Investigating the mechanism by which Tacr1 Neurons Regulate Neurovascular Coupling

研究 Tacr1 神经元调节神经血管耦合的机制

基本信息

项目摘要

PROJECT SUMMARY/ABSTRACT Neurovascular coupling (NVC) is a mechanism that translates neural activity into either slow or fast hemodynamic responses. This mechanism is critical for blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) studies, and for maintaining healthy brain tissue. Also, disruptions to NVC have been linked to an increased risk of cerebrovascular disorders, such as stroke. Despite the importance NVC has in ensuring a functional brain, the exact process of this complex mechanism is poorly understood. Different mediators responsible for the hemodynamic responses have been proposed. One of these proposed mediators is nitric oxide (NO), a strong vasodilator. NO is catalyzed by the enzyme neuronal nitric oxide synthase (nNOS) in specific neurons. Our lab has identified a subset of cortical inhibitory neurons that co-express nNOS and Tachykinin Receptor 1 (TACR1), also known as substance P receptor. These Tacr1 neurons have been observed to be in proximity with the neurovascular unit. Moreover, optogenetic stimulation of Tacr1 neurons results in increased cerebral blood flow (CBF). Based on our findings, Tacr1 neurons mediate NVC. Even though Tacr1 neurons express nNOS, whether NO is responsible for the observed changes in CBF during optogenetic stimulation is unknown. Furthermore, no studies have investigated the cellular inputs that activate Tacr1 neurons. Previous studies suggest that Tacr1 neurons are depolarized by substance P (SP), but where the source of SP is coming from is unknown. One possibility is parvalbumin (PV) neurons, which are known to release SP. Additionally, PV neurons are known to produce gamma-band oscillations, which are strongly correlated to the BOLD signal . PV neurons may be providing a source of SP for Tacr1 neurons during high gamma-band activity. As such, Tacr1 neuron activity may increase during high gamma-band activity causing the release of NO. I propose to determine whether My proposal comprises of the following aims: Aim 1: Determine the molecular mechanism through which Tacr1 neuron activity increases cerebral blood flow (CBF). Aim 2: Examine the cellular inputs that activate Tacr1 neurons. Aim 3: Characterize the endogenous activity of Tacr1 neurons across brain states. Together, these experiments may reveal the circuitry underlying NVC and the association with state-dependent changes. This knowledge is fundamental to our understanding of BOLD signal and cerebrovascular disorders. Finally, in this proposal, I outlined a combination of rigorous mentored research training, coursework, and professional and leadership development activities that along with this fellowship training period will be instrumental in my development as an aspiring independent investigator. (an indirect measure of NVC) SP causes a state-dependent increase in Tacr1 neuron activity, resulting in vasodilation.
项目概要/摘要 神经血管耦合 (NVC) 是一种将神经活动转化为慢速或快速的机制 血流动力学反应。这种机制对于血氧水平依赖性(BOLD)功能至关重要 磁共振成像(fMRI)研究,以及维持健康的脑组织。此外,NVC 也受到干扰 与中风等脑血管疾病的风险增加有关。尽管雷士很重要 在确保大脑功能正常的过程中,人们对这种复杂机制的确切过程知之甚少。不同的 已经提出了负责血流动力学反应的介质。这些提议的调解员之一 是一氧化氮(NO),一种强血管扩张剂。 NO 由神经元一氧化氮合酶 (nNOS) 催化 在特定的神经元中。我们的实验室已经鉴定出皮质抑制神经元的一个子集,它们共同表达 nNOS 和 速激肽受体 1 (TACR1),也称为 P 物质受体。这些 Tacr1 神经元 观察到靠近神经血管单元。此外,Tacr1神经元的光遗传学刺激 导致脑血流量(CBF)增加。根据我们的发现,Tacr1 神经元介导 NVC。虽然 Tacr1 神经元表达 nNOS,NO 是否与光遗传学过程中观察到的 CBF 变化有关 刺激未知。此外,还没有研究调查激活 Tacr1 神经元的细胞输入。 先前的研究表明 Tacr1 神经元被 P 物质 (SP) 去极化,但 SP 的来源 来自未知。一种可能性是小清蛋白 (PV) 神经元,已知它会释放 SP。 此外,PV 神经元会产生伽马带振荡,这与 粗体信号。 PV 神经元可能为 Tacr1 神经元提供 SP 来源 在高伽玛能带活动期间。因此,Tacr1 神经元活动在高伽马带活动期间可能会增加 导致NO的释放。我建议确定是否 我的建议包括以下目标: 目标 1:确定 Tacr1 神经元活动增加脑血流量 (CBF) 的分子机制。目标 2:检查 激活 Tacr1 神经元的细胞输入。目标 3:表征 Tacr1 神经元的内源活性 跨越大脑状态。总之,这些实验可能会揭示 NVC 的底层电路及其关联 与状态相关的变化。这些知识对于我们理解 BOLD 信号和 脑血管疾病。最后,在这个提案中,我概述了严格的指导研究的结合 培训、课程作业以及专业和领导力发展活动以及该奖学金 培训期将有助于我成为一名有抱负的独立调查员的发展。 (NVC 的间接衡量) SP 导致 Tacr1 状态依赖性增加 神经元活动,导致血管舒张。

项目成果

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