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.

项目摘要除了其在运动控制中的良好作用外，小脑越来越被公认为是调节器边缘功能，包括目标指导的行为和情感学习。机械贡献这些功能的小脑尚不清楚，但假设涉及助记符处理，预测错误的响应和/或计算，这些错误驱动行为和学习。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与行为范式；以及将小脑与必不可少的边缘大脑联系起来的基础远程电路的知识中心。我们的初步数据表明我们已经完成了两者：首先，我们已经确定了灭绝恐惧是这些研究的合适范式。第二，我们对解剖学和小脑电路的功能性蓝图已经揭示了（1）之间存在无关连通性小脑和杏仁核和（2）小脑和伏隔核。这个项目的目标是剖析这些小脑膜电路的结构和功能，并定义它们在学习的行为中的作用。在AIMS 1和2中，我们将使用电路跟踪，单细胞测序和光体生理学来定义构成这些小脑电路并将其链接的单个细胞类型的基本功能特性到位置和转录组轮廓。在AIM 3中，我们将使用对个体活动的体内操纵电路元素和神经活动的测量，以查明小脑 - 边缘电路对学习行为的灭绝。我们对小脑连通性的多层次询问将大大增加我们对其对非运动功能的贡献的理解，并可能提供对（DYS）调节学到的恐惧，这在诸如创伤后应激障碍之类的疾病中普遍存在。