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

• 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
• 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

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.

项目总结/文摘