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)影响了近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，阻碍重返劳动力和社区。长期以来，人们一直认为，轻度脑外伤后，睡眠不佳和日间过度嗜睡是常见和持续的症状。数据表明，睡眠不佳会干扰脑损伤的恢复。目前尚不清楚的是，为什么脑损伤后仍存在睡眠-觉醒干扰。需要更有效的治疗方法来治疗脑损伤和相关的脑震荡后症状。因此，迫切需要了解睡眠-觉醒障碍的潜在机制，以便确定更好的治疗靶点。我们的长期目标是了解为什么轻度脑外伤后仍有睡眠-觉醒障碍。我们的中心假设是，脑损伤会扰乱生理皮质功能，进而改变下丘脑睡眠-觉醒回路的谷氨酸能输入，导致睡眠-觉醒碎片化，从而延缓脑损伤患者的认知恢复。我们的假说是基于我们自己的初步数据提出的，这些数据表明，在脑外伤的小鼠模型中，下丘脑觉醒活性神经元的兴奋性降低，并通过实施被认为增加突触谷氨酸含量的饮食疗法来改善觉醒。这项拟议研究的基本原理是，一旦知道大脑谷氨酸的变化如何导致脑损伤的睡眠-觉醒碎片，在睡眠-唤醒回路中对谷氨酸的药理操作可能会产生从脑损伤中恢复的新方法。我们计划通过追求以下三个具体目标来验证我们的中心假设：1.表征脑外伤患者睡眠-觉醒功能障碍的区域模式。2.观察颅脑损伤患者睡眠和清醒状态下谷氨酸和GABA的变化。3.观察饮食疗法对脑外伤患者谷氨酸、GABA和局部睡眠-觉醒功能障碍的影响。为了实现这些目标，我们将首先对行为自由、脑损伤的小鼠进行跨不同皮质脑区的慢性活体电生理记录，分析睡眠和清醒时的定量脑电测量，并将这些测量与行为相关联。接下来，我们将在脑损伤小鼠中进行体内微透析结合脑电，以确定睡眠和清醒状态下丘脑细胞外谷氨酸和GABA的水平。然后，我们将使用定量电子显微镜(EM)来确认谷氨酸和GABA在下丘脑中的突触变化。最后，假设我们的饮食疗法可以补充下丘脑唤醒活性神经元神经末梢中的谷氨酸含量，将对脑损伤小鼠实施饮食疗法，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，以及睡眠唤醒措施(EEG)。关于预期结果，目标1、2和3中提出的工作有望确定预测功能恢复的脑外伤患者睡眠-觉醒功能障碍的定量脑电指标，并检查脑损伤患者睡眠-觉醒回路的兴奋性和抑制性输入，这些输入可以接受治疗干预。这些结果有望对我们对脑外伤和脑震荡后症状的理解产生深远的影响，加深我们对脑外伤引起的睡眠-觉醒障碍中皮质-下丘脑相互作用的理解，并评估一种具有巨大潜力的疗法，以优化脑损伤的觉醒状态，从而使其康复。