Neuronal mechanisms of cerebellar cognitive function

小脑认知功能的神经机制

• 批准号: 10305668
• 负责人: DETLEF H HECK
• 金额: $ 39.63万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10305668
• 关键词: Aging; Alzheimer' s Disease; Animal Model; Animals; Area; BRAIN initiative; Behavior; Brain; Centers for Disease Control and Prevention (U.S.); Cerebellar Cortex; Cerebellar Diseases; Cerebellum; Characteristics; Clinical; Cognition; Cognition Disorders; Cognitive; Data; Decision Making; Dementia; Electrophysiology (science); Fracture; Goals; Head; Hippocampus (Brain); Human; Light; Link; Maps; Measurement; Measures; Medial; Memory Loss; Memory impairment; Mental disorders; Mission; Motor; Mus; Neurons; Outcome; Performance; Play; Prefrontal Cortex; Problem Solving; Process; Purkinje Cells; Research; Research Design; Rodent; Role; Schizophrenia; Short-Term Memory; Site; Stimulus; Structure; Synaptic Transmission; Techniques; Testing; Thalamic structure; United States National Institutes of Health; Ventral Tegmental Area; Work; autism spectrum disorder; awake; base; behavior test; cognitive function; cognitive testing; experimental study; extracellular; improved; motor control; mouse model; neuropathology; optogenetics; response; therapy development; tool

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.

了解人类认知是疾病预防控制中心健康大脑倡议的基石之一（见 https://www.cdc.gov/aging/healthybrain/).小脑长期以来被认为是一个专门与运动有关的 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，临床和动物研究表明，小脑激活与 认知功能，如空间工作记忆，小脑神经病理学可导致缺陷， 这些功能。小脑神经病理学也被认为与自闭症等精神疾病有关， 精神分裂症、痴呆症和老年痴呆症。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性和神经元机制尚未确定。 研究小脑认知功能的主要障碍是获得因果关系证据， 探索神经元机制需要实验，包括小脑的控制操作， 功能，同时观察认知行为和神经元活动。神经系统的可用性- 和光遗传学工具，唤醒行为电生理技术和认知的定量测试 小鼠的行为现在允许这一障碍被克服。我们提出的研究旨在回答 关于小脑在认知中的作用的基本问题，使用小鼠作为我们的模型生物， 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， 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 控制内侧前额叶皮层（mPFC）之间神经元振荡的决策相关一致性 和海马体（HC）。mPFC和HC分别与小脑相连， SWM中的关键角色。SWM任务中的决策过程的特点是， 中期方案财务委员会和人道主义协调委员会之间的一致性。这种与决策有关的一致性被认为是以下方面的一项要求： SWM性能正常。 我们建议使用一种新的小脑功能障碍的小鼠模型， 在自由活动的小鼠中进行电生理记录，以检验小脑功能丧失 导致严重的SWM缺陷和SWM决策相关一致性增加的损失。我们建议雇用 光遗传学技术来操纵SWM行为期间的小脑活动，以提供 小脑参与SWM和映射小脑皮质区参与控制SWM。我们 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以及小脑神经病理学与 精神疾病，这使得这个项目直接关系到国家卫生研究院的使命。

项目成果

Cerebellar control of thalamocortical circuits for cognitive function: A review of pathways and a proposed mechanism.

• DOI: 10.3389/fnsys.2023.1126508
• 发表时间: 2023
• 期刊: FRONTIERS IN SYSTEMS NEUROSCIENCE
• 影响因子: 3
• 作者: Heck, Detlef H.;Fox, Mia B.;Chapman, Brittany Correia;McAfee, Samuel S.;Liu, Yu
• 通讯作者: Liu, Yu

"The great mixing machine": multisensory integration and brain-breath coupling in the cerebral cortex.

“伟大的混合机器”：大脑皮层的多感觉整合和脑呼吸耦合。

• DOI: 10.1007/s00424-022-02738-z
• 发表时间: 2023-01
• 期刊: PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
• 影响因子: 4.5
• 作者: Heck, Detlef H.;Varga, Somogy
• 通讯作者: Varga, Somogy

Cerebellar Coordination of Neuronal Communication in Cerebral Cortex.

• DOI: 10.3389/fnsys.2021.781527
• 发表时间: 2021
• 期刊: Frontiers in systems neuroscience
• 影响因子: 3
• 作者: McAfee SS;Liu Y;Sillitoe RV;Heck DH
• 通讯作者: Heck DH

Recent insights into respiratory modulation of brain activity offer new perspectives on cognition and emotion.

• DOI: 10.1016/j.biopsycho.2022.108316
• 发表时间: 2022-04
• 期刊: BIOLOGICAL PSYCHOLOGY
• 影响因子: 2.6
• 作者: Heck, Detlef H.;Correia, Brittany L.;Fox, Mia B.;Liu, Yu;Allen, Micah;Varga, Somogy
• 通讯作者: Varga, Somogy