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: 9099953
• 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/9099953
• 关键词: Accelerometer; 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; Dissection; Dopamine; Dopamine D1 Receptor; Dose; Electrophysiology (science); Fright; Functional disorder; Future; GTP-Binding Proteins; Genetic; Goals; Grant; Health; Hippocampus (Brain); Human; Image; Immunohistochemistry; Investigation; Language; Limbic System; Measures; Mental Depression; Mental disorders; Midbrain structure; Molecular; 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; neuropsychiatric disorder; neuropsychiatric symptom; neurotransmitter release; programs; receptor; research study; skills; social; tool

DESCRIPTION (provided by applicant): 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 n 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 populatios 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.

描述（由申请人提供）：小脑以其在时间和感觉运动过程中的作用而闻名。小脑的较少认识，但同样重要的是其在认知，社会功能和情感状态中的作用。具有离散小脑病变的人类表现出神经精神症状，包括：扁平的情感，抑郁，减少语言和社交互动，工作记忆的干扰，空间认知，注意力，甚至在没有运动缺陷的情况下进行精神病。在具有精神分裂症，小脑功能障碍的神经解剖学和临床标记的人中，与负面症状的严重程度相关。小脑与已知在包括前额叶皮层在内的精神病中起重要作用的多个边缘结构相互联系 纹状体，腹侧对段区域，杏仁核和海马。实际上，对于特定细胞类型如何影响小脑功能或离散小脑核中的特定神经元种群如何影响行为，尤其是在认知，情感和社会领域中，几乎一无所知。我建议特定的深脑核（小脑的主要输出）对于小脑依赖的认知功能，社会功能和情感状态至关重要。为了检验这一假设，我建议完成两个具体目标。为了我的第一个目标，我将确定对特定神经元的可逆沉默和小脑齿状核对与社会功能，情感状态和认知有关的行为的影响。为了实现这一目标，我将通过有条件地表达设计器受体的有条件表达，由设计器（Dreadd）（Dreadd）HM4DI，通过有条件地表达设计器受体的有条件表达，可以瞬时和可逆地抑制小脑齿状核中表达神经元的特异性人群。在第二个目标中，我将确定在使用体内电生理学和体内钙成像的行为相关任务中，小脑齿状核中的D1受体阳性神经元如何反应。我根据该提案的目标是建立一个独立的研究计划，该计划将开始解决以下问题：在小脑特定区域中特定神经元种群的功能是否改变了与精神病有关的特定症状领域的贡献？这些神经元的分子和神经生理表型是什么？该培训赠款将为我提供开发和实施基于小鼠的先进药物遗传学实验所需的技能，并使用体内神经元活动监测工具，例如电生理学和钙成像，以检查关键神经循环术如何调节与神经精神疾病相关的行为领域。