Behavior Control; Behavioral; Biological; Brain; Cell Nucleus; Cells; Chronic stress; Cognitive; Compulsive Behavior; Corpus striatum structure; Couples; DNA; Data; Decision Making; Development; Diagnosis; Disease; Dorsal; Electrophysiology (science); Epigenetic Process; Equilibrium; Evaluation; Exposure to; Forms Controls; Functional disorder; Future; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genomics; Goals; HDAC3 gene; Habits; Investigation; Knowledge; Lateral; Learning; Medial; Mental disorders; Modification; Molecular; Motor output; Neurons; Obsessive-Compulsive Disorder; Operant Conditioning; Output; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Procedures; Process; Psychological reinforcement; Regulation; Research; Rewards; RiboTag; Schizophrenia; Specificity; Stress; Symptoms; Synapses; System; Testing; Transcription Repressor; Work; addiction; behavior influence; cell type; combat; comorbidity; conditioning; epigenetic regulation; gene function; habit learning; innovation; insight; maladaptive behavior; nervous system disorder; neural circuit; optogenetics; patch clamp; promoter; prospective; relating to nervous system; transcriptome; transcriptome sequencing

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.

项目总结 越来越多的证据表明，成瘾和其他行为控制疾病是由于 不适应的习惯。事实上，对习惯的过度依赖与强迫症表型有关。 被诊断为成瘾和酗酒，以及包括强迫症在内的共病的患者 精神障碍和精神分裂症。成瘾物质和压力被认为劫持了大脑系统， 正常情况下支持习惯学习，导致习惯形成得比正常更快，对行为的影响也更大。 这导致了对其后果不敏感的行为，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，允许压力和 暴露在令人上瘾的物质中以促进这些不适应的习惯。为了实现这一点，我们在这里的具体目标 揭示了机械地理解自适应和 不适应的习惯。因此，这项工作将深入了解病理状态是如何产生的，以及可以做些什么 来对抗他们。 众所周知，纹状体在习惯学习中起着重要作用。缺乏信息的地方是关于每个人 纹状体投射通路，直接和间接投射到基底节输出核团，贡献和如何 它们的功能可能因内侧纹状体和外侧纹状体的解剖和功能不同而不同。 细分。我们将用多方面和综合的方法来揭示生理和分子方面的 在目标导向和习惯学习过程中，每个纹状体亚回路中发生的变化。我们的预赛 研究表明，一个主要的表观遗传抑制因子，HDAC3，在纹状体中起负性作用 习惯养成的调节器。我们的假设是背侧纹状体HDAC3起着分子门的作用 习惯，参与关键神经活动基因的启动子，以减缓向习惯和存在的转变 当习惯占据主导地位的条件成熟时，就会被移除。因此，长期的压力和暴露会使人上瘾 物质可能会打开这扇门，创造一种表观遗传格局，使未来的行为战略偏向于 习惯，即使这样，也是不适应的，产生了标志着许多精神疾病的强迫症。我们的建议 研究开始通过研究HDAC3的分子和细胞机制来测试这一点 规范习惯。这将使未来能够调查这些机制的中断是如何促进 适应不良的行为。