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: 10852028
• 负责人: Guoping Feng
• 金额: $ 13.31万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10852028
• 关键词: Address; Anatomy; Animals; Area; Arousal; Attention; Attention deficit hyperactivity disorder; BRAIN initiative; Behavioral; Brain; Brain region; Cell Nucleus; Cognition; Complement; Data; Diagnostic; Disease; Dissection; Dissociation; Electrodes; Electrophysiology (science); Enterobacteria phage P1 Cre recombinase; Experimental Designs; Generations; Genes; Genetic; Individual; Knowledge; Maps; Mediating; Methods; Modality; Motor; Mus; Neurons; Output; Pattern; Play; Population; Positioning Attribute; Process; Property; Role; Schizophrenia; Sensory; Sensory Physiology; Shapes; Signal Transduction; Sleep; Source; Specificity; Structure; Structure/Function Nuclei; Subgroup; Testing; Thalamic Nuclei; Thalamic structure; Therapeutic; Thinking; Thinness; Training; Transgenic Mice; anatomical tracing; autism spectrum disorder; cell type; designer receptors exclusively activated by designer drugs; experimental study; memory consolidation; mouse model; novel; optogenetics; rabies viral tracing; sensory discrimination; sensory gating; sensory integration; single-cell RNA sequencing; sleep regulation; tool; transcriptomics; translational study

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.

项目总结 丘脑网状核(TRN)是丘脑抑制的主要来源，在 感觉加工、唤醒和认知。从皮质和皮质下区域接收输入，这 结构是影响丘脑-大脑皮层相互作用的战略位置。在静止期间，TRN 参与睡眠节律的产生、睡眠的稳定和记忆的巩固，而在活跃的状态下，TRN 神经元对潜在注意力的感觉过滤起到了作用。受扰的TRN功能可能是行为 从精神分裂症、自闭症到ADHD等各种疾病的缺陷。然而，尽管它很重要，但有几个 关键的挑战限制了我们确定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。这项提议旨在通过以下方式解决这一严重的知识差距 利用我们产生的一组新的发现和工具。TRN是GABA能的一个薄壳 丘脑投射核团周围的神经元。在TRN内，具有不同结构和 功能属性可以部分混合在一起。这一解剖特征一直是 功能研究，因为选择性靶向TRN神经元，这些神经元具有与 传统的方法具有挑战性。利用单细胞RNAseq，我们最近发现TRN神经元 可分为两个主要亚型，具有不同的转录谱，解剖定位， 电生理特性和丘脑连通性。一组，位于TRN的“核心”区域 并可通过Spp1基因的表达来标记，靶向于丘脑的一级感觉核，以及 另一个位于TRN的“外壳”区域，以Ecel1基因的表达为标志，靶向更高- 点一份。我们已经在这两个种群中分别产生了表达Cre重组酶的转基因小鼠 单独的。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 加工、唤醒和认知。