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

项目概要/摘要 这个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 在决策、运动规划和运动执行过程中的活动。研究将采用 小鼠作为最合适的物种，以使现代光遗传学和遗传编码传感器 技术来填补我们对大脑功能理解的这一关键空白。在目标1中，我们讨论了 基底神经节输出对感觉和运动区皮质网络活动的影响。为此将使用 遗传编码的钙传感器选择性地表达在接受基底神经元输入的丘脑神经元中， 神经节（BGT），以记录这些丘脑轴突的激活模式，在皮层与宽场成像。我们 将进一步成像在光遗传学上对皮质中这些丘脑末梢的激活或抑制 在安静清醒的小鼠和进行强迫选择的小鼠中操纵基底神经节输出活动 左/右舔任务。在aim 1的第二项研究中，我们将使用遗传编码电压传感器来成像 特定皮质细胞类型在光遗传基底神经节输出操纵后的突触后激活。 这些研究的预期结果是，我们将有特点的影响，基底神经节 调节丘脑活动对皮层网络激活的影响。在目标2中，我们将讨论如何解决这些问题 在细胞和亚细胞水平上机械地实现网络效应。我们假设输入 BGT主要局限于表层皮质层，将导致非线性激活。 锥体细胞树突的树突特性，如钙或NMDA尖峰。为了解决这个假设 我们将在丘脑末梢和皮质树突中同时使用双光子钙成像， of our behavioral行为task任务.在第二项研究中，我们将使用全细胞记录行为小鼠， 光遗传学基底神经节输出操纵以确定兴奋和抑制效应的平衡 由于基底神经节活动而聚集在锥体细胞上。最后，在我们提出的目标3中， 我们将使用详细的生物物理神经建模来构建一个丘脑-皮层网络模型， 可以复制观察到的对基底神经节输出操纵的生理反应。亚细胞 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 锥体神经元树突的类型，需要解释观察到的反应。在网络层面，我们 将使用该模型搜索大量的光遗传基底神经节输出操作， 识别指示特定工作机制的候选刺激模式。然后我们将使用这些 我们记录的模式来测试模型预测，并更好地理解网络交互 是由基底神经节活动引起的总的来说，我们希望我们的工作将大大改善 机制的理解，基底神经节丘脑-皮质信号传递，以及如何功能障碍，这 在基底神经节疾病如帕金森氏病中，神经传导通路导致症状。

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.