Inhibitory Neuron Sub-populations and Their Influence on Hemodynamic Imaging

抑制性神经元亚群及其对血流动力学成像的影响

• 批准号: 10210750
• 负责人: ALBERTO L VAZQUEZ
• 金额: $ 54.52万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10210750
• 关键词: Air; Animals; Autopsy; Basic Science; Blood Vessels; Blood flow; Brain; Brain imaging; Brain region; Cerebrovascular system; Clinical; Clinical Research; Cognitive; Complex; Development; Disease; Early Diagnosis; Fluorescence; Foundations; Functional Magnetic Resonance Imaging; Functional disorder; GABA Receptor; Glutamate Receptor; Goals; Head; Health; Human; Image; Impairment; Location; Measures; Methods; Modeling; Monitor; Mus; Nerve Degeneration; Neurons; Nitric Oxide Synthase; Optical Methods; Parvalbumins; Pathway interactions; Physiology; Population; Positioning Attribute; Regulation; Reporter; Reporting; Rest; Role; Sensory; Shapes; Signal Transduction; Somatosensory Cortex; Somatostatin; Techniques; Tissues; Transgenic Mice; Vascular blood supply; Vasoactive Intestinal Peptide; Vibrissae; Viral; Work; awake; base; cell type; design; experimental study; frontal lobe; hemodynamics; human subject; imaging study; improved; inhibitory neuron; insight; mouse model; multimodality; nervous system disorder; neurovascular; optical imaging; optogenetics; relating to nervous system; response; somatosensory

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.

项目总结/摘要 神经元活动积极调节局部脑血管。这种神经血管的相互作用是 对健康和疾病中的人脑功能进行成像研究。这些研究是常规进行的， 受试者执行任务（诱发活动）或躺下休息（无任务或休息状态活动），他们假设， 成像信号忠实地反映局部神经元活动。然而，神经血管信号机制是 复杂的和解偶联的实例已被报道，限制了这些研究的可解释性。最近 报告显示不同类型的神经元可以比其他神经元更强地调节局部血液供应， 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，特别是考虑到神经系统疾病与 特异性抑制性神经元亚群的功能障碍。本提案的目的是确定 不同亚群的抑制性神经元在诱发刺激过程中对局部血流的调节， 以及在静息状态活动期间。将使用独特的转基因小鼠进行实验 模型此外，我们将确定这些发现是否适用于不同的皮质区域， 通过比较抑制性神经元的分布，探索这些发现对人类受试者的可翻译性 在小鼠和人类大脑的目标区域强烈调节局部血流。我们的团队拥有广泛的 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 建议，我们处于独特的地位，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调节局部 在不同皮质区域中由光遗传学刺激诱发的血流变化;（目的2）确定是否 相同的抑制性神经元亚群在持续的清醒活动期间调节局部血流变化 （目的3）确定目的1和2中鉴定的抑制性神经元的亚群是否 类似地分布在小鼠和人类大脑的目标区域。由于抑制神经元的形状 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的影响， 局部血液供应和基于血流动力学的成像信号的功能障碍，扩展了可解释性， 人类大脑成像研究在健康和疾病中的临床应用。