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

• 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
• 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

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.

项目概要/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大脑皮层 研究将采用决策、运动规划和运动执行过程中的活动。 小鼠是最适合带来现代光遗传学和基因编码传感器的物种 技术来弥补我们对大脑功能理解的这一关键差距，在目标 1 中，我们解决了这一影响。 基底神经节输出对感觉和运动区域皮层网络活动的影响。 基因编码的钙传感器选择性地在丘脑神经元中表达，接收来自基底细胞的输入 神经节（BGT），通过宽视野成像记录皮质中这些丘脑轴突的激活模式。 将进一步通过光遗传学成像皮层中这些丘脑末梢的激活或抑制 操纵安静清醒的小鼠和执行强迫选择的小鼠的基底神经节输出活动 在目标 1 下的第二项研究中，我们将使用基因编码的电压传感器来成像。 光遗传学基底神经节输出操作后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描述基底神经节的影响 在目标 2 中，我们将解决这些如何调节丘脑活动对皮质网络激活的问题。 网络效应是在细胞和亚细胞水平上机械地实现的。 BGT 主要局限于浅表皮质层，将导致非线性的激活 锥体细胞树突的树突特性，例如钙或 NMDA 尖峰，以解决这一假设。 我们将在丘脑末梢和皮质树突中使用同步 2 光子钙成像 在第二项研究中，我们将结合使用小鼠行为的全细胞记录。 光遗传学基底神经节输出操作以确定兴奋性和抑制性效应的平衡 最后，我们提出的目标 3 是由于基底神经节活动而聚集在锥体细胞上。 研究中我们将使用详细的生物物理神经模型来构建丘脑皮质网络模型 可以在亚细胞上复制观察到的基底神经节输出操作的生理反应。 水平，我们将使用该模型来确定特定的突触输入强度和电压门控离子通道 锥体神经树突的类型需要在网络层面上解释观察到的反应。 将使用该模型搜索大量光遗传学基底神经节输出操作 确定表明工作中特定机制的候选刺激模式，然后我们将采用这些模式。 我们记录中的模式来测试模型预测并更好地理解网络交互 总体而言，我们预计我们的工作将带来很大的改善。 对基底节丘脑皮质信号传递的机制的理解，以及这种功能障碍是如何发生的 该通路会导致帕金森病等基底神经节疾病的症状。