Sleep-wake disturbances in traumatic brain injury

创伤性脑损伤中的睡眠-觉醒障碍

• 批准号: 8915905
• 负责人: Miranda M Lim
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-10-01 至 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8915905
• 关键词: Attention; Behavior; Brain; Brain Injuries; Brain region; Branched-Chain Amino Acids; Chronic; Cognitive; Communities; Comorbidity; Data; Development; Diet; Electroencephalography; Electron Microscopy; Electrophysiology (science); Employment; Event; Excessive Daytime Sleepiness; Functional disorder; Glutamates; Goals; Hypothalamic structure; Impaired cognition; Impairment; Individual; Link; Measures; Memory; Microdialysis; Mus; Nerve; Neurologic; Neurons; Outcome; Pattern; Physiological; Play; Population; Post-Concussion Syndrome; Recovery; Recovery of Function; Rehabilitation therapy; Research; Role; Sleep; Sleep Wake Cycle; Symptoms; Synapses; Techniques; Testing; Therapeutic Intervention; Traumatic Brain Injury; Traumatic Brain Injury recovery; Veterans; Wakefulness; Work; base; behavioral impairment; clinical Diagnosis; cognitive recovery; common symptom; community reintegration; disability; effective therapy; experience; extracellular; gamma-Aminobutyric Acid; hypocretin; improved; in vivo; mild traumatic brain injury; mouse model; neurobehavioral; neuropsychiatry; new therapeutic target; novel strategies; persistent symptom; prevent; public health relevance; temporal measurement; therapeutic target

 DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) impacts nearly 2% of the population and is a major cause of disability in the Veteran population, often resulting in long-term physical, cognitive and neurobehavioral impairments that prevent return to the workforce and community. It has long been appreciated that poor sleep and excessive daytime sleepiness are common and persistent symptoms after mild TBI. Data suggests that poor sleep interferes with recovery from TBI. What is not known is why sleep-wake disturbances persist after TBI. More effective therapies are needed for the treatment of TBI and associated post-concussive symptoms. Thus, there is an urgent need to understand mechanisms underlying sleep-wake disturbances in order to identify better therapeutic targets. Our long-term goal is to understand why sleep-wake disturbances persist after mild TBI. Our central hypothesis is that TBI disrupts physiological cortical function which in turn alters glutamatergic inputs to hypothalamic sleep-wake circuits, resulting in sleep-wake fragmentation, and subsequently delaying cognitive recovery in individuals with TBI. Our hypothesis was formulated on the basis of our own preliminary data showing decreased excitability of hypothalamic wake-active neurons in a mouse model of TBI, and improved wakefulness with administration of a dietary therapy that is thought to increase synaptic glutamate content. The rationale for the proposed research is that, once it is known how changes in brain glutamate cause sleep-wake fragmentation in TBI, pharmacological manipulation of glutamate in sleep-wake circuits could yield novel approaches for recovery from TBI. We plan to test our central hypothesis by pursuing the following three specific aims: 1. Characterize regional patterns of sleep-wake dysfunction in TBI. 2. Assess glutamate and GABA changes during sleep and wakefulness in TBI. 3. Examine the effect of a dietary therapy on glutamate, GABA, and regional sleep-wake dysfunction in TBI. To accomplish these aims, we will first perform chronic, in vivo electrophysiological recordings across different cortical brin regions in freely behaving, brain-injured mice, analyze quantitative EEG measures in sleep and wakefulness, and correlate these metrics with behavior. Next, we will perform in vivo microdialysis in combination with EEG in brain-injured mice to determine extracellular glutamate and GABA levels in the hypothalamus during sleep and wake states. We will then use quantitative electron microscopy (EM) to confirm synaptic changes in glutamate and GABA in the hypothalamus. Lastly, given the hypothesis that our dietary therapy replenishes glutamate content in nerve terminal inputs onto wake-active neurons in the hypothalamus, dietary therapy will be administered to brain- injured mice to determine the recovery of extracellular glutamate and GABA (microdialysis), synaptic glutamate and GABA (EM), and sleep-wake measures (EEG). With respect to expected outcomes, the work proposed in aims 1, 2 and 3 is expected to identify quantitative EEG metrics of sleep-wake dysfunction in TBI that predict functional recovery, and examine excitatory and inhibitory inputs to sleep-wake circuits in TBI that are amenable to therapeutic intervention. Such results are expected to have a profound impact on our understanding of TBI and post-concussive symptoms, by deepening our understanding of cortico-hypothalamic interactions in TBI-induced sleep-wake disturbances, and evaluating a therapy that has enormous potential to optimize wakefulness, and therefore recovery, from TBI.

 描述（由申请人提供）： 创伤性脑损伤 (TBI) 影响着近 2% 的人口，是退伍军人群体残疾的主要原因，通常会导致长期的身体、认知和神经行为障碍，从而阻碍他们重返工作岗位和社区。认识到睡眠不佳和白天过度嗜睡是轻度 TBI 后的常见且持续的症状。数据表明，睡眠不佳会干扰 TBI 的恢复，但尚不清楚为什么 TBI 后仍需要更有效的治疗方法。因此，迫切需要了解睡眠-觉醒障碍的机制，以便确定更好的治疗目标。我们的长期目标是了解轻度 TBI 后睡眠-觉醒障碍持续存在的原因。我们的中心假设是，TBI 会破坏生理皮质功能，进而改变下丘脑睡眠-觉醒回路的谷氨酸输入，导致睡眠-觉醒碎片化，从而延迟 TBI 患者的认知恢复。我们自己的初步数据表明，TBI 小鼠模型中下丘脑觉醒活动神经元的兴奋性降低，并且通过饮食疗法改善觉醒，该假设被认为可以增加突触谷氨酸含量。研究表明，一旦了解大脑谷氨酸的变化如何导致 TBI 中的睡眠-觉醒碎片，对睡眠-觉醒回路中谷氨酸的药理学操作可能会产生 TBI 恢复的新方法。通过追求以下三个具体目标来检验我们的中心假设： 1. 描述 TBI 中睡眠-觉醒功能障碍的区域模式 2. 评估 TBI 中睡眠和清醒期间谷氨酸和 GABA 的变化 3. 检查饮食疗法对谷氨酸的影响。 、GABA 和 TBI 中的区域性睡眠-觉醒功能障碍 为了实现这些目标，我们将首先在自由行为的大脑损伤的不同皮质布林区域进行慢性体内电生理记录。接下来，我们将结合脑损伤小鼠的脑电图进行体内微透析，以确定睡眠和清醒状态下下丘脑的细胞外谷氨酸和 GABA 水平。然后，我们将使用定量电子显微镜（EM）来确认下丘脑中谷氨酸和 GABA 的突触变化。最后，假设我们的饮食疗法补充了谷氨酸含量。在下丘脑唤醒活动神经元的神经末梢输入中，将对脑损伤小鼠进行饮食治疗，以确定细胞外谷氨酸和 GABA（微透析）、突触谷氨酸和 GABA (EM) 的恢复情况以及睡眠-觉醒测量。关于预期结果，目标 1、2 和 3 中提出的工作预计将确定 TBI 中睡眠-觉醒功能障碍的定量脑电图指标，以预测功能恢复并检查兴奋性。通过加深我们对 TBI 诱发的皮质-下丘脑相互作用的理解，预计这些结果将对我们对 TBI 和脑震荡后症状的理解产生深远的影响。睡眠-觉醒障碍，并评估一种具有巨大潜力的治疗方法，可以优化 TBI 的觉醒状态，从而促进恢复。