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）连接神经元活动的增加，并在空间上迅速限制增加 在局部血流中。关于驱动NVC的细胞机制的知识已集中在瞬态 外部感官刺激，仅限于背侧大脑区域（皮层）。因此，少得多 关于较深大脑区域的NVC动力学，可以通过缓慢，持续和广泛的刺激激活 （例如，身体稳态的生理障碍）。稳态过程中的扰动是关键驱动程序 患病性疾病中的病理机制，例如心力衰竭（HF）中的神经肿瘤激活。到 在我们的知识上解决了这个关键差距，我们开发了一种新型的实验方法，以实现 在挑战身体稳态的挑战期间，感知性诱导的NVC。我们的初步数据表明 规范的NVC响应，一种系统性和生理稳态挑战（急性盐加载） 逐渐增加血管加压素（VP）神经元射击，诱发活性依赖性血管收缩和 下丘脑上核核（SON）的局部血流减少。盐诱导的逆NVC（INVC） 反应缓慢，持续和广泛，并由儿子内副总裁的树突释放介导。 INVC导致局部组织缺氧，这引起了VP神经元的进一步激发。基于这些 观察结果，我们假设INVC是一个有助于积极反馈的生理过程 VP神经元种群的调节，以便可以有效纠正生理障碍。仍然， 精确的信号传导机制和细胞靶标介导这种新型NVC的生理方式，并 更重要的是，异常INVC响应是否有助于加剧的VP神经元活动 患有心脏代谢性疾病（例如HF）的特征仍然未知。使用多学科 接近，在目标1中，我们将阐明介导活性的精确信号传导机制和细胞靶 儿子中的依赖Invc（神经元到船尾信号传导）。在AIM 2中，我们将确定机制和 INVC唤起VP神经元放电活性的正反馈调制的目标（Vasculo-to-to 神经元信号）。最后，在AIM3中，我们将阐明有助于加重Invc介导的机制 疾病状态（HF）中VP神经元的阳性反馈调节。体内和Ex ex Vivo小说方法 （2光子成像，斑块钳电生理学和儿子小动物的体内插管）将用于 新型转基因大鼠模型，可以实现可视化（EGFP）和操纵（光学和化学上的操纵） 儿子中的VP神经元。酸性离子通道（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标进行研究。我们希望这项工作的结果 有助于更好地理解不同大脑中NVC反应的基本机制 区域以及不同活动依赖性的方式。而且，我们预计我们的研究将推出小说 病理机制和治疗靶标，用于治疗高度普遍的心脏代谢疾病。 1