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

基本信息

批准号：
10553602
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10553602
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 Functional disorder Future Gene Expression Gene Expression Profile Genes Genetic 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 habit learning innovation insight maladaptive behavior nervous system disorder neural neural circuit optogenetics patch clamp promoter prospective transcriptome transcriptome sequencing

项目摘要

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.

项目概要越来越多的证据表明成瘾和其他行为控制疾病是由于适应不良的习惯。事实上，对习惯的过度依赖与以下发现的强迫表型有关：被诊断患有成瘾和酗酒以及合并症（包括强迫症）的患者障碍和精神分裂症。人们认为成瘾物质和压力会劫持大脑系统通常支持习惯学习，使习惯形成得更快，对行为的影响比平时更强烈。这导致行为对其后果不敏感，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-功能通道，它允许压力和接触成瘾物质会促进这些适应不良的习惯。为了实现这一目标，我们的具体目标在这里是为了揭示适应性和适应性的机械理解所需的多层生物结构适应不良的习惯。因此，这项工作将深入了解病理状态如何产生以及可以做什么来对抗他们。人们早就知道纹状体在习惯学习中发挥作用。缺乏的信息是关于每个人如何纹状体投射通路，对基底神经节输出核的直接和间接投射，贡献以及如何它们的功能可能会有所不同，具体取决于解剖学和功能上不同的内侧和外侧纹状体细分。我们将采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蛋白 HDAC3 在纹状体中发挥负调控作用。习惯形成的调节器。我们的假设是背侧纹状体 HDAC3 充当分子门习惯，参与关键神经元活动基因的启动子，以减缓向习惯的转变，并当习惯占主导地位的条件成熟时，就将其移除。因此，长期压力和接触成瘾物质物质可能会打开这扇门，创造一种表观遗传景观，使未来的行为策略偏向于习惯，即使这样也不是适应性的，会产生标志着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 HDAC3 的分子和细胞机制来测试这一点调节习惯。这将使未来能够调查这些机制的破坏如何促进适应不良行为。