Circuit Assembly in the developing thalamus

项目摘要/摘要 丘脑网状核(TRN)是围绕丘脑背侧的壳状结构，起着 丘脑和新皮质之间双向信号传递的关键抑制接口。与.一起 从丘脑、皮质、脑干和基底前脑的胆碱能核传入，TRN调节许多 感觉、运动和认知过程的各个方面。当这些结构之间的连接是 受到疾病、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信号和回路的障碍。尽管它的 在丘脑皮质功能中起关键作用，令人惊讶的是，人们对网状回路是如何在 开发并投入使用。为了解决这一实质性的知识差距，我们开发了一种强大的 小鼠模型作为可视化、操控和解剖发生和发展的实验平台 网状电路。我们计划进行解剖学、电生理学和光遗传学实验 转基因小鼠，允许对特定细胞类型进行可视化和实验操作 发自TRN、丘脑一级感觉核团、皮质VI层和脑干胆碱能核团 和基底前脑。这项提案的目标集中在关于TRN发展的三个悬而未决的问题上。 首先，TRN的感觉部分是如何建立的；来自丘脑初级感觉核团和 皮质的相应区域弥漫地支配TRN，然后分离形成特定的通道 域名？第二，TRN的驱动和调节神经支配的顺序和模式是什么；做类似驱动的 来自丘脑感觉核团的输入，如膝状体背外侧核，在调制之前到达 是来自大脑皮层，还是来自脑干和基底前脑？第三，如何以及何时进行反馈和反馈 将TRN连接到丘脑和皮质的回路在发育过程中出现，以控制丘脑皮质信号？ 最后，对于这些问题中的每一个，我们都计划采取功能丧失的方法来评估是否缺席 感觉输入(视觉)的变化影响网状回路的发育、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有价值的信息 新生儿的大脑，也许揭示了对由异常引起的儿童障碍的新理解 连接模式。

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.