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.

项目总结/文摘