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CRH dysregulation of brainstem autonomic circuits increases SUDEP risk

脑干自主回路的 CRH 失调会增加 SUDEP 风险

基本信息

批准号：
10607623
负责人：
Jamie Lynn Maguire
金额：
$ 62.03万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-09 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607623
关键词：
Apical Apnea Autonomic Dysfunction Behavioral Biological Markers Brain Stem Cardiac Cardiovascular system Chronic Chronic stress Corticotropin-Releasing Hormone Data Electrophysiology (science)Environmental Risk Factor Epilepsy Exhibits Functional disorder Genetic Genetically Engineered Mouse Heart Arrest Heart Rate Hyperactivity Hypothalamic structure Impairment Incidence Injections Laboratories Link Lung Mediating Methods Modeling Motor Motor output Mus Neurons Neurosecretory Systems Nucleus solitarius Output Pathway interactions Patients Physiology Radio Reflex action Regulation Risk Role Seizures Sensory Stress Sudden Death Tachycardia Telemetry Testing Therapeutic Whole Body Plethysmography comorbidity genetic approach hypothalamic-pituitary-adrenal axis innovation novel paraventricular nucleus pharmacologic respiratory response sudden unexpected death in epilepsy

项目摘要

Project Summary The overarching objective of this proposal is to investigate a novel mechanism for sudden unexpected death in epilepsy (SUDEP). Our laboratory recently made the unexpected discovery that mice genetically engineered for hyperactive stress circuits exhibit an increased incidence of SUDEP, a finding that was verified to be translationally relevant from observed neuroendocrine abnormalities in patients that died of confirmed or suspected SUDEP. Given that both stress and SUDEP link to disruption of central circuits responsible for the regulation of cardiorespiratory function, we propose that exaggerated activity of central stress circuits on downstream brainstem autonomic control centers represents a novel mechanism contributing to increased SUDEP risk. Corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) are at the apex of the stress axis and project directly to brainstem regions critical for autonomic regulation, including the nucleus of the solitary tract (PVN-NTSCRH). PVN-NTSCRH has a well-established role in integrating cardiorespiratory responses to stress, making them a likely driver of cardiorespiratory dysfunction related to central stress axis hyperexcitability and, potentially, SUDEP. In fact, our preliminary data demonstrate that chemogenetic activation of PVN-NTSCRH increases SUDEP incidence. The current application will build on the expertise of, Drs. Jamie Maguire and Carie Boychuk, to test the hypothesis that HPA axis hyperexcitability in chronically epileptic mice increases the risk for SUDEP through increased PVN-NTSCRH drive, exaggerating cardiac vagal output during homeostatic challenges. We will investigate this hypothesis by examining whether there is increased PVN-NTSCRH drive associated with SUDEP risk and whether excessive activation of this pathway is sufficient to increase SUDEP incidence. We will interrogate potential, novel pathophysiological mechanisms mediating the impact of hyperactive stress circuits on SUDEP risk by examining the impact on cardiac vagal output. Finally, we will investigate whether environmental factors associated with hyperactive stress circuits, such as chronic stress, can impact cardiac vagal function and SUDEP risk. This application has the potential to uncover a novel mechanism contributing to SUDEP risk, which may also be relevant to other forms of sudden death.

项目总结