Investigating the mechanism by which Tacr1 Neurons Regulate Neurovascular Coupling

项目总结/摘要 神经血管耦合（NVC）是一种机制，它将神经活动转换为慢或快 血流动力学反应。这种机制对于血氧水平依赖性（BOLD）功能性 磁共振成像（fMRI）研究，并保持健康的脑组织。此外，对雷士的破坏 与脑血管疾病如中风的风险增加有关。尽管NVC 在确保大脑功能正常方面，人们对这种复杂机制的确切过程知之甚少。不同 已经提出了负责血液动力学反应的介质。这些被提议的调解人之一 是一氧化氮（NO），一种强血管扩张剂。NO由神经元型一氧化氮合酶（nNOS）催化 在特定的神经元中。我们的实验室已经确定了一个皮质抑制性神经元的子集，它们共表达nNOS， 速激肽受体1（TACR 1），也称为P物质受体。这些Tacr 1神经元 观察到其与神经血管单元接近。此外，Tacr 1神经元的光遗传学刺激 导致脑血流量（CBF）增加。根据我们的研究结果，Tacr 1神经元介导NVC。即使 Tacr 1神经元表达nNOS，无论NO是否负责光遗传学过程中观察到的CBF变化， 刺激未知。此外，没有研究调查激活Tacr 1神经元的细胞输入。 以前的研究表明，Tacr 1神经元被P物质（SP）去极化，但SP的来源 是从哪里来的还不清楚一种可能性是小清蛋白（PV）神经元，已知其释放SP。 此外，已知PV神经元产生伽马带振荡，这与神经元的运动密切相关。 粗体信号。PV神经元可能为Tacr 1神经元提供SP来源 在高伽玛波段活动。因此，Tacr 1神经元活动可能在高γ-波段活动期间增加 我建议决定是否 我的建议包括以下目标：目标1：确定 Tacr 1神经元活动增加脑血流量（CBF）的分子机制。目标2：检查 激活Tacr 1神经元的细胞输入。目的3：表征Tacr 1神经元的内源性活性 跨越大脑状态。总之，这些实验可能揭示NVC的潜在电路以及 与状态相关的变化。这些知识是我们理解BOLD信号的基础， 脑血管疾病最后，在这个建议中，我概述了一个严格的指导研究的组合， 培训，课程，以及专业和领导力发展活动，沿着这个奖学金 培训期间将有助于我发展成为一个有抱负的独立调查员。 (an NVC的间接测量） SP导致Tacr 1的状态依赖性增加 神经元活动，导致血管舒张。

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.