Impact of subcortical inputs on frontal cortex via thalamus

皮层下输入通过丘脑对额叶皮层的影响

基本信息

批准号：
10294403
负责人：
Adam G Carter
金额：
$ 51.91万
依托单位：
ALLEN INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-15 至 2026-12-31
项目状态：
未结题

项目摘要

Summary, Project 3 (Impact of subcortical inputs on frontal cortex via thalamus) The goal of this project is to elucidate the functional influence of subcortical inputs on the frontal cortex via non- sensory ('higher-order') thalamus. Each part of the frontal cortex receives inputs from multiple thalamic nuclei, each of which in turn receives inputs from diverse subcortical brain regions. Our recent work has established clear motifs for how different thalamic inputs can engage specific populations of pyramidal cells and interneurons in the frontal cortex. However, we still lack even a basic understanding of how subcortical inputs are organized in the thalamus, including how they are routed at the level of thalamic nuclei and single thalamocortical (TC) cells. Here we test the hypothesis that each subcortical input either excites or inhibits a defined subset of TC cells to engage specific networks in the frontal cortex. In Aim 1, we use electrophysiology to study the organization and influence of specific subcortical inputs on the thalamus and cortex in the intact brain. This work leverages new, high-density Neuropixels 2.4 probes that allow dense sampling of TC cell activity across thalamic nuclei. These experiments will define convergence and divergence rules in the thalamus and determine how subcortical signals propagate to frontal cortex. In Aim 2, we use brain slice electrophysiology to determine the properties of subcortical connections onto identified TC cells in the thalamus. We incorporate patch-Seq analysis to assess gene expression of each recorded neuron, linking processing of subcortical inputs with TC cell type. This work builds on Projects 1 and 2 and the Molecular Science Core, providing a foundational analysis of subcortical connections to the thalamus. In Aim 3, we then use voltage imaging in slices to examine how specific subcortical-thalamic pathways engage distinct networks across the frontal cortex, focusing on medial prefrontal cortex and motor cortex. Here we use anterograde viruses to conditionally express optogenetic tools in TC cells that then engage specific networks in the frontal cortex. We also employ mFISH to assess the genetic signatures of imaged excitatory and inhibitory cells, again allowing for sub-populations to be determined. Together, our experiments will establish the organization and properties of connections from subcortical inputs to higher-order thalamus and in turn the frontal cortex. They will serve as a strong foundation for our behavioral studies in Project 4, and constrain multi-regional models of neural computation developed in Project 5.

摘要，项目 3（皮层下输入通过丘脑对额叶皮层的影响）该项目的目标是阐明皮层下输入对额叶皮层的功能影响感觉（“高阶”）丘脑。额叶皮层的每个部分接收来自多个丘脑核的输入，每个神经元依次接收来自不同皮层下大脑区域的输入。我们最近的工作已经建立关于不同丘脑输入如何参与特定锥体细胞和中间神经元群体的清晰主题在额叶皮层。然而，我们仍然缺乏对皮层下输入如何组织的基本了解在丘脑中，包括它们如何在丘脑核和单个丘脑皮质 (TC) 水平上路由细胞。在这里，我们测试以下假设：每个皮层下输入要么兴奋要么抑制 TC 的定义子集细胞参与额叶皮层中的特定网络。在目标 1 中，我们使用电生理学来研究特定皮质下输入对完整大脑中丘脑和皮质的组织和影响。这部作品利用新型高密度 Neuropixels 2.4 探针，可对整个丘脑的 TC 细胞活动进行密集采样原子核。这些实验将定义丘脑的收敛和发散规则，并确定如何皮层下信号传播到额叶皮层。在目标 2 中，我们使用脑切片电生理学来确定皮层下连接到丘脑中已识别的 TC 细胞的特性。我们整合了 patch-Seq 分析评估每个记录神经元的基因表达，将皮层下输入的处理与 TC 细胞类型联系起来。这项工作建立在项目 1 和 2 以及分子科学核心的基础上，提供了以下方面的基础分析：皮质下与丘脑的连接。在目标 3 中，我们随后使用切片中的电压成像来检查具体如何皮质下丘脑通路涉及额叶皮层的不同网络，重点关注内侧前额叶皮层和运动皮层。在这里，我们使用顺行病毒在TC细胞中条件表达光遗传学工具然后参与额叶皮层的特定网络。我们还使用 mFISH 来评估遗传特征成像的兴奋性和抑制性细胞，再次允许确定亚群。在一起，我们的实验将建立从皮层下输入到高阶连接的组织和属性丘脑，然后是额叶皮层。它们将为我们的项目行为研究奠定坚实的基础 4，并约束项目5中开发的神经计算的多区域模型。