Multi-level dissection of cerebello-limbic connectivity

小脑边缘连接的多层次解剖

基本信息

批准号：
10597655
负责人：
Diasynou Fioravante
金额：
$ 59.84万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10597655
关键词：
Affective Amygdaloid structure Anatomy Area Behavior Behavioral Genetics Behavioral Paradigm Brain Calcium Cell Nucleus Cells Cerebellum Cognitive Communication Data Dimensions Disease Dissection Electrophysiology (science)Elements Emotional Experimental Genetics Extinction Fiber Fright Generations Goals Habenula Hippocampus Image Impairment Individual Investigation Knowledge Lateral Learning Limbic System Link Maps Measurement Medial Mediating Memory Mental Health Mental disorders Molecular Molecular Profiling Monitor Movement Mus Neurons Nodal Nucleus Accumbens Pathway interactions Photometry Post-Traumatic Stress Disorders Process Property Psyche structure Reaction Time Regulation Reporting Resolution Role Signal Transduction Structure Synapses Testing Thalamic structure Time Ventral Tegmental Area Viral Well in self autism spectrum disorder cell type emotional behavior entorhinal cortex experimental study in vivo in vivo calcium imaging innovation insight learned behavior learning extinction metaplastic cell transformation motor control motor learning neural novel optogenetics patch sequencing response reward processing single cell sequencing single-cell RNA sequencing stem transcriptomics

项目摘要

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.

项目概要除了在运动控制中的既定作用外，小脑也越来越被认为是一个调节器边缘功能，包括目标导向行为和情感学习。的机械贡献小脑对这些功能的作用尚不清楚，但推测涉及记忆处理、记忆时间安排响应和/或预测误差的计算，从而驱动行为和学习。我们测试这些的能力假设取决于两件事：建立明确的小脑相关行为范式；以及连接小脑和重要边缘脑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这两件事：首先，我们已经确定了灭绝习得性恐惧作为这些研究的合适范式。其次，我们对解剖学和小脑回路的功能蓝图揭示了 (1) 之间存在突触连接小脑和杏仁核以及（2）小脑和伏隔核。该项目的目标是剖析这些小脑边缘回路的结构和功能，并定义它们在学习行为中的作用。在目标 1 和 2 中，我们将使用电路追踪、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位置和转录组图谱。在目标 3 中，我们将利用体内操纵个体的活动电路元件和神经活动测量，以查明小脑边缘电路对习得行为的消失。我们对小脑边缘连接的多层次询问将大大增加我们了解其对非运动功能的贡献，并可能提供对对习得性恐惧的调节（失调），这种现象在创伤后应激障碍等疾病中普遍存在。