Inverse neurovascular coupling in the hypothalamus and its role in positive feedback regulation of Vasopressin neurons in health and disease

下丘脑的逆神经血管耦合及其在健康和疾病中加压素神经元正反馈调节中的作用

• 批准号: 10531928
• 负责人: JESSICA A FILOSA
• 金额: $ 67.19万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10531928
• 关键词: ASIC channel; Acute; Address; Area; Astrocytes; Automobile Driving; Blood Vessels; Blood flow; Brain; Brain region; Cannulations; Cardiometabolic Disease; Cardiovascular Diseases; Cells; Characteristics; Chronic; Data; Disease; Dorsal; Electrophysiology (science); Feedback; Functional disorder; Glucose; Glutamate Transporter; Health; Heart failure; Homeostasis; Hypertension; Hypothalamic structure; Hypovolemia; Hypovolemics; Hypoxia; Image; Isotonic Exercise; Knowledge; Link; Masks; Measurement; Measures; Mediating; Modality; Modeling; Molecular Target; Monitor; Neurons; Neuropeptides; Neurosecretory Systems; Nitric Oxide; Operative Surgical Procedures; Pathologic; Peripheral; Physiological; Physiological Processes; Population; Process; Rat Transgene; Regulation; Response to stimulus physiology; Rodent Model; Role; Sensory; Signal Transduction; Sodium Chloride; Stimulus; System; Techniques; Time; Tissues; Vasodilation; Vasopressins; Viral Vector; Visualization; Work; adeno-associated viral vector; arteriole; cellular targeting; designer receptors exclusively activated by designer drugs; hypoperfusion; in vivo; innovation; interdisciplinary approach; neurotransmission; neurovascular coupling; novel; novel strategies; patch clamp; pharmacologic; response; supraoptic nucleus; therapeutic target; two-photon; vasoconstriction

Neurovascular coupling (NVC) links increases in neuronal activity with a rapid and spatially restricted increase in local blood flow. Knowledge on the cellular mechanisms driving NVC has been focused on transient exteroceptive sensory stimulation and limited to superficial dorsal brain areas (cortex). Thus, less is understood on NVC dynamics of deeper brain regions, which can be activated by slow, sustained, and widespread stimuli (e.g., physiological disturbances of bodily homeostasis). Derangement in homeostatic processes is a key driver of pathological mechanisms in prevalent diseases such as neurohumoral activation in heart failure (HF). To address this critical gap in our knowledge, we developed a novel experimental approach that enables interoceptive-induced NVC during a challenge to bodily homeostasis. Our preliminary data show that contrary to the canonical NVC response, a systemic and physiological homeostatic challenge (acute salt-loading) progressively increased vasopressin (VP) neuronal firing, evoked activity-dependent vasoconstriction and decreased local blood flow in the hypothalamic supraoptic nucleus (SON). The salt-induced inverse NVC (iNVC) response was slow, sustained and widespread, and mediated by the dendritic release of VP within the SON. iNVC resulted in local tissue hypoxia, which evoked further excitation of VP neurons. Based on these observations, we hypothesize that iNVC is a physiological process that contributes to positive feedback modulation of the VP neuronal population so that the physiological disturbance can be efficiently corrected. Still, the precise signaling mechanisms and cellular targets mediating this novel physiological modality of NVC, and more importantly, whether an aberrant iNVC response contributes to exacerbated VP neuronal activity characteristic of prevalent cardiometabolic diseases, such as HF, remains unknown. Using a multidisciplinary approach, in Aim 1 we will elucidate the precise signaling mechanisms and cellular targets mediating activity- dependent iNVC in the SON (neuron-to-vessel signaling). In Aim 2, we will determine the mechanisms and targets by which the iNVC evokes the positive feedback modulation of VP neuronal firing activity (vasculo-to- neuron signaling). Finally, in Aim3, we will elucidate mechanisms contributing to exacerbated iNVC-mediated positive feedback regulation of VP neurons in a disease state (HF). Both in vivo and ex vivo novel approaches (2-photon imaging, patch-clamp electrophysiology, and ex vivo cannulation of SON arterioles) will be used in novel transgenic rat models that enable visualization (eGFP) and manipulation (opto- and chemogenetically) of VP neurons in the SON. The activation of acid-sensing ion channels (ASIC) and modulation of astrocyte glutamate transporters will be investigated as key molecular targets. We expect results from this work to contribute to a better understanding of fundamental mechanisms underlying NVC responses in different brain regions and under different activity-dependent modalities. Moreover, we anticipate our studies to unveil novel pathological mechanisms and therapeutic targets for the treatment of highly prevalent cardiometabolic diseases. 1

神经血管耦合（NVC）将神经元活动的增加与快速且空间受限的增加联系起来 在局部血流中。关于驱动 NVC 的细胞机制的知识一直集中在瞬态 外感受感觉刺激仅限于浅表背侧大脑区域（皮质）。所以理解的比较少 深层大脑区域的 NVC 动态，可以通过缓慢、持续和广泛的刺激激活 （例如，身体稳态的生理紊乱）。稳态过程紊乱是一个关键驱动因素 常见疾病的病理机制，例如心力衰竭（HF）中的神经体液激活。到 为了解决我们知识中的这一关键差距，我们开发了一种新颖的实验方法，该方法能够 在身体稳态受到挑战期间内感受诱发的 NVC。我们的初步数据显示，与 典型的 NVC 反应，一种全身性和生理性稳态挑战（急性盐负荷） 逐渐增加的加压素（VP）神经元放电，诱发活动依赖性血管收缩和 下丘脑视上核（SON）局部血流量减少。盐诱导逆NVC（iNVC） 反应缓慢、持续且广泛，并由 SON 内 VP 的树突释放介导。 iNVC 导致局部组织缺氧，从而引起 VP 神经元的进一步兴奋。基于这些 根据观察，我们假设 iNVC 是一个有助于正反馈的生理过程 调节 VP 神经元群，从而有效纠正生理紊乱。仍然， 介导这种新型 NVC 生理模式的精确信号传导机制和细胞靶标，以及 更重要的是，异常的 iNVC 反应是否会导致 VP 神经元活动加剧 流行的心脏代谢疾病（例如心力衰竭）的特征仍然未知。使用多学科 方法，在目标 1 中，我们将阐明精确的信号传导机制和介导活动的细胞靶点 - SON（神经元到血管信号传导）中依赖 iNVC。在目标 2 中，我们将确定机制和 iNVC 激发 VP 神经元放电活动（血管到神经元）的正反馈调节的目标 神经元信号）。最后，在 Aim3 中，我们将阐明导致 iNVC 介导的恶化的机制 疾病状态（HF）下 VP 神经元的正反馈调节。体内和离体新方法 （2 光子成像、膜片钳电生理学和 SON 小动脉的离体插管）将用于 新型转基因大鼠模型，可实现可视化（eGFP）和操作（光遗传学和化学遗传学） SON 中的 VP 神经元。酸敏感离子通道 (ASIC) 的激活和星形胶质细胞的调节 谷氨酸转运蛋白将作为关键分子靶点进行研究。我们期望这项工作的结果 有助于更好地理解不同大脑中 NVC 反应的基本机制 区域和不同的活动依赖模式。此外，我们预计我们的研究将揭示新颖的 治疗高度流行的心脏代谢疾病的病理机制和治疗靶点。 1