Neuronal mechanisms of cerebellar cognitive function

了解人类认知是疾控中心健康大脑倡议的基石之一(见 Https://www.cdc.gov/aging/healthybrain/).长期以来，小脑被认为是一种完全与运动有关的 结构，但现在也越来越多地认识到它参与认知，在人类和 动物。近年来的临床和动物研究表明，小脑的激活与 认知功能，如空间工作记忆，以及小脑神经病理可导致 那些功能。众所周知，小脑神经病理与自闭症等精神疾病有关， 精神分裂症、痴呆症和阿尔茨海默病。因此，理解认知功能和心理 疾病需要了解小脑在认知中的作用。然而，现有的证据纯粹是 小脑认知参与的相关机制和神经机制尚未确定。 研究小脑认知功能的主要障碍是获得因果证据和 探索神经机制需要涉及小脑控制操作的实验 功能，同时观察认知行为和神经元活动。神经的可用性- 以及光遗传工具、清醒行为电生理技术和认知定量测试 小鼠的行为现在可以克服这一障碍。我们提出的研究目的是为了回答 关于小脑在认知中的作用的基本问题--以小鼠为模型生物和 空间工作记忆(SWM)作为一种可量化的认知功能，已知涉及小脑和 人类和啮齿动物。我们的中心假设是，小脑通过以下方式控制SWM决策 控制内侧前额叶皮质(MPFC)间神经元振荡的决策相关连贯性 和海马体(HC)。MPFC和HC分别与小脑相互连接并发挥作用 SWM中的关键角色。SWM任务的决策过程的特点是 MPFC和HC之间的一致性。这种与决策相关的连贯性被认为是 SWM性能正常。 我们建议使用一种新的小鼠小脑功能障碍模型，该模型由共同的Pi Sillitoe和 自由活动小鼠的电生理记录以验证小脑功能丧失的假说 导致SWM严重缺失和SWM决策相关连贯性丧失增加。我们建议聘用 光遗传学技术在SWM行为过程中操纵小脑活动提供病因证据 并绘制控制SWM的小脑皮质区域图。我们的 初步数据有力地支持了我们的假设。我们的工作将广泛影响我们对 小脑在认知脑功能中的作用及其与小脑神经病理机制的关系 精神疾病，这使得这个项目与国家卫生研究院的任务直接相关。

Understanding human cognition is one of the cornerstones of the CDC's Healthy Brain Initiative (see https://www.cdc.gov/aging/healthybrain/). The cerebellum was long perceived as an exclusively motor-related structure, but it is now also increasingly recognized for its involvement in cognition, in both humans and animals. In recent years clinical and animal studies have shown that cerebellar activation is correlated with cognitive functions such as spatial working memory, and that cerebellar neuropathology can cause deficits in those functions. Cerebellar neuropathology is also known to be correlated with mental illnesses like autism, schizophrenia, dementia and Alzheimer's disease. Thus, understanding cognitive function and mental illnesses requires understanding the role of the cerebellum in cognition. However, existing evidence is purely correlational and a neuronal mechanism for cerebellar cognitive involvement has yet to be identified. The main barrier to investigating cerebellar cognitive function is that obtaining causal evidence and exploring neuronal mechanisms requires experiments involving controlled manipulations of cerebellar function while simultaneously observing cognitive behavior and neuronal activity. The availability of neuro- and optogenetic tools, awake-behaving electrophysiological techniques and quantitative tests for cognitive behaviors in mice now allow this barrier to be surmounted. We propose studies designed to answer fundamental questions about the role of the cerebellum in cognition using mice as our model organism and spatial working memory (SWM) as a quantifiable cognitive function known to involve the cerebellum in both humans and rodents. Our central hypothesis is that the cerebellum controls SWM decision-making by controlling decision-related coherence of neuronal oscillations between the medial prefrontal cortex (mPFC) and the hippocampus (HC). The mPFC and HC each are reciprocally connected with the cerebellum and play key roles in SWM. The decision-making process in SWM tasks is characterized by a temporary increase in coherence between the mPFC and HC. This decision-related coherence is believed to be a requirement for normal SWM performance. We propose to use a new mouse model of cerebellar dysfunction created by co-PI Sillitoe and electrophysiological recordings in freely moving mice to test the hypothesis that loss of cerebellar function causes severe SWM deficits and loss of SWM decision-related coherence increase. We propose to employ optogenetic techniques to manipulate cerebellar activity during SWM behavior to provide causal evidence for cerebellar involvement in SWM and to map cerebellar cortical areas involved in controlling SWM. Our preliminary data strongly support our hypotheses. Our work will broadly impact our understanding of the role of the cerebellum in cognitive brain function and the mechanisms linking cerebellar neuropathology to mental illness, which makes this project directly relevant to the mission of the NIH.