Multiscale analysis of how the basal ganglia impact cortical processing in behaving mice

基底神经节如何影响行为小鼠皮质处理的多尺度分析

基本信息

批准号：
10172989
负责人：
DIETER JAEGER
金额：
$ 47.53万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10172989
关键词：
Address Affect Area Axon Basal Ganglia Basal Ganglia Diseases Behavior Behavioral Bilateral Biophysics Brain Butterflies Calcium Calcium Spikes Cerebrum Decision Making Dendrites Distal Dorsal Elements Equilibrium Food Forelimb Functional disorder Future Globus Pallidus Goals Image Interneurons Ion Channel Gating Knowledge Left Medial Mediating Membrane Modeling Modernization Motor Movement Mus N-Methylaspartate Neurons Outcome Outcome Study Output Parkinson Disease Pathway interactions Pattern Photons Physiological Preparation Process Property Pyramidal Cells Research Resolution Rewards Sensory Signal Transduction Spatial Distribution Stimulus Substantia nigra structure Symptoms Synapses Task Performances Techniques Testing Thalamic structure Ursidae Family Whole-Cell Recordings Work awake base cell type cognitive process excitatory neuron experimental study hippocampal pyramidal neuron improved innovation interest network models neural model optogenetics postsynaptic postsynaptic neurons predictive modeling relating to nervous system response selective expression sensor sensor technology transmission process two-photon voltage

项目摘要

Project Summary/Abstract The overall goal of this project is to determine how output from the basal ganglia influences cerebral cortical activity in the processes of decision making, motor planning, and movement execution. The studies will employ mice as the best suited species in order to bring modern optogenetic and genetically encoded sensor technologies to bear on this critical gap in our understanding of brain function. In aim 1 we address the impact of basal ganglia output on network activity in cortex across sensory and motor areas. To this end will use genetically encoded calcium sensors selectively expressed in thalamic neurons receiving input from the basal ganglia (BGT) to record the pattern of activation of these thalamic axons in cortex with wide-field imaging. We will further image the resulting activation or inhibition of these thalamic terminals in cortex upon optogenetic manipulations of basal ganglia output activity in quietly awake mice and mice performing a forced choice left/right licking task. In a second study under aim 1 we will use genetically encoded voltage sensors to image the postsynaptic activation of specific cortical cell types upon optogenetic basal ganglia output manipulations. The expected outcome of these studies is that we will have characterized the impact of basal ganglia modulated thalamic activity on cortical network activation. In aim 2 we will address the question of how these network effects are mechanistically achieved at the cellular and subcellular level. We hypothesize that the input of BGT, which is primarily restricted to superficial cortical layers, will result in the activation of non-linear dendritic properties of pyramidal cell dendrites such as calcium or NMDA spikes. To address this hypothesis we will use simultaneous 2-photon calcium imaging in thalamic terminals and cortical dendrites in the context of our behavioral task. In a second study we will use whole cell recordings in behaving mice in conjunction with optogenetic basal ganglia output manipulations to determine the balance of excitatory and inhibitory effects converging on pyramidal cells as a consequence of basal ganglia activity. Finally, in aim 3 of our proposed research we will use detailed biophysical neural modeling to construct a thalamo-cortical network model that can replicate the observed physiological responses to basal ganglia output manipulations. On the subcellular level, we will use this model to determine the specific synaptic input strengths and voltage-gated ion channel types in pyramidal neuron dendrites that are required to explain observed responses. On the network level we will use the model to search through a large number of optogenetic basal ganglia output manipulations to identify candidate stimulus patterns that indicate specific mechanisms at work. We will then employ these patterns in our recordings to test model predictions and come to a better understanding of network interactions resulting from basal ganglia activity. Overall, we expect that our work will result in a much improved mechanistic understanding of basal ganglia thalamo-cortical signal transmission, and how dysfunction of this pathway contributes to symptoms in basal ganglia disorders such as Parkinson’s disease.

项目摘要/摘要该项目的总体目标是确定基底神经节的输出如何影响脑皮质在决策，运动计划和移动执行过程中的活动。研究将采用小鼠是最适合的物种，以携带现代光学遗传学和遗传编码的传感器在我们对大脑功能的理解时，要遵守这一关键差距的技术。在目标1中，我们解决了影响基底神经节输出在感觉和运动区域的皮质中的网络活动上。为此，将使用遗传编码的钙传感器在丘脑神经元中选择性表达，从基本神经节（BGT）记录了这些丘脑轴突在皮质中的激活模式，并带有广场成像。我们将进一步成像在光遗传学时在皮质中这些丘脑末端的激活或抑制在静静清醒老鼠和执行强迫选择的小鼠中，低音节的输出活动操纵左/右舔任务。在AIM 1的第二项研究中，我们将使用一般编码的电压传感器进行图像在光遗传性巴萨神经节输出操纵下，特定皮质细胞类型的突触后激活。这些研究的预期结果是，我们将表征巴萨神经节的影响对皮质网络激活的丘脑活性调节活性。在AIM 2中，我们将解决这些问题的问题网络效应是在细胞和亚细胞水平上实现的。我们假设输入 BGT的主要仅限于浅表皮质层的BGT将导致非线性激活锥体细胞树突（例如钙或NMDA尖峰）的树突状性能。解决这一假设我们将在丘脑末端和皮质树突中使用Simpletaneous 2-Photon钙成像我们的行为任务。在第二项研究中，我们将在行为小鼠中使用全细胞记录以及光遗传学基础神经节输出操纵以确定兴奋和抑制作用的平衡由于基底神经节活性而在金字塔细胞上融合。最后，在我们提议的目标3中研究我们将使用详细的生物物理神经建模来构建一种丘脑皮层网络模型，该模型可以复制观察到的对基底神经节输出操作的物理反应。在亚细胞上级别，我们将使用此模型来确定特定的突触输入强度和电压门控离子通道用于解释观察到的反应所需的金字塔神经元树突中的类型。在网络级别我们将使用该模型搜索大量光遗传性巴萨神经节输出操作确定指示工作中特定机制的候选刺激模式。然后，我们将雇用这些 patterns in our recordings to test model predictions and come to a better understanding of network interactions 由基底神经节活动引起的。总体而言，我们希望我们的工作将带来很大改善对基底神经节丘脑 - 皮质信号传播的机械理解，以及如何功能障碍途径会导致基底神经节疾病（例如帕金森氏病）的症状。