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具有快速和空间限制的增加