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

项目摘要/摘要 这个项目的总体目标是确定基底节的输出如何影响大脑皮层。 在决策、运动规划和动作执行过程中的活动。这些研究将采用 老鼠作为最适合的物种，才能带来现代的光遗传和基因编码传感器 填补我们对大脑功能理解上的这一关键差距的技术。在目标1中，我们讨论了影响 基底节输出对感觉和运动区皮质网络活动的影响。为此，将使用 基因编码的钙感受器选择性地表达在接受基底细胞输入的丘脑神经元中 神经节(BGT)，用广野成像记录这些丘脑轴突在皮质的激活模式。我们 将进一步成像这些丘脑终末在光发生时在皮层的激活或抑制 安静清醒小鼠和强迫选择小鼠对基底神经节输出活动的操纵 左/右舔任务。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 光发生基底节输出操作时特定皮质细胞类型的突触后激活。 这些研究的预期结果是，我们将表征基底节的影响 调节丘脑活动对皮质网络的激活。在目标2中，我们将解决以下问题： 网络效应是在细胞和亚细胞水平上机械实现的。我们假设输入的是 BGT的主要局限于皮质浅层，将导致非线性 锥体细胞树突的树突特性，如钙或NMDA刺激物。要解决这一假设 在本文中，我们将在丘脑终末和皮质树突中同时使用双光子钙成像 我们的行为任务。在第二项研究中，我们将使用全细胞记录来表现小鼠的行为， 光发生基底节输出操作确定兴奋和抑制效应的平衡 由于基底节活动而聚集在锥体细胞上。最后，在我们建议的目标3中 研究我们将使用详细的生物物理神经建模来构建丘脑-皮质网络模型， 可以复制观察到的对基底节输出操作的生理反应。在亚细胞上 水平，我们将使用这个模型来确定特定的突触输入强度和电压门控离子通道 锥体神经元树突中需要用来解释观察到的反应的类型。在网络层面上，我们 将使用该模型通过大量的光发生基底节输出操作来搜索 确定表明特定作用机制的候选刺激模式。然后我们将使用这些 我们录音中的模式，用于测试模型预测并更好地理解网络交互 由基底节活动引起。总体而言，我们预计我们的工作将会有很大的改善 对基底节-丘脑-皮质信号传递的机制理解，以及这种信号传递的功能障碍 通路与帕金森氏病等基底节疾病的症状有关。

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.