Functional connectivity in a novel cerebellar-amygdala circuit that regulates fear extinction

摘要 小脑(CB)长期以来被认为是一种纯粹的运动结构；然而，过去几年的研究 几十年来，也揭示了重要的非运动功能，包括在边缘处理中的关键作用。这个 小脑既参与情绪体验，也参与控制适当的自主神经， 认知和行为反应，在情绪记忆的所有阶段都发挥着重要作用，包括 获取、合并、存储和检索以及消亡。小脑功能障碍一直是 与各种神经和神经精神障碍有关，如认知情感综合征， 精神分裂症、焦虑和抑郁。为了在运动和认知领域都取得如此多的成就， 小脑被认为整合了不同的输入，并将关于最佳行为输出的预测发送到 大脑的其余部分。然而，这类过程中涉及的途径和机制仍然很差 明白了。我的实验室最近发现了连接小脑和大脑 杏仁核经丘脑(Th)(中央内侧核和束旁核)和腹侧被盖 脑区(VTA)可能在这些认知和情绪功能的扩展中起重要作用。这个 这项提案中概述的实验将集中于检查新的小脑-丘脑-杏仁核通路 参与恐惧消退学习，在这种学习中，关于意外结果的信号被认为引导变化 在行为上。在这些实验中，我将使用纤维的钙成像来测量通路中的活动 利用光遗传学进行光度测量和信号处理。同时，在切片电生理实验中，我 将研究CB-Th连接的细胞和突触属性。总而言之，这项提案将提供 对小脑在情绪学习背景下可能做的事情的新颖见解，以及 非运动行为中的特定路径，以及每个微电路中的信号特性。这些 这些探索将增加我们对小脑边缘功能的了解，并有助于指导未来的研究 在神经精神障碍中，这些回路可能会受到损害，从而推动寻找更有效的治疗方法。

ABSTRACT The cerebellum (CB) has long been considered a purely motor structure; however, studies over the last few decades have revealed vital, non-motor functions as well, including a key role in limbic processing. The cerebellum is involved in both the experience of emotion and in controlling the appropriate autonomic, cognitive, and behavioral responses, and plays an important part in all phases of emotional memory, including acquisition, consolidation, storage and retrieval, and extinction. Dysfunctions of the cerebellum have been associated with various neurological and neuropsychiatric disorders such as cognitive affective syndrome, schizophrenia, anxiety, and depression. To accomplish so much in both the motor and cognitive domains, the cerebellum is thought to integrate diverse inputs and send predictions about optimal behavioral outputs to the rest of the brain. However, the pathways and mechanisms involved in this type of processing remain poorly understood. My lab has recently discovered novel disynaptic pathways connecting the cerebellum and the amygdala via the intralaminar thalamus (Th) (centromedial and parafascicular nuclei) and ventral tegmental area (VTA) which may play a fundamental role in these expanded cognitive and emotional functions. The experiments outlined in this proposal will focus on examining if the novel cerebello-thalamo-amygdala pathway is involved in fear extinction learning, where signals about unexpected outcomes are thought to guide changes in behavior. In these experiments, I will measure activity in the pathway using calcium imaging with fiber photometry and manipulate signaling with optogenetics. In tandem, in slice electrophysiology experiments, I will examine the cellular and synaptic properties of CB-Th connectivity. Together, this proposal will provide novel insights into what the cerebellum might be doing in the context of emotional learning, the necessity of the specific pathway in non-motor behavior, and the signaling properties within each microcircuit. These explorations will add to our understanding of cerebellar limbic functions and help guide future studies of how these circuits may be impaired in neuropsychiatric disorders to propel the search for more effective treatments.