Multi-level dissection of cerebello-limbic connectivity

项目摘要 除了在运动控制中的作用外，小脑越来越被认为是一种调节器 包括目标导向行为和情感学习。机械的贡献 小脑对这些功能的作用尚不清楚，但假设与记忆处理、 响应，和/或预测误差的计算，这驱动行为和学习。我们测试这些的能力 假设取决于两件事：建立一个定义明确的小脑相关行为范式; 以及连接小脑和大脑边缘系统的潜在远程回路的知识 中心.我们的初步数据表明，我们已经完成了两个：第一，我们已经确定灭绝 学习恐惧作为这些研究的一个合适的范例。其次，我们对解剖学和 小脑回路的功能蓝图揭示了以下两种神经元之间存在双突触连接： 小脑和杏仁核;（2）小脑和延髓核。该项目的目标是 解剖这些小脑边缘回路的结构和功能，并确定它们在学习行为中的作用。 在目标1和2中，我们将使用电路跟踪、单细胞测序和光生理学来定义 构成这些小脑回路并将它们连接起来的单个细胞类型的基本功能特性 定位和转录组学特征。在目标3中，我们将使用体内操纵个体的活性， 电路元件和神经活动的测量，以查明小脑边缘电路的贡献， 学习行为的消失。我们对小脑边缘连接的多层次询问将大大增加 我们对它对非运动功能的贡献的理解，并可能提供对 （dys）调节习得性恐惧，这在创伤后应激障碍等疾病中很普遍。

PROJECT SUMMARY In addition to its well-established role in motor control, the cerebellum is increasingly recognized as a regulator of limbic functions, including goal-directed behavior and affective learning. The mechanistic contribution of the cerebellum to these functions remains unclear but is hypothesized to involve mnemonic processing, timing of responses, and/or computation of prediction errors, which drive behavior and learning. Our ability to test these hypotheses depends on two things: establishment of a well-defined cerebellum-relevant behavioral paradigm; and knowledge of the underlying long-range circuits that connect the cerebellum to essential limbic brain centers. Our preliminary data demonstrate that we have accomplished both: first, we have identified extinction of learned fear as a suitable paradigm for these studies. Second, our investigations of the anatomical and functional blueprints of cerebellar circuits have revealed the existence of disynaptic connectivity between (1) the cerebellum and the amygdala and (2) the cerebellum and nucleus accumbens. The goal of this project is to dissect the structure and function of these cerebello-limbic circuits and to define their role in learned behavior. In Aims 1 and 2, we will use circuit tracing, single-cell sequencing and optophysiology to define the fundamental functional properties of individual cell types that comprise these cerebellar circuits and link them to positional and transcriptomic profiles. In Aim 3, we will use in vivo manipulation of the activity of individual circuit elements and measurements of neural activity to pinpoint the contribution of cerebello-limbic circuits to extinction of learned behavior. Our multi-level interrogation of cerebello-limbic connectivity will greatly increase our understanding of its contributions to non-motor functionality and may provide insight into the (dys)regulation of learned fear, which is prevalent in diseases such as post-traumatic stress disorder.