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.

项目摘要/摘要 偏头痛是轻度创伤性脑损伤(MTBI)后最常见的主诉之一， 然而，这些头痛背后的机制尚不清楚。一条可能的线索是，睡眠中断也是 创伤性脑损伤后的常见症状。睡眠障碍是偏头痛的常见诱因，而睡眠是一种 广泛有效的偏头痛流产。基于mTBI、头痛和睡眠之间的临床联系 我们假设睡眠中断会导致创伤后头痛的发生。 (PTH)在mTBI后。 一种可能联系mTBI、睡眠和甲状旁腺激素的机制是淋巴系统的损害，这是一种 最近表征了全脑血管周围空间网络，支持快速交换 脑脊液和间质液体。睡眠期的淋巴通路功能最强。它被抑制了 在清醒时，由中枢去甲肾上腺素能紧张，并被mTBI减少。我们建议，减损 MTBI后的淋巴功能可能有助于PTH症状的发展和持续。在……里面 支持这一点，我们的初步数据表明，用中枢活性的α1-肾上腺素能药物治疗 拮抗剂哌唑嗪既能改善小鼠的淋巴功能，又能改善甲状旁腺素症状。这项建议 将通过比较重复撞击和冲击性mTBI对淋巴功能的影响来扩展这些发现， 检测哌唑嗪治疗能否恢复创伤后淋巴功能。使用成熟的 小鼠mTBI模型和甲状旁腺激素症状的有效行为测量(光厌恶和机械性 面部疼痛)，然后我们将通过以下方式确定淋巴功能障碍在甲状旁腺功能障碍症状发展中的作用 在转基因小鼠模型中测试这些症状是否加剧，在转基因小鼠模型中，淋巴功能 体质受损和是否增加创伤后淋巴功能的药理学 哌唑嗪可改善甲状旁腺激素症状。在第二组实验中，我们将测试目标睡眠 为改善创伤后淋巴功能障碍和改善甲状旁腺激素症状提供了途径。在……里面 这些研究我们将确定睡眠增加对甲状旁腺素行为的影响是否独立于 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β1 肾上腺素能信号是创伤后淋巴功能障碍的关键驱动因素，以及是否针对这些 过程可以通过影响淋巴功能或通过 创伤后睡眠的调节。 这一研究结果将为甲状旁腺激素的发病机制提供一个新的视角 这可能会支持将睡眠干扰和淋巴功能作为治疗策略的潜在支持 MTBI患者。