Functional dissection of thalamocortical interactions through genetically-defined TRN subnetworks

通过基因定义的 TRN 子网络对丘脑皮质相互作用进行功能剖析

基本信息

批准号：
10198061
负责人：
Guoping Feng
金额：
$ 70.84万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10198061
关键词：
Address Anatomy Animals Area Arousal Attention Attention deficit hyperactivity disorder BRAIN initiative Behavioral Brain Brain region Cell Nucleus Cognition Complement Data Diagnostic Disease Dissection Electrodes Electrophysiology (science)Enterobacteria phage P1 Cre recombinase Gene Targeting Generations Genetic Individual Knowledge Maps Mediating Methods Modality Motor Mus Neurons Output Pattern Play Population Positioning Attribute Process Property Role Schizophrenia Sensory Sensory Physiology Shapes Signal Transduction Sleep Source Specificity Structure Structure/Function Nuclei Subgroup Testing Thalamic Nuclei Thalamic structure Therapeutic Thinking Thinness Training Transgenic Mice anatomical tracing autism spectrum disorder cell type design designer receptors exclusively activated by designer drugs experimental study memory consolidation mouse model novel optogenetics rabies viral tracing sensory discrimination sensory gating sensory integration single-cell RNA sequencing sleep regulation tool transcriptomics translational study

项目摘要

PROJECT SUMMARY The thalamic reticular nucleus (TRN), the major source of thalamic inhibition, plays essential roles in sensory processing, arousal and cognition. Receiving inputs from cortical and subcortical regions, this structure is strategically positioned to influence thalamo-cortical interactions. During quiescence, the TRN participate in sleep rhythm generation, sleep stability and memory consolidation, while in active states, TRN neurons contribute to sensory filtering underlying attention. Perturbed TRN function may underlie behavioral deficits in disorders ranging from schizophrenia and autism to ADHD. Despite its importance, however, several key challenges have limited our ability to determine exactly how TRN circuitry contributes to various brain functions, a prerequisite for determining how it malfunctions in diseases and how its circuitry can be leveraged for diagnostic and therapeutic purposes. This proposal aims to address this critical gap in knowledge by capitalizing on a novel set of findings and tools that we generated. The TRN is a thin shell of GABAergic neurons surrounding thalamic projection nuclei. Within the TRN, neurons that have distinct structural and functional properties can be partially intermingled. This anatomical feature has been a major impediment for functional studies, since selective targeting of TRN neurons that share structural and functional properties with traditional methods is challenging. Using single cell RNAseq, we have recently discovered that TRN neurons can be dissociated into two major subtypes with distinct transcriptomic profiles, anatomical localizations, electrophysiological properties and thalamic connectivity. One group, located in the “core” region of the TRN and can be marked by the expression of the Spp1 gene, targets first-order sensory thalamic nuclei, and the other, located in the “shell” region of the TRN and marked by the expression of Ecel1 gene, targets higher- order ones. We have generated transgenic mice expressing Cre recombinase in each of these two populations individually. Here, we propose to use these new knowledge and genetic tools to answer fundamental questions about TRN structure-function organization as well as the contribution of this brain region to sensory processing, arousal and cognition.

项目概要丘脑网状核 (TRN) 是丘脑抑制的主要来源，在感觉处理、唤醒和认知。接收来自皮质和皮质下区域的输入。 TRN 结构的战略定位是影响丘脑皮质相互作用。参与睡眠节律的产生、睡眠稳定性和记忆巩固，在活跃状态下，TRN 神经元有助于注意力的感觉过滤扰动的 TRN 功能可能是行为的基础。尽管它很重要，但从精神分裂症、自闭症到多动症等多种疾病中的缺陷。关键挑战限制了我们准确确定 TRN 电路如何对不同大脑做出贡献的能力功能，这是确定其在疾病中如何发生故障以及如何利用其电路的先决条件该提案旨在通过以下方式解决这一关键的知识差距。利用我们生成的一组新颖的发现和工具，TRN 是 GABAergic 的薄壳。丘脑投射核周围的神经元在 TRN 内，具有不同结构和特征的神经元。功能特性可能部分混合，这种解剖学特征一直是主要障碍。功能研究，因为选择性靶向与 TRN 神经元共享结构和功能特性的 TRN 神经元传统方法具有挑战性，使用单细胞 RNAseq，我们最近发现 TRN 神经元。可以分为两个主要亚型，具有不同的转录组特征、解剖定位、一组位于 TRN 的“核心”区域。可以通过 Spp1 基因的表达来标记，目标是一级感觉丘脑核，以及另一个位于 TRN 的“壳”区域，以 Ecel1 基因的表达为标志，目标更高我们已经在这两个群体中产生了表达 Cre 重组酶的转基因小鼠。在这里，我们建议使用这些新知识和遗传工具来回答基本问题。关于 TRN 结构功能组织以及该大脑区域对感觉的贡献处理、唤醒和认知。