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

项目总结 几乎所有发往大脑皮层的感觉信息都是通过丘脑传递的。丘脑 网状核(TRN)是环绕在丘脑背侧的GABA能神经元的薄壳，接受这两种物质 侧支来自皮质-丘脑和丘脑-皮质谷氨酸能传入，但发挥其单向强大 对丘脑有抑制作用。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。尽管这一点很重要 TRN很早就被人们认识到，我们对它的细胞类型、组织结构和分子身份的了解 它们的功能特性落后于它们控制的丘脑皮质回路。稀缺的 这些知识限制了我们确定TRN回路如何对不同大脑做出贡献的能力 功能，这是确定它在疾病中如何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。我们最新的工作填补了这一关键的知识空白。通过 利用单核RNAseq，我们首次发现TRN神经元可以分离成 两个主要亚型具有不同的转录谱、解剖定位、电生理 属性和丘脑连通性。一个亚型，位于TRN的核心区域，可被标记为 通过Spp1基因的表达，靶向一级感觉丘脑核团，另一个位于 TRN的“外壳”区域以Ecel1基因的表达为标志，针对的是更高阶的基因。我们有 在这两个种群中分别产生表达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来提供TRN细胞的全面图谱- 类型特定的连接模式、TRN亚路的电生理特性和突触机制， 以及不同的TRN亚回路的异常功能如何导致自闭症谱系的行为缺陷 使用一种新的单基因形式的ASD，PTCHD1缺失小鼠模型。

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.