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

• 批准号: 10678077
• 负责人: Maria Fernanda Juarez Anaya
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678077
• 关键词: Brain; Brain imaging; Calcium; Cerebrovascular Circulation; Cerebrovascular Disorders; Complex; Development; Disease; Electroencephalography; Ensure; Enzymes; Fellowship; Frequencies; Functional Magnetic Resonance Imaging; Future; G-Protein-Coupled Receptors; Goals; Health; Human; Image; Knowledge; Laser-Doppler Flowmetry; Ligands; Link; Measures; Mediating; Mediator; Mentors; Microscopy; Molecular; Mus; Neurons; Neuropeptides; Nitric Oxide; Nitric Oxide Synthase Type I; Nitric Oxide Synthetase Inhibitor; Nutrient; Oxygen; Parvalbumins; Pathway interactions; Perfusion; Process; Production; Research Personnel; Research Training; Risk; Scientist; Signal Transduction; Sleep; Somatosensory Cortex; Source; Stroke; Substance P; TAC1 gene; TACR1 gene; Testing; Therapeutic; Tissues; Training; Translating; Vasodilation; Vasodilator Agents; Viral; Wakefulness; antagonist; awake; blood oxygen level dependent; brain health; brain tissue; cerebrovascular; experimental study; hemodynamics; imaging study; in vivo; inhibitory neuron; leadership development; nervous system disorder; neural; neurovascular; neurovascular coupling; neurovascular unit; optogenetics; response; training opportunity; two-photon

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.

项目摘要/摘要 神经血管偶联(NVC)是一种将神经活动转换为慢或快的机制 血流动力学反应。这一机制对血氧水平依赖(BOLD)功能至关重要 磁共振成像(FMRI)研究，并用于维护健康的脑组织。此外，NVC的中断 与中风等脑血管疾病的风险增加有关。尽管NVC很重要 在确保大脑功能方面，这一复杂机制的确切过程尚不清楚。不同 已经提出了负责血流动力学反应的介体。这些被提议的调解人中的一个 是一氧化氮(NO)，一种强大的血管扩张剂。NO由神经元型一氧化氮合酶(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)，又称P物质受体。这些Tacr1神经元一直是 观察到靠近神经血管单位。此外，对Tacr1神经元的光发生刺激 结果脑血流量(CBF)增加。根据我们的发现，Tacr1神经元介导NVC。即使 Tacr1神经元表达nNOS，NO是否与光发生过程中观察到的CBF变化有关 刺激是未知的。此外，还没有研究过激活Tacr1神经元的细胞输入。 以前的研究表明，Tacr1神经元被P物质(SP)去极化，但SP的来源 从哪里来是未知的。一种可能性是小白蛋白(PV)神经元，它可以释放SP。 此外，众所周知，PV神经元会产生伽马频段振荡，这与 大胆的信号。PV神经元可能为Tacr1神经元提供SP来源 在高伽马频段活动期间。因此，在高伽马频段活动期间，Tacr1神经元的活性可能会增加 导致NO的释放。我提议确定是否 我的建议包括以下目标：目标1：确定 Tacr1神经元活性增加脑血流量的分子机制。目标2：检查 激活Tacr1神经元的细胞输入。目的3：研究Tacr1神经元的内源性活性 不同的大脑状态。综上所述，这些实验可能会揭示NVC及其关联的电路 与状态相关的变化。这一知识是我们理解粗体信号和 脑血管疾病。最后，在这个提案中，我概述了严格指导的研究的组合 培训、课程作业以及专业和领导力发展活动，与此奖学金一起 培训期间将有助于我作为一名有抱负的独立调查员的发展。 (NVC的间接衡量标准) SP导致Tacr1的状态依赖性增加 神经元活动，导致血管扩张。