Cerebellar Output Circuits

建议书摘要 描述(申请人提供)：前额叶皮质功能障碍 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，蚯蚓-小脑的一小部分，以其 在姿势和眼球运动中的作用-与这些都有很大的关联 精神错乱。眼球跳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记物，与 蚯蚓对运动和前额叶皮质功能均有调节作用。然而，无论是 连接小脑前额叶和前额叶皮质的神经回路底物 了解这些连接的功能影响。这一点的中心假设是 建议是小脑蠕虫的情感和认知功能是 由一类特定类型的小脑核神经元介导，这些神经元进行电路连接 在网状激活系统中，觉醒和皮质状态的关键调节因素，如 以及内侧丘脑的神经元，这些神经元对前额叶皮质至关重要 功能。拟议中的实验将通过以下组合来验证这一假设 现代解剖学、生理学、药理学、光遗传学和行为学 战略。小脑与网状激活系统的接触缺陷和 丘脑可能是情绪调节失调和认知障碍的原因 精神障碍。实现拟议研究的目标将导致 有关远程电路连接的史无前例的细胞类型特定信息 连接小脑前额叶皮质和小脑的前额叶皮质 情感和认知功能的调节。因此，这项研究将产生新的 对调节目前尚不清楚的经颅手术疗效的机制的见解 刺激小脑对改善精神病患者认知和情绪障碍的作用 精神错乱。

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.