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: 10455621
• 负责人: Zhanyan Fu
• 金额: $ 39万
• 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/10455621
• 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.

项目概要 几乎所有发往新皮质的感觉信息都是通过丘脑传递的。丘脑 网状核 (TRN) 是背侧丘脑周围 GABA 能神经元的薄壳，接收 来自皮质丘脑和丘脑皮质谷氨酸输入的侧枝，但发挥其单向强大的作用 仅抑制丘脑。因此，TRN 被认为是丘脑皮质回路的主控制器 调节丘脑和新皮质之间的信息流。扰动的 TRN 功能可能是其背后的原因 精神分裂症、多动症和自闭症等疾病的行为缺陷。虽然重要性 TRN 早已得到认可，我们对其细胞类型的分子身份、组织和结构的了解 它们的功能特性落后于它们控制的丘脑皮质回路。的匮乏 这些知识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 用于诊断和治疗目的。我们最近的工作填补了这一知识空白。经过 使用单核RNAseq，我们第一次发现TRN神经元可以解离成 两种主要亚型具有不同的转录组学特征、解剖定位、电生理学特征 属性和丘脑连接。一种亚型，位于TRN的“核心”区域，可以被标记 通过 Spp1 基因的表达，目标是一级感觉丘脑核，另一个目标是位于 TRN 的“壳”区域以 Ecel1 基因的表达为标志，目标是高阶基因。我们有 生成了在这两个群体中分别表达 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来提供TRN细胞的全面图谱- 类型特定的连接模式、TRN 子电路电生理特性和突触机制， 以及不同 TRN 子电路的异常功能如何导致自闭症谱系的行为缺陷 使用一种新型单基因形式的 ASD（Ptchd1 缺失小鼠模型）来治疗 ASD。