Cerebellar Output Circuits

提案摘要 描述（由申请人提供）：前额叶皮质功能受损， 与许多精神疾病有关，包括精神分裂症，情绪障碍， 和自闭症。令人惊讶的是，小脑的一小部分，以其 在姿势和眼球运动中的作用-在这些中的每一个中都有强烈的牵连 紊乱扫视眼球运动的执行控制缺陷被用作 精神分裂症，自闭症和抑郁症的生物标志物，与精神分裂症的双重作用一致。 蚓部在调节运动和前额叶皮质功能中的作用。然而，无论是 连接小脑蚓部和前额皮质的神经回路基底， 了解这些连接的功能影响。这个问题的核心假设是 建议是，小脑蚓部的情感和认知功能， 由一种特殊的小脑核神经元介导， 与网状激活系统，唤醒和皮质状态的关键调节器， 以及内侧丘脑的神经元，这些神经元对前额叶皮层至关重要 功能拟议的实验将测试这一假设的组合， 现代解剖学、生理学、药理学、光遗传学和行为学 战略布局小脑与网状激活系统的接合缺陷和 丘脑可以解释情绪失调和认知缺陷常见的几个 精神疾病实现拟议研究的目标将导致 关于远程电路连接的前所未有的细胞类型特定信息 连接小脑蚓部和前额叶皮层， 情感和认知功能的调节。这项研究将产生新的 深入了解介导目前无法解释的经颅给药疗效的机制 刺激小脑改善精神病患者的认知和情绪功能障碍 紊乱

Proposal Summary DESCRIPTION (provided by applicant): Impairments in prefrontal cortical function are associated with many psychiatric disorders, including schizophrenia, mood disorders, and autism. Surprisingly, the vermis - a small part of the cerebellum best known for its role in posture and eye movements - has been strongly implicated in each of these disorders. Deficits in executive control of saccadic eye movements are used as biomarkers for schizophrenia, autism, and depression, consistent with a dual role of the vermis in regulating both motoric and prefrontal cortical function. However, neither the neural circuit substrates that link the cerebellar vermis with the prefrontal cortex nor the functional impact of these connections are understood. The central hypothesis of this proposal is that the affective and cognitive functions of the cerebellar vermis are mediated by a specific class of cerebellar nucleus neuron that makes circuit connections with the reticular activating system, a critical regulator of arousal and cortical state, as well as with neurons of the medial thalamus that are essential for prefrontal cortical function. The proposed experiments will test this hypothesis with a combination of modern anatomical, physiological, pharmacological, optogenetic, and behavioral strategies. Deficits in cerebellar engagement with the reticular activating system and the thalamus could account for mood dysregulation and cognitive deficits common to several psychiatric disorders. Accomplishing the aims of the proposed research will result in unprecedented cell type specific information about the long-range circuit connections that link the cerebellar vermis with the prefrontal cortex that account for cerebellar modulation of affective and cognitive function. This research will thus generate new insights into the mechanisms that mediate currently unexplained efficacy of transcranial stimulation of the cerebellum in improving cognitive and mood dysfunction in psychiatric disorders.