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 神经血管耦合（NVC）是一种将神经活动转化为慢或快速的机制 血液动力学反应。该机制对于血氧水平依赖（粗体）功能至关重要 磁共振成像（fMRI）研究，用于维持健康的脑组织。此外，对NVC的破坏 与脑血管疾病（例如中风）的风险增加有关。尽管很重要NVC 在确保功能性的大脑时，这种复杂机制的确切过程知之甚少。不同的 已经提出了负责血液动力学反应的介质。这些提议的调解员之一 是一氧化氮（NO），一种强的血管扩张剂。 NO是由酶神经元一氧化氮合酶（NNOS）催化的 在特定的神经元中。我们的实验室已经确定了共表达nNO和 速素受体1（TACR1），也称为物质P受体。这些TACR1神经元已经 观察到与神经血管单元相近。此外，TACR1神经元的光遗传学刺激 导致脑血流增加（CBF）。根据我们的发现，TACR1神经元介导了NVC。虽然 TACR1神经元表达NNO，是否造成光遗传学期间观察到的CBF的变化负责 刺激是未知的。此外，没有研究研究了激活TACR1神经元的细胞输入。 先前的研究表明，TACR1神经元被P（SP）去极化，但SP的来源 来自未知。一种可能性是白蛋白（PV）神经元，已知会释放Sp。 另外，已知PV神经元会产生γ波段振荡，这与 粗体信号。 PV神经元可能为TACR1神经元提供SP来源 在高γ波段活动中。因此，在高γ波段活性期间，TACR1神经元活性可能会增加 导致释放否。我建议确定是否 我的建议包括以下目的：目标1：确定 TACR1神经元活性增加脑血流（CBF）的分子机制。目标2：检查 激活TACR1神经元的细胞输入。 AIM 3：表征TACR1神经元的内源性活性 跨大脑状态。这些实验共同揭示了NVC的基础电路和关联 与国家有关的变化。这些知识是我们对大胆信号和的理解至关重要的 脑血管疾病。最后，在此提案中，我概述了严格的指导研究的组合 培训，课程工作以及专业和领导力发展活动以及该奖学金 培训期将有助于我作为有抱负的独立研究者的发展。 （NVC的间接度量） SP会导致状态依赖性TACR1增加 神经元活性，导致血管舒张。