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Role of Sleep Disruption after mTBI as a Driver of Chronic Post-traumatic Headache

mTBI 后睡眠中断是慢性创伤后头痛的驱动因素

基本信息

批准号：
10736602
负责人：
Jeffrey J Iliff
金额：
$ 61.15万
依托单位：
SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10736602
关键词：
Acceleration Acute Adrenergic Agents Adrenergic Antagonists Adrenergic beta-Antagonists Agreement Behavior Biological Assay Blood - brain barrier anatomy Blood Vessels Brain Brain Concussion Calcitonin Gene-Related Peptide Cerebrospinal Fluid Chronic Clinical Clinical Trials Data Development Electroencephalography Electromyography Face Filament Gene Deletion Headache Human Impairment Inflammation Mediators Injury Intercellular Fluid Intervention Light Link Mechanics Mediating Migraine Mus Neuropeptides Pathogenesis Pathway interactions Patients Peripheral Photosensitivity Post-Traumatic Headaches Prazosin Prevention Process Reporting Rodent Rodent Model Role Signal Transduction Sleep Sleep Architecture Sleep Deprivation Sleep disturbances Slow-Wave Sleep Sodium Oxybate Support System Symptoms System Testing Therapeutic Time Transgenic Mice Veterans active duty allodynia antagonist aquaporin 4 associated symptom awake behavior measurement brain dysfunction cerebrospinal fluid flow common symptom defined contribution experimental study fluorescence imaging glymphatic clearance glymphatic dysfunction glymphatic function glymphatic system improved insight interstitial mechanical allodynia mild traumatic brain injury mouse model noradrenergic novel novel strategies pharmacologic prevent service member sleep behavior solute wasting water channel

项目摘要

PROJECT SUMMARY/ABSTRACT Migraine-like headaches are among the most frequent complaints following mild traumatic brain injury (mTBI), yet the mechanisms underlying these headaches are unknown. A possible clue is that sleep disruption is also a common complaint after mTBI. Sleep disruption is a frequently-reported migraine trigger, while sleep is a widely effective migraine abortive. Based on the clinical connections between mTBI, headache and sleep disruption, we hypothesize that sleep disruption contributes to the development of post-traumatic headache (PTH) following mTBI. A mechanism that may link mTBI, sleep and PTH is the impairment of the glymphatic system, which is a recently characterized brain-wide network of perivascular spaces that support the rapid exchange of cerebrospinal and interstitial fluid. Glymphatic pathway function is greatest during sleep. It is suppressed during waking by central noradrenergic tone and is reduced by mTBI. We propose that the impairment of glymphatic function following mTBI may contribute to the development and persistence of PTH symptoms. In support of this, our preliminary data demonstrate that treatment with the centrally-active α1-adrenergic antagonist prazosin improves both glymphatic function and ameliorates PTH symptoms in mice. This proposal will extend these findings by comparing the effects of repetitive impact and blast mTBI on glymphatic function, testing whether treatment with prazosin can restore post-traumatic glymphatic function. Using well established mouse models of mTBI and validated behavioral measures of PTH symptoms (light aversion and mechanical facial allodynia), we will then define the role of glymphatic dysfunction in the development of PTH symptoms by testing whether these symptoms are exacerbated in a transgenic mouse model in which glymphatic function is constitutively impaired and whether increasing post-traumatic glymphatic function pharmacologically with prazosin improves PTH symptoms. In a second set of experiments, we will test whether targeting sleep provides a pathway for improving post-traumatic glymphatic impairment and ameliorating PTH symptoms. In these studies we will define whether the effect of sleep augmentation on PTH behaviors is independent of glymphatic function. In our final studies, we will evaluate whether peripheral or central alpha1 or beta adrenergic signaling is a key driver of post-traumatic glymphatic impairment, and whether targeting these processes can improve PTH-associated behaviors either through effect on glymphatic function or through modulation of post-traumatic sleep. The results of this study will provide a novel perspective on the mechanisms underlying development of PTH that will potentially support targeting sleep disruption and glymphatic function as therapeutic strategies for mTBI patients.