Genetic Dissection of Cerebellar Circuitry in Cognitive and Affective Behavior

描述(申请人提供)：众所周知，小脑在协调颞叶和感觉运动过程中的作用。小脑在认知、社会功能和情感状态中的作用不太为人所知，但同样重要。有离散小脑损伤的人类表现出神经精神症状，包括：平坦的情感，抑郁，语言和社会互动减少，工作记忆，空间认知，注意力障碍，甚至在没有运动障碍的情况下精神错乱。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症状的严重程度相关。小脑与几个已知在精神疾病中发挥重要作用的边缘结构相互连接，包括前额叶皮质， 纹状体、腹侧被盖区、杏仁核和海马体。关于特定细胞类型如何影响小脑功能，或离散小脑核团中的特定神经元群体如何影响行为，尤其是在认知、情感和社交领域，几乎一无所知。我认为，特定的小脑深层核团(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的调节是必不可少的。为了验证这一假设，我建议完成两个具体目标。为了我的第一个目标，我将确定小脑齿状核中特定神经元群体的可逆性沉默对与社会功能、情感状态和认知相关的行为的影响。为了实现这一目标，我将通过有条件地表达由设计药物(DREADD)hM4Di独占激活的Designer受体，来瞬时和可逆地抑制小脑齿状核中特定数量的D1受体表达神经元。对于第二个目标，我将利用体内电生理学和体内钙成像来确定小脑齿状核中的D1受体阳性神经元在行为相关任务中的反应。根据这项提议，我的目标是建立一个独立的研究计划，开始解决以下问题：小脑特定区域特定神经元群体的功能改变是否有助于与精神疾病相关的特定症状领域？这些神经元的分子和神经生理表型是什么？这笔培训拨款将为我提供必要的技能，以开发和实施先进的基于老鼠的药物遗传学实验，并使用体内神经活动监测工具，如电生理学和钙成像，以检查关键神经回路如何调节与神经精神障碍相关的行为领域。

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.