Mechanisms underlying neurovascular coupling

神经血管耦合的机制

• 批准号: RGPIN-2018-05948
• 负责人: Girouard, Hélène
• 金额: $ 4.74万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=691341
• 关键词: Mechanisms; underlying; neurovascular; coupling

Neurovascular coupling (NVC) -the dynamic linkage between neuronal energy needs and local blood supply- is critical to the maintenance of brain homeostasis. In the brain, increased neuronal synaptic activity is accompanied by an increase in local cerebral blood flow (CBF) that serves to satisfy enhanced glucose and oxygen demand. Beside its crucial physiological role, a better understanding of the mechanisms underlying NVC is very important because this concept is at the basis of modern neuroimaging techniques such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET). Despite the fact that these techniques are, in fact, measuring cerebral oxygen, glucose or CBF levels and that the relationship between these variables and neuronal activity are non-linear, results are still falsely interpreted as a direct reflection of neuronal activity. It is thus imperative to better understand the mechanisms underlying NVC. Among the vasoactive factors that could participate in NVC, one powerful vasodilator and endogenously produced gas have been identified, nitric oxide (NO). NO may potentially act on all type of cells of the neurovascular unit (neurons, astrocytes and vascular cells). Astrocytes, which are uniquely positioned between synapses and vessels, have been recognized as integrators of the neuronal signals to relay information to the vessels and could be an interesting target and source of NO. We indeed demonstrated that astrocytes produce NO upon different neurological stimulations. The major focus of the present proposal is to understand how NO and astrocytic signaling pathways interact together to modulate NVC. We HYPOTHETIZE that NO modulates NVC mostly but not uniquely by regulating astrocytic-dependent pathways. To verify this hypothesis, we propose three specific AIMS: 1) To elucidate the effect of NO on Ca2+-dependent astrocytic pathways in the context of NVC ; 2) To elucidate how astrocytic nNOS and eNOS mediated NO production regulates NVC ; 3) To discriminate the importance of NO from interneurons, pyramidal neurons and astrocytes in NVC. These mechanisms will be studied using transgenic mice and pharmacological tools with two-photon microscopy and laser Doppler flowmetry. The proposed concept is very INNOVATIVE because it is assumed that NO is produced by neurons or endothelial cells to act as vasodilators whereas the potential presence of astrocytic NO had been ignored. It also suggests that each constitutive NOS in astrocytes is associated to a specific pathway and possibly to a specific function. The LONG-TERM GOALS are to define the mechanisms underlying NVC and to verify how these findings correlate with MRI signals. RELEVANCE: results obtained from the present proposal will greatly enhance our understanging of how neural activity is related to CBF and may help to understand, improve and develop brain imaging techniques.

神经血管耦合（NVC）——神经元能量需求和局部血液供应之间的动态联系——对于维持大脑稳态至关重要。在大脑中，神经元突触活动的增加伴随着局部脑血流量（CBF）的增加，以满足增加的葡萄糖和氧气需求。除了其重要的生理作用外，更好地理解 NVC 的机制也非常重要，因为这个概念是功能性磁共振成像 (fMRI) 和正电子发射断层扫描 (PET) 等现代神经影像技术的基础。尽管这些技术实际上是在测量脑氧、葡萄糖或CBF水平，并且这些变量与神经元活动之间的关系是非线性的，但结果仍然被错误地解释为神经元活动的直接反映。因此，必须更好地理解 NVC 的潜在机制。在可能参与 NVC 的血管活性因子中，已经确定了一种强大的血管扩张剂和内源性产生的气体，即一氧化氮 (NO)。 NO 可能作用于神经血管单元的所有类型的细胞（神经元、星形胶质细胞和血管细胞）。星形胶质细胞独特地位于突触和血管之间，已被认为是神经元信号的整合者，可将信息传递给血管，并且可能是一氧化氮的有趣目标和来源。我们确实证明星形胶质细胞在不同的神经刺激下产生一氧化氮。本提案的主要重点是了解 NO 和星形细胞信号通路如何相互作用来调节 NVC。我们假设 NO 主要但不是唯一通过调节星形胶质细胞依赖性途径来调节 NVC。为了验证这一假设，我们提出了三个具体目标：1）阐明 NVC 背景下 NO 对 Ca2+ 依赖性星形细胞通路的影响； 2) 阐明星形细胞nNOS和eNOS介导的NO产生如何调节NVC； 3) 区分 NVC 中 NO 与中间神经元、锥体神经元和星形胶质细胞的重要性。这些机制将使用转基因小鼠和药理学工具以及双光子显微镜和激光多普勒血流测定法进行研究。所提出的概念非常具有创新性，因为它假设 NO 由神经元或内皮细胞产生，充当血管舒张剂，而星形细胞 NO 的潜在存在却被忽略了。它还表明星形胶质细胞中的每个组成型 NOS 都与特定途径相关，并且可能与特定功能相关。长期目标是定义 NVC 的潜在机制，并验证这些发现如何与 MRI 信号相关。相关性：从本提案中获得的结果将极大地增强我们对神经活动与 CBF 之间关系的理解，并可能有助于理解、改进和开发大脑成像技术。