Modulatory control of basal ganglia microcircuitry in cognitive flexibility and psychiatric disease

基底神经节微电路在认知灵活性和精神疾病中的调节控制

• 批准号: 9163529
• 负责人: Scott Owen
• 金额: $ 12.79万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9163529
• 关键词: Acetylcholine; Address; Affect; Amygdaloid structure; Autistic Disorder; Award; Basal Ganglia; Behavior; Behavior Control; Behavioral Assay; Brain region; Chronic; Cognitive; Conflict (Psychology); Corpus striatum structure; Data; Decision Making; Defect; Disease; Disease Outcome; Dissection; Dystonia; Electrophysiology (science); Experimental Designs; Foundations; Functional disorder; Funding; Gilles de la Tourette syndrome; Goals; Hippocampus (Brain); Individual; Interneuron function; Interneurons; Lead; Learning; Link; Measures; Mediating; Mental disorders; Motor; Movement Disorders; Muscarinic Acetylcholine Receptor; Neurons; Obsessive-Compulsive Disorder; Outcome; Output; Performance; Physiological; Physiology; Prefrontal Cortex; Psychiatrist; Receptor Signaling; Research; Reversal Learning; Rodent; Running; Signal Pathway; Signal Transduction; Site; Slice; Structure; Synapses; Task Performances; Testing; Thalamic structure; Time; Ventral Striatum; Work; cell type; cholinergic; cognitive testing; designer receptors exclusively activated by designer drugs; feeding; flexibility; improved; in vivo; insight; nervous system disorder; neuropsychiatric disorder; neuroregulation; novel; optogenetics; programs; receptor; research study; response; sequence learning; skills

ABSTRACT The striatum is the primary input structure of the basal ganglia. While the striatum has been associated with many neuropsychiatric and neurological disorders, the circuit mechanisms underlying these disorders are largely unknown. Several of these disorders, including obsessive-compulsive disorder (OCD), Tourette's syndrome, and dystonia, have been linked to defects in fast-spiking interneurons (FSIs), a class of GABAeric interneurons in the striatum. My preliminary data established a connection between striatal FSIs, feed-forward inhibitory microcircuits, and motor-sequence learning that is relevant to movement disorders. Through the proposed research, I will investigate the mechanisms by which the striatal inhibitory microcircuitry contributes to neuropsychiatric disease and cognitive flexibility. Ragozzino and colleagues have shown that acetylcholine levels in the striatum are elevated during reversal learning tests of cognitive flexibility, a basal ganglia-related form of learning that is impaired in neuropsychiatric disorders. They also showed that task performance relies on muscarinic acetylcholine receptor (mAChR) signaling in the striatum. My preliminary results show that striatal mAChR signaling predominantly suppresses FSI-mediated feed-forward inhibition, supporting the idea that modulation of FSIs is critical for task performance. Indeed, striatal FSIs are active when rodents make choices, especially in decision-making under conflict, and are therefore likely involved in cognitive flexibility. Thus, I will combine slice physiology, behavior, and in vivo recordings to test the hypothesis that activation of mAChRs suppresses FSI-mediated feed-forward inhibition to increase the variability of striatal network responses for reversal learning and cognitive flexibility. With slice physiology, I will investigate the microcircuit, neuromodulatory, and physiological mechanisms linking feed-forward inhibition to variability in network responses. With a novel reversal-learning task that I developed, I will then test the importance of mAChR signaling and striatal FSIs in cognitive flexibility. Then, with optogenetic manipulation and in vivo physiology, I will answer the controversial question of whether FSIs inhibit medium spiny neurons (MSNs) in vivo. I will directly test how this circuit affects the variability of network responses in vivo by manipulating FSIs and cholinergic signaling while recording striatal network activity during reversal learning. These experiments will expand my expertise in behavioral assays of cognitive flexibility and analysis of in vivo physiology data. I have assembled an outstanding Advisory Council that includes world experts in basal ganglia physiology, dissection of inhibitory microcircuitry, and neuromodulation. Two psychiatrists on this team will provide guidance on disease relevance of the experimental design and results. The proposed work will allow me to gain the necessary skills and preliminary data to establish and run a productive independent research program and successfully compete for R01 funding to study striatal microcircuitry in cognitive flexibility and neuropsychiatric disease.

抽象的 纹状体是基底神经节的主要输入结构。纹状体已关联 由于许多神经精神病学和神经系统疾病，这些疾病的基础机制是 在很大程度上未知。其中几种疾病，包括强迫症（OCD），图雷特的疾病 综合征和肌张力障碍已与快速刺激性中间神经元（FSIS）的缺陷联系在一起，该类别是一类Gabaeric 纹状体中的神经元。我的初步数据建立了纹状体FSI之间的联系 与运动障碍有关的抑制微电路和运动序列学习。通过 拟议的研究，我将研究纹状体抑制微环路贡献的机制 神经精神病和认知灵活性。 Ragozzino及其同事表明乙酰胆碱 在认知灵活性的逆转学习测试期间，纹状体中的水平升高，这是基础神经节相关的 在神经精神疾病中受损的学习形式。他们还表明任务绩效依赖 在纹状体中的毒蕈碱乙酰胆碱受体（MACHR）信号上。我的初步结果表明 纹状体MACHR信号主要抑制FSI介导的进料向前抑制，支持该想法 FSI的调节对于任务执行至关重要。确实，啮齿动物使纹状体FSI处于活动状态 选择，尤其是在冲突下的决策中，因此很可能参与认知灵活性。 因此，我将结合切片生理学，行为和体内记录，以检验激活的假设 MACHR抑制FSI介导的前馈抑制以增加纹状体网络的变异性 逆转学习和认知灵活性的响应。通过切片生理，我将研究微电路， 神经调节性和生理机制将馈送抑制与网络变异性联系起来 回答。凭借我开发的新颖的逆转学习任务，我将测试MACHR的重要性 认知灵活性中的信号传导和纹状体FSI。然后，通过光遗传操作和体内生理学，I 将回答有争议的问题，即FSI是否在体内抑制培养基神经元（MSN）。我会 直接测试该电路如何通过操纵FSI和 在逆转学习过程中记录纹状体网络活动时，胆碱能信号传导。这些实验会 扩展我在体内生理数据的认知灵活性和分析的行为测定方面的专业知识。我有 组建了一个杰出的咨询委员会，其中包括基底神经节生理学的世界专家 抑制性微电路和神经调节。该团队中的两名精神科医生将提供有关的指导 实验设计和结果的疾病相关性。拟议的工作将使我获得 必要的技能和初步数据，以建立和运行一项富有成效的独立研究计划和 成功竞争R01资金来研究认知灵活性和神经精神病学的纹状体微环路 疾病。