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 感觉处理，唤醒和认知。从皮质和皮层下区域接收输入，这 结构在战略上定位以影响丘脑皮层相互作用。在静止期间，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 神经元有助于感官过滤的基本注意力。扰动的TRN功能可能是行为的基础 从精神分裂症和自闭症到多动症的疾病中排名。尽管很重要，但有几个 主要挑战限制了我们确切确定TRN电路如何贡献各种大脑的能力 功能，确定其在疾病中发生故障以及如何利用其电路的先决条件 用于诊断和治疗目的。该建议旨在通过 利用我们生成的一组新颖的发现和工具。 TRN是薄的gabaergic壳 丘脑投影核周围的神经元。在TRN中，具有独特结构和的神经元 功能性能可以部分混合。这种解剖学特征是主要障碍 功能研究，因为选择性靶向具有与结构和功能特性的TRN神经元与 传统方法是挑战。使用单细胞RNASEQ，我们最近发现TRN神经元 可以分离为具有不同的转录组分布，解剖学局部的两个主要亚型， 电生理特性和丘脑连通性。一组位于TRN的“核心”区域 并且可以用SPP1基因的表达来标记，靶向一阶感觉丘脑核和 其他位于TRN的“壳”区域中，并以Ecel1基因的表达为标志，靶向更高 订购。我们已经在这两个种群中产生了表达Cre重组酶的转基因小鼠 单独。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。