Circuit Assembly in the developing thalamus

发育中丘脑的电路组装

• 批准号: 9905521
• 负责人: WILLIAM GUIDO
• 金额: $ 46.59万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905521
• 关键词: Acute; Address; Adult; Affect; Anatomy; Area; Attention; Attention Deficit Disorder; Axon; Biological Models; Brain; Brain Stem; CRH gene; Cell Differentiation process; Cell Nucleus; Childhood; Childhood Neurological Disorder; Cognitive; Conscious; Cre driver; Deafferentation procedure; Decision Making; Development; Development Plans; Diffuse; Disease; Dorsal; Electrophysiology (science); Epilepsy; Failure; Feedback; Gap Junctions; Generations; Genetic; Glutamates; Goals; In Vitro; Injections; Knowledge; Lateral Geniculate Body; Light; Link; Modality; Motor; Mus; Nature; Neocortex; Neurons; Pathway interactions; Pattern; Play; Preparation; Reporter; Retinal Ganglion Cells; Role; Schizophrenia; Sensory; Series; Signal Transduction; Sleep; Sleep Disorders; Slice; Source; Structure; Synapses; Testing; Thalamic Nuclei; Thalamic structure; Tomatoes; Trauma; Viral; Vision; Visual; Visual Cortex; Visualization; Wakefulness; autism spectrum disorder; awake; basal forebrain; basal forebrain cholinergic neurons; cell type; cellular development; cholinergic; cognitive function; developmental disease; experimental study; in vivo; insight; loss of function; mouse model; mutant; neonatal brain; nerve supply; nervous system disorder; optogenetics; postnatal; postsynaptic; response; retinogeniculate; sensory input

Project Summary/Abstract The thalamic reticular nucleus (TRN), is a shell like structure that surrounds the dorsal thalamus and serves as a key inhibitory interface for the bidirectional signaling between thalamus and the neocortex. Together with inputs from thalamus, cortex, and cholinergic nuclei of brainstem and basal forebrain, the TRN regulates many aspects of sensory, motor, and cognitive processing. When the connections between these structures are disrupted by disease, degeneration, or trauma, they have devastating consequences. In fact, many adult and childhood neurological disorders have at their core, a disturbance in TRN signaling and circuitry. Despite its key role in thalamocortical function, remarkably little is known about how reticular circuitry emerges during development and becomes operational. To address this substantive gap in knowledge we developed a robust mouse model as an experimental platform to visualize, manipulate, and dissect emergent and developing reticular circuitry. We plan to conduct anatomical, electrophysiological, and optogenetic experiments in genetically modified mice that allow for the visualization and experimental manipulation of specific cell types arising from the TRN, first-order thalamic sensory nuclei, layer VI of cortex, and cholinergic nuclei of brainstem and basal forebrain. The goals of this proposal focus on three unanswered questions about TRN development. First, how are the sensory sectors of TRN established; do inputs from primary sensory thalamic nuclei and corresponding regions of cortex innervate TRN diffusely and then segregate to form modality specific domains? Second, what is the sequence and pattern of driver and modulator innervation of TRN; do driver-like inputs from sensory thalamic nuclei such as the dorsal lateral geniculate nucleus, arrive prior to modulatory input from cortex, or brainstem and basal forebrain? Third, how and when do feed-forward and feedback circuits linking TRN to thalamus and cortex emerge during development to control thalamocortical signaling? Finally, for each of these questions, we plan to take a loss of function approach to assess whether the absence of sensory input (vision) affects the development, form, and function of reticular circuitry. These studies will provide valuable information about the organizing principles that guide the emergence of reticular circuitry in the neonatal brain, and perhaps reveal a new understanding into childhood disorders that result from abnormal patterns of connectivity.

项目概要/摘要 丘脑网状核（TRN）是一个围绕背侧丘脑的壳状结构，充当 丘脑和新皮质之间双向信号传导的关键抑制界面。连同 TRN 的输入来自丘脑、皮质、脑干和基底前脑的胆碱能核，调节许多 感觉、运动和认知处理方面。当这些结构之间的连接 由于疾病、退化或创伤的破坏，它们会产生毁灭性的后果。事实上，许多成年人和 儿童神经系统疾病的核心是 TRN 信号和电路的紊乱。尽管其 网状电路在丘脑皮质功能中发挥着关键作用，但人们对网状电路如何在丘脑皮质功能中出现的情况知之甚少。 开发并投入运营。为了解决这一知识上的实质性差距，我们开发了一个强大的 小鼠模型作为实验平台，用于可视化、操作和剖析新兴和发展中的事物 网状电路。我们计划在以下领域进行解剖学、电生理学和光遗传学实验 转基因小鼠可以对特定细胞类型进行可视化和实验操作 源自 TRN、丘脑一级感觉核、皮质 VI 层和脑干胆碱能核 和基底前脑。该提案的目标重点关注有关 TRN 开发的三个悬而未决的问题。 首先，TRN的感觉部分是如何建立的；从初级感觉丘脑核进行输入 皮质的相应区域广泛地支配 TRN，然后分离以形成特定的模态 域？其次，TRN的驱动器和调节器神经支配的顺序和模式是什么；像司机一样 来自感觉丘脑核（例如背外侧膝状核）的输入在调节之前到达 来自皮质、脑干和基底前脑的输入？三、如何以及何时进行前馈和反馈 连接 TRN 与丘脑和皮质的电路在发育过程中出现以控制丘脑皮质信号传导？ 最后，对于每个问题，我们计划采取功能丧失的方法来评估是否缺席 感觉输入（视觉）的影响影响网状电路的发育、形式和功能。这些研究将 提供有关指导网状电路出现的组织原则的宝贵信息 新生儿大脑，也许揭示了对由异常引起的儿童期疾病的新认识 连接模式。