Genetic Dissection of Cerebellar Circuitry in Cognitive and Affective Behavior

项目摘要 小脑以其协调时间和感觉运动过程的作用而闻名。较小 小脑的重要功能是它在认知、社会功能和 情感状态患有离散性小脑病变的人表现出神经精神症状，包括： 情绪低落，抑郁，语言和社会交往减少，工作记忆障碍， 空间认知，注意力，甚至精神病在没有运动缺陷。在精神分裂症患者中， 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， 症状小脑与几个边缘系统结构紧密相连， 在精神疾病中的作用，包括前额叶皮层，纹状体，腹侧被盖区，杏仁核， 海马体。事实上，对于特定的细胞类型如何影响小脑功能， 离散小脑核内的特定神经元群体影响行为，特别是在认知， 情感和社会领域。我建议，特定的小脑深部核（小脑的主要输出）， 小脑）对于认知功能、社会功能和 情感状态为了验证这个假设，我提出了两个具体的目标。我的第一个目标， 确定可逆沉默的影响，在齿状核的神经元的特定群体， 小脑对与社会功能、情感状态和认知相关的行为的影响。为了实现这一目标，我将 瞬时和可逆地抑制齿状核中表达D1受体的神经元的特定群体 通过设计者受体的条件表达， 药物（DREADD），hM4Di.对于第二个目标，我将确定D1受体阳性神经元在齿状回 小脑核在行为相关任务中的反应， 体内钙显像我的目标是建立一个独立的研究计划， 开始解决以下问题：是否改变了功能的特定神经元群体在一个特定的 小脑区域与精神疾病相关的特定症状域有关？是什么 这些神经元的分子和神经生理表型？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，并使用 体内神经元活动监测工具，例如电生理学和钙成像， 关键神经回路如何调节与神经精神障碍相关的行为领域。

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.