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.

项目概要/摘要 偏头痛样头痛是轻度创伤性脑损伤 (mTBI) 后最常见的症状之一， 然而这些头痛背后的机制尚不清楚。一个可能的线索是睡眠中断也会导致 mTBI 后常见的主诉。睡眠中断是一种常见的偏头痛触发因素，而睡眠则是一种常见的偏头痛诱因。 偏头痛流产广泛有效。基于 mTBI、头痛和睡眠之间的临床联系 干扰，我们假设睡眠干扰会导致创伤后头痛的发生 (PTH) 继 mTBI 后。 可能将 mTBI、睡眠和 PTH 联系起来的一个机制是类淋巴系统的损伤，这是一种 最近描述了支持血管周围空间快速交换的全脑网络 脑脊液和间质液。类淋巴通路的功能在睡眠期间最强。它被压制了 醒来时由中枢去甲肾上腺素能张力引起，并由 mTBI 减少。我们建议减值 mTBI 后的类淋巴功能可能导致 PTH 症状的发生和持续。在 支持这一点，我们的初步数据表明，用中枢活性α1-肾上腺素能药物治疗 拮抗剂哌唑嗪可改善小鼠的类淋巴功能并改善 PTH 症状。这个提议 将通过比较重复冲击和爆炸 mTBI 对类淋巴功能的影响来扩展这些发现， 测试哌唑嗪治疗是否可以恢复创伤后类淋巴功能。使用成熟的 mTBI 小鼠模型和经过验证的 PTH 症状行为测量（避光和机械性 面部异常性疼痛），然后我们将定义类淋巴功能障碍在 PTH 症状发展中的作用： 测试这些症状是否在类淋巴功能受损的转基因小鼠模型中加剧 组成性受损以及是否可以通过药理学增加创伤后类淋巴功能 哌唑嗪可改善 PTH 症状。在第二组实验中，我们将测试是否针对睡眠 提供了改善创伤后类淋巴损伤和改善 PTH 症状的途径。在 在这些研究中，我们将定义睡眠增强对 PTH 行为的影响是否独立于 类淋巴功能。在我们的最终研究中，我们将评估外周或中枢 α1 或 β 肾上腺素信号传导是创伤后类淋巴管损伤的关键驱动因素，并且是否针对这些 过程可以通过影响类淋巴功能或通过 创伤后睡眠的调节。 这项研究的结果将为 PTH 发展的机制提供新的视角 这将有可能支持以睡眠中断和类淋巴功能为目标的治疗策略 转移性脑损伤患者。