Multi-level dissection of cerebello-limbic connectivity

项目总结 小脑除了在运动控制中起着公认的作用外，还日益被认为是一种调节器。 边缘功能，包括目标导向行为和情感学习。美国经济的机械性贡献 小脑对这些功能的影响尚不清楚，但推测涉及助记加工，计时 响应和/或预测误差的计算，这驱动了行为和学习。我们测试这些的能力 假设依赖于两件事：建立定义明确的与小脑相关的行为范式； 以及连接小脑和基本边缘脑的潜在长程回路的知识 中锋。我们的初步数据表明，我们已经做到了这两点：第一，我们已经确定了物种灭绝 将习得性恐惧作为这些研究的合适范例。第二，我们的解剖学和 小脑回路的功能蓝图揭示了双突触连接的存在(1) 小脑和杏仁核；(2)小脑和伏隔核。这个项目的目标是 剖析这些小脑-边缘环路的结构和功能，并确定它们在习得行为中的作用。 在目标1和目标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联系在一起的单个细胞类型的基本功能特性 位置和转录组的特征。在目标3中，我们将使用体内操纵个体的活动 神经活动的电路元件和测量，以确定小脑-边缘回路对 习得性行为的灭绝。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，可能会为我们提供对 (DYS)对习得性恐惧的调节，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.