Genetic Dissection of Cerebellar Circuitry in Cognitive and Affective Behavior

小脑回路在认知和情感行为中的基因解剖

• 批准号: 8749902
• 负责人: Erik Sean Carlson
• 金额: $ 17.91万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8749902
• 关键词: Address; Affect; Affective; Amygdaloid structure; Attention; Behavior; Behavioral; Calcium; Cell Nucleus; Cells; Cerebellar Diseases; Cerebellar Nuclei; Cerebellum; Clinical Markers; Clozapine; Cognition; Cognitive; Corpus striatum structure; Coupled; Dentate nucleus; Designer Drugs; Disease; Dissection; Dopamine; Dopamine D1 Receptor; Dose; Electrophysiology (science); Fright; Functional disorder; Future; GTP-Binding Proteins; Genetic; Goals; Grant; Hippocampus (Brain); Human; Image; Immunohistochemistry; Investigation; Language; Limbic System; Measures; Mental Depression; Mental disorders; Midbrain structure; Molecular; Monitor; Mus; Mutation; National Institute of Mental Health; Neurons; Neurotransmitters; Output; Oxides; Performance; Persons; Pharmacogenetics; Phenotype; Play; Population; Prefrontal Cortex; Process; Production; Proteins; Psychotic Disorders; Regulation; Research; Research Domain Criteria; Rewards; Role; Schizophrenia; Severities; Short-Term Memory; Signal Transduction; Social Functioning; Social Interaction; Structure; Symptoms; System; Techniques; Testing; Training; Ventral Tegmental Area; base; behavior influence; cell type; cerebellar lesion; cognitive function; dopamine system; in vivo; motor deficit; motor learning; neurophysiology; neuropsychiatry; neurotransmitter release; programs; public health relevance; receptor; research study; skills; social; tool

Project Abstract The cerebellum is well known for its role in coordinating temporal and sensorimotor processes. A lesser appreciated, but no less important function of the cerebellum is its role in cognition, social function, and affective state. Humans with discrete cerebellar lesions manifest neuropsychiatric symptoms, including: flattened affect, depression, reduced language and social interactions, disturbances of working memory, spatial cognition, attention, and even psychosis in the absence of motor deficits. In persons with schizophrenia, neuroanatomical and clinical markers of cerebellar dysfunction correlate with the severity of negative symptoms. The cerebellum is reciprocally connected with several limbic structures known to play important roles in psychiatric illnesses, including the prefrontal cortex, striatum, ventral tegmental area, amygdala, and hippocampus. Virtually nothing is known about how specific cell types influence cerebellar function or how specific neuronal populations within discrete cerebellar nuclei influence behavior, particularly in cognitive, affective, and social domains. I propose that specific deep cerebellar nuclei (the major output of the cerebellum) are essential for cerebellar-dependent regulation of cognitive functions, social functions and affective state. To test this hypothesis, I have proposed to complete two specific aims. For my first aim, I will determine the impact of reversible silencing of a specific population of neurons in the dentate nucleus of the cerebellum on behaviors related to social function, affective state, and cognition. To accomplish this aim, I will transiently and reversibly inhibit specific populations of D1 receptor expressing neurons in the dentate nucleus of the cerebellum through conditional expression of Designer Receptor Exclusively Activated by a Designer Drug (DREADD), hM4Di. For the second aim, I will determine how D1 receptor positive neurons in the dentate nucleus of the cerebellum respond during behaviorally relevant tasks using in vivo electrophysiology and in vivo calcium imaging. My goals under this proposal are to establish an independent research program that will begin to address the following questions: Does altered function of specific neuronal population in a specific region of the cerebellum contribute to specific symptom domains relevant to psychiatric illness? What is the molecular and neurophysiological phenotype of these neurons? This training grant will provide me with the skills necessary to develop and implement advanced mouse-based pharmacogenetic experiments, and to use in vivo neuronal activity monitoring tools such as electrophysiology and calcium imaging in order to examine how critical neurocircuitry regulates behavioral domains relevant to neuropsychiatric disorders.

项目摘要 小脑因其在协调时间和感觉运动过程中的作用而闻名。较小的 小脑的功能虽然受到赞赏，但同样重要的是它在认知、社会功能和 情感状态。患有离散小脑病变的人类会表现出神经精神症状，包括： 情感平淡、抑郁、语言和社交互动减少、工作记忆障碍、 在没有运动缺陷的情况下，空间认知、注意力甚至精神错乱。对于精神分裂症患者来说， 小脑功能障碍的神经解剖学和临床标志物与阴性的严重程度相关 症状。小脑与几个已知发挥重要作用的边缘结构相互连接 在精神疾病中的作用，包括前额皮质、纹状体、腹侧被盖区、杏仁核和 海马体。事实上，我们对特定细胞类型如何影响小脑功能或如何影响小脑功能一无所知。 离散小脑核内的特定神经元群影响行为，特别是在认知、 情感和社交领域。我建议特定的小脑深部核团（小脑的主要输出） 小脑）对于认知功能、社会功能和小脑依赖性调节至关重要 情感状态。为了检验这个假设，我提议完成两个具体目标。为了我的第一个目标，我会 确定齿状核中特定神经元群的可逆沉默的影响 小脑对与社会功能、情感状态和认知相关的行为的影响。为了实现这个目标，我将 短暂且可逆地抑制齿状核中表达 D1 受体的特定神经元群 通过设计者独家激活的设计者受体的条件表达来改变小脑 药物（DREADD），hM4Di。对于第二个目标，我将确定齿状中的 D1 受体阳性神经元如何 使用体内电生理学和在行为相关任务期间小脑核的反应 体内钙成像。我在该提案中的目标是建立一个独立的研究计划， 开始解决以下问题：特定神经元群体的功能是否发生改变？ 小脑区域导致与精神疾病相关的特定症状领域？什么是 这些神经元的分子和神经生理学表型？这笔培训补助金将为我提供 开发和实施先进的基于小鼠的药物遗传学实验所需的技能，以及使用 体内神经元活动监测工具，例如电生理学和钙成像，以便检查 关键神经回路如何调节与神经精神疾病相关的行为领域。