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

• 批准号: 10622039
• 负责人: Guoping Feng
• 金额: $ 10.21万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-10 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10622039
• 关键词: Address; Anatomy; Arousal; Attention; Attention deficit hyperactivity disorder; Behavioral; Brain; Brain region; Cell Nucleus; Cognition; Diagnostic; Disease; Dissection; Electrophysiology (science); Enterobacteria phage P1 Cre recombinase; Gene Targeting; Generations; Genetic; Individual; Knowledge; Methods; Neurons; Play; Population; Positioning Attribute; Process; Property; Role; Schizophrenia; Sensory; Sleep; Source; Structure; Structure/Function Nuclei; Subgroup; Testing; Thalamic Nuclei; Thalamic structure; Therapeutic; Thinness; Transgenic Mice; autism spectrum disorder; memory consolidation; novel; single-cell RNA sequencing; tool; transcriptomics

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.

项目摘要 丘脑网状核（TRN）是丘脑抑制的主要来源，在 感官处理、唤醒和认知。接受来自皮层和皮层下区域的输入， 结构的战略地位，影响丘脑-皮质的相互作用。在静止期，TRN 参与睡眠节律的产生、睡眠稳定性和记忆巩固，而在活跃状态下，TRN 神经元对引起注意的感觉过滤有贡献。TRN功能紊乱可能是行为 从精神分裂症、自闭症到多动症等各种疾病的缺陷。尽管它的重要性，但是， 关键的挑战限制了我们准确确定TRN电路如何促进各种大脑功能的能力。 这是确定它在疾病中如何失灵以及如何利用其电路的先决条件 用于诊断和治疗目的。本提案旨在通过以下方式弥补这一重大知识差距： 利用我们的一系列新发现和工具。TRN是GABA能的薄壳 丘脑投射核周围的神经元。在TRN内，具有不同结构和 功能特性可以部分混合。这一解剖特征一直是一个主要的障碍， 功能研究，因为选择性靶向TRN神经元，与TRN神经元共享结构和功能特性， 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 可以分离成两个主要亚型，具有不同的转录组学特征，解剖学定位， 电生理特性和丘脑连接性。一组位于TRN的“核心”区域， 并且可以通过Spp 1基因的表达来标记，靶向一级感觉丘脑核团， 另一个位于TRN的“壳”区，以Ecel 1基因的表达为标志，靶向更高的- 点一份。我们已经在这两个种群中的每一个中产生了表达Cre重组酶的转基因小鼠 单独地在这里，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的结构-功能组织以及该脑区对感觉的贡献， 处理、唤醒和认知。