A novel output pathway from the cerebellum for regulation of diverse non-motor behaviors

小脑调节多种非运动行为的新型输出途径

• 批准号: 10543790
• 负责人: WADE G REGEHR
• 金额: $ 56.56万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543790
• 关键词: Address; Aggressive behavior; Amygdaloid structure; Anatomy; Animal Model; Behavior; Brain region; Breathing; Cerebellar Cortex; Cerebellar Nuclei; Cerebellar vermis structure; Cerebellum; Cholera Toxin Protomer B; Desire for food; Diameter; Epilepsy; Extinction; Fright; Heart Rate; Hippocampus; Human; Hypothalamic structure; Image; Impairment; In Situ Hybridization; Label; Medial; Mediating; Motor; Motor Pathways; Mus; Neurons; Output; Pathway interactions; Post-Traumatic Stress Disorders; Prevalence; Pupil; Purkinje Cells; Regulation; Rewards; Role; Short-Term Memory; Signal Transduction; Slice; Social Behavior; Synapses; Testing; Thalamic structure; awake; basal forebrain; behavior influence; cell type; conditioned fear; high resolution imaging; in vivo; insight; motor learning; nervous system disorder; novel; optogenetics; parabrachial nucleus; targeted imaging

Abstract/Summary In addition to its well-established role in motor function and motor learning, the cerebellum is implicated in a myriad of non-motor behaviors. In humans, cerebellar damage can impair abstract reasoning and working memory, and result in PTSD. In animal models, the cerebellum regulates heart rate, breathing, aggression, appetite, fear conditioning and many other behaviors. In general, the role of the cerebellum in regulating these behaviors is not well understood. An important step in understanding these nonmotor behaviors is to determine the output pathway and downstream targets that allow the cerebellum to regulate these behaviors. It is known that Purkinje cells (PCs) relay signals from the cerebellar cortex to the deep cerebellar nuclei (DCN), which in turn activate the motor thalamus. It was assumed that DCN outputs are also responsible for nonmotor behaviors. Here, we describe powerful and direct inhibitory connections between PCs in regions of the cerebellum implicated in nonmotor behaviors, and neurons in the parabrachial nucleus (PBN). This is intriguing, because the PBN contributes to many of the same nonmotor behaviors influenced by the cerebellum. Based on our preliminary findings, we hypothesize that the PBN is a specialized cerebellar output that allows the cerebellum to regulate nonmotor behaviors. The first step in testing this hypothesis will be to characterize the connections between PCs and the PBN. The studies will determine the strength and prevalence of the direct PC to PBN synapse and determine the extent to which PCs regulate the activity of neurons in the PBN. The second major step is to identify the regions targeted by the PCPBN pathway and to determine the contribution of this pathway to various behaviors. Preliminary studies suggest that this pathway projects to the hypothalamus, the amygdala, and the basal forebrain, and thus has the appropriate connectivity to allow the cerebellum to regulate diverse behaviors ranging from aggression to fear extinction. This promises to lead to a new appreciation of the roles of the cerebellum in numerous behaviors, it will provide insight into the circuits involved in these behaviors and it has important implications for many neurological disorders.

摘要/总结 除了在运动功能和运动学习中的既定作用外，小脑还与 在人类中，小脑损伤会损害多种非运动行为。 在动物模型中，小脑调节心率、呼吸、攻击性、 一般来说，小脑在调节这些行为中发挥着作用。 理解这些非运动行为的一个重要步骤是确定。 众所周知，小脑调节这些行为的输出途径和下游目标。 浦肯野细胞 (PC) 将信号从小脑皮质传递到小脑深核 (DCN)， 假设 DCN 输出也负责非运动丘脑。 在这里，我们描述了 PC 区域中强大且直接的抑制联系。 与非运动行为有关的小脑和臂旁核（PBN）中的神经元。 有趣的是，因为 PBN 有助于许多受 根据我们的初步发现，我们认为 PBN 是一种特殊的小脑输出。 允许小脑调节非运动行为 检验这一假设的第一步是 表征 PC 和 PBN 之间的连接。研究将确定强度和连接。 直接 PC 到 PBN 突触的普遍性，并确定 PC 调节 PBN 突触活动的程度 PBN 中的神经元的第二个主要步骤是识别 PCPBN 通路的目标区域并 确定该途径对各种行为的贡献。初步研究表明该途径。 投射到下丘脑、杏仁核和基底前脑，因此具有适当的连接性 让小脑调节从攻击到消除恐惧的各种行为。 为了让人们对小脑在众多行为中的作用有一个新的认识，它将提供对 参与这些行为的回路，它对许多神经系统疾病具有重要意义。