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: 10391639
• 负责人: JESSICA A FILOSA
• 金额: $ 68.22万
• 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/10391639
• 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; Hypoxia; Image; Image-Guided Surgery; Isotonic Exercise; Knowledge; Lead; Light; Link; Masks; Measurement; Measures; Mediating; Modality; Modeling; Molecular Target; Monitor; Neurons; Neuropeptides; Neurosecretory Systems; Nitric Oxide; Pathologic; Peripheral; Pharmacology; Physiological; Physiological Processes; Population; Process; Rattus; Regulation; Response to stimulus physiology; Rodent Model; Role; Sensory; Signal Transduction; Sodium Chloride; Stimulus; System; Techniques; Time Study; Tissues; Transgenic Organisms; Vasodilation; Vasopressins; Viral Vector; Visualization; Work; adeno-associated viral vector; arteriole; base; cellular targeting; designer receptors exclusively activated by designer drugs; hypoperfusion; in vivo; innovation; interdisciplinary approach; neurovascular coupling; novel; novel strategies; patch clamp; 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

神经血管偶联（NVC）连接神经元活动的快速和空间限制性增加 局部血流中。关于驱动NVC的细胞机制的知识一直集中在瞬时 外感受性感觉刺激，并且仅限于浅表背侧脑区（皮层）。因此， NVC动力学的更深的大脑区域，可以激活缓慢，持续和广泛的刺激 (e.g.,身体内稳态的生理紊乱）。稳态过程的紊乱是 流行病的病理机制，如心力衰竭（HF）的神经体液激活。到 为了解决我们知识中的这一关键差距，我们开发了一种新的实验方法， 内感受性诱导的NVC在身体稳态的挑战。我们的初步数据显示， 典型的NVC反应，一种全身和生理稳态挑战（急性盐负荷） 进行性增加血管加压素（VP）神经元放电，诱发活动依赖性血管收缩， 下丘脑视上核（SON）局部血流量减少。盐诱导逆NVC（iNVC） 反应是缓慢的，持续的和广泛的，并介导的树突状细胞内的VP释放的SON。 iNVC导致局部组织缺氧，引起VP神经元的进一步兴奋。基于这些 通过观察，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，使得可以有效地校正生理干扰。不过， 精确的信号传导机制和细胞靶点介导NVC的这种新的生理形态，以及 更重要的是，异常的iNVC反应是否有助于VP神经元活动的加剧 流行的心脏代谢疾病，如HF的特征仍然未知。采用多学科 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性的细胞靶点- SON中的依赖性iNVC（神经元-血管信号传导）。在目标2中，我们将确定机制， iNVC引起VP神经元放电活动的正反馈调节的靶点（血管- 神经元信号传导）。最后，在Aim 3中，我们将阐明导致iNVC介导的 疾病状态（HF）中VP神经元的正反馈调节。体内和离体新方法 （双光子成像、膜片钳电生理学和SON小动脉的离体插管）将用于 新的转基因大鼠模型，使可视化（eGFP）和操作（光学和化学遗传学）， SON中的VP神经元。酸敏感离子通道（ASIC）的激活与星形胶质细胞的调节 谷氨酸转运蛋白将作为关键的分子靶点进行研究。我们希望这项工作的结果， 有助于更好地了解不同脑中NVC反应的基本机制 区域和不同的活动依赖模式。此外，我们期望我们的研究能够揭示新的 用于治疗高度流行的心脏代谢疾病的病理机制和治疗靶点。 1