Inhibitory Neuron Sub-populations and Their Influence on Hemodynamic Imaging

项目摘要/摘要 神经元活动积极调节局部脑血管系统。这种神经-血管的相互作用是 对健康和疾病中人类大脑功能的成像研究。这些研究是常规进行的，而 受试者执行任务(诱发的活动)或躺着休息(无任务或休息状态的活动)，并且他们假设 成像信号忠实地反映了局部神经元的活动。然而，神经-血管信号机制是 已经报道了复杂的解偶联和实例，限制了这些研究的可解释性。近期 报告显示，不同类型的神经元比其他类型的神经元更能调节局部血液供应， 尤其是抑制性神经元。这些发现强调了理解血管调节作用的必要性。 不同的神经元群体，特别是考虑到神经障碍与 特异性抑制性神经元亚群的功能障碍。这项提案的目标是确定 不同亚群抑制神经元在诱发刺激时对局部血流的调节作用 以及在休息状态活动期间。实验将使用独特的转基因小鼠进行 模特们。此外，我们将确定这些发现是否适用于不同的皮质区域和 通过比较抑制性神经元的分布来探索这些发现对人类的可译性 强烈调节小鼠和人脑目标区域的局部血液流动。我们集团拥有广泛的 神经血管(和神经代谢)生理学的多模式专业知识，包括模型和技术 我们有得天独厚的优势，能够成功地完成这个项目的目标。我们将实现 这些目标通过三个目标：(目标1)确定哪些抑制性神经元亚型强烈地调节局部 光发生刺激引起的不同皮质区域的血流变化；(目标2)确定 在持续的清醒活动中，相同的抑制神经元亚群调节局部血流变化 周期；以及(目标3)确定目标1和目标2中识别的抑制神经元的亚群是否 同样分布在小鼠和人脑的目标区域。由于抑制性神经元的形状 网络活动，这些研究将详细说明特定抑制性神经元亚型功能和 功能障碍对局部血液供应和基于血流动力学的成像信号，扩大了可解释性和 人脑成像研究在健康和疾病中的临床应用。

PROJECT SUMMARY/ABSTRACT Neuronal activity actively modulates local cerebral vasculature. This neuro-vascular interaction is the foundation of imaging studies of human brain function in health and disease. These studies are routinely performed while subjects perform tasks (evoked activity) or lie resting (task-free or resting-state activity), and they assume that imaging signals loyally reflect local neuronal activity. However, the neuro-vascular signaling mechanism is complex and instances of uncoupling have been reported, limiting the interpretability of these studies. Recent reports have shown that different types of neurons can regulate local blood supply stronger than others, especially inhibitory neurons. These findings underscore the need to understand the vaso-regulatory roles of different neuronal populations, especially considering that neurological disorders have been associated with dysfunction of specific inhibitory neuron sub-populations. The goal of this proposal is to determine the role of different sub-populations of inhibitory neurons on the regulation of local blood flow during evoked stimulation as well as during resting-state activity periods. Experiments will be performed using unique transgenic mouse models. In addition, we will determine whether these findings generalize over different cortical regions and explore the translatability of these findings to human subjects by comparing the distribution of inhibitory neurons that strongly regulate local blood flow in targeted regions of mouse and human brains. Our group has extensive multi-modal expertise in neuro-vascular (and neuro-metabolic) physiology, including the models and techniques proposed, and we are uniquely positioned to successfully complete the aims of this project. We will achieve these goals through three aims: (Aim 1) Determine which inhibitory neuron sub-types strongly regulate local blood flow changes evoked by optogenetic stimulation in different cortical regions; (Aim 2) Determine whether the same sub-population of inhibitory neurons regulate local blood flow changes during ongoing awake activity periods; and (Aim 3) Determine whether the sub-populations of inhibitory neurons identified in Aims 1 and 2 are similarly distributed across the targeted regions of mouse and human brains. Since inhibitory neurons shape network activity, these studies will detail the impact of specific inhibitory neuronal sub-type function and dysfunction on local blood supply and hemodynamic-based imaging signals, expanding the interpretability and clinical utility of human brain imaging studies in health and disease.