Characterization of structure-function relationships in distinct thalamic reticular nucleus networks

不同丘脑网状核网络结构-功能关系的表征

• 批准号: 10279075
• 负责人: Zhanyan Fu
• 金额: $ 37.32万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-22 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10279075
• 关键词: Acute; Address; Anatomy; Animals; Arousal; Attention; Attention deficit hyperactivity disorder; Attentional deficit; Behavior; Behavioral; Brain; CRISPR/Cas technology; Cell Nucleus; Cells; Characteristics; Cognition; Diagnostic; Disease; Dorsal; Electrodes; Electrophysiology (science); Enterobacteria phage P1 Cre recombinase; Functional disorder; Gene Targeting; Genes; Genetic; Glutamates; Health; Individual; Injections; Knock-out; Knowledge; Label; Link; Maps; Mediating; Molecular; Mutant Strains Mice; Neocortex; Neurodevelopmental Disorder; Neurons; Noise; Output; Pathway interactions; Pattern; Physiological; Play; Population; Positioning Attribute; Process; Property; Role; Schizophrenia; Sensory; Sleep disturbances; Slice; Source; Structure-Activity Relationship; Structure/Function Nuclei; Synapses; System; Testing; Thalamic Nuclei; Thalamic structure; Therapeutic; Thinness; Time; Tracer; Transgenic Mice; Work; anatomical tracing; autism spectrum disorder; awake; base; cell type; in vivo; information processing; mouse model; mutant mouse model; novel; optogenetics; patch clamp; rabies viral tracing; tool; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Nearly all sensory information destined for the neocortex is relayed through the thalamus. The thalamic reticular nucleus (TRN), a thin shell of GABAergic neurons surrounding the dorsal thalamus, receives both collaterals from cortico-thalamic and thalamo-cortical glutamatergic inputs, but exerts its unidirectional powerful inhibition only to the thalamus. TRN thus is considered as a master controller of thalamo-cortical circuits regulating the flow of the information between thalamus and neocortex. Perturbed TRN function may underlie behavioral deficits in disorders ranging from schizophrenia, ADHD and autism. Although the importance of the TRN has long been recognized, our knowledge of its molecular identity of cell types, their organization and their functional properties has lagged behind that of the thalamocortical circuits they control. The paucity of such knowledge has 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. Our most recent work has filled this critical gap in knowledge. By using single nucleus RNAseq, for the first time we have discovered that TRN neurons can be dissociated into two major subtypes with distinct transcriptomic profiles, anatomical localizations, electrophysiological properties and thalamic connectivity. One subtype, 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. This proposal aims to use these new knowledge and genetic tools to provide a comprehensive map of TRN cell- type specific connectivity patterns, TRN subcircuit electrophysiological properties and synaptic mechanism, and how abnormal function of distinct TRN subcircuits contribute to behavioral deficits of autism spectrum disorder (ASD) using a novel monogenic form of ASD, Ptchd1 deletion mouse model.

项目摘要 几乎所有送往新皮层的感觉信息都是通过丘脑传递的。丘脑 网状核（TRN），一个围绕背侧丘脑的GABA能神经元的薄壳，接受 从皮质-丘脑和丘脑-皮质神经元传入，但发挥其单向强大的 只对丘脑有抑制作用因此，TRN被认为是丘脑-皮层回路的主控制器 调节丘脑和新皮层之间的信息流。扰动的TRN函数可能是 精神分裂症、多动症和自闭症等疾病的行为缺陷。虽然重要的是 TRN早已被认识，我们对其细胞类型的分子身份，它们的组织和 它们的功能特性已经落后于它们所控制的丘脑皮层回路。的缺乏 这些知识限制了我们准确确定TRN回路如何影响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。我们最近的工作填补了这一关键的知识空白。通过 使用单核RNAseq，我们第一次发现TRN神经元可以解离成 具有不同转录组学特征、解剖学定位、电生理学 性质和丘脑连通性。一种亚型，位于TRN的“核心”区域，可以标记为 通过Spp 1基因的表达，靶向一级感觉丘脑核，另一个位于 TRN的“壳”区，以Ecel 1基因的表达为标志，靶向更高阶的基因。我们有 分别在这两个群体中的每一个中产生表达Cre重组酶的转基因小鼠。这 该提案旨在利用这些新知识和遗传工具提供TRN细胞的全面图谱， 类型特异性连接模式，TRN子电路电生理特性和突触机制， 以及不同TRN子回路的异常功能如何导致自闭症谱系的行为缺陷 使用ASD的新单基因形式，Ptchd 1缺失小鼠模型，对ASD进行研究。