Sleep-wake disturbances in traumatic brain injury

 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，阻止返回劳动力和社区。长期以来，人们一直认为睡眠不良和白天过度嗜睡是轻度TBI后常见且持续的症状。数据表明，睡眠不好会影响TBI的恢复。目前尚不清楚为什么TBI后睡眠-觉醒障碍持续存在。需要更有效的疗法来治疗TBI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，以确定更好的治疗靶点。 我们的长期目标是了解为什么轻度TBI后睡眠-觉醒障碍持续存在。我们的中心假设是，TBI破坏了生理皮层功能，这反过来又改变了下丘脑睡眠-觉醒回路的神经递质输入，导致睡眠-觉醒碎片化，并随后延迟TBI患者的认知恢复。我们的假设是根据我们自己的初步数据制定的，这些数据显示，在TBI小鼠模型中，下丘脑唤醒活性神经元的兴奋性降低，并且通过给予被认为可以增加突触谷氨酸含量的饮食疗法来改善觉醒。这项研究的基本原理是，一旦知道脑谷氨酸的变化如何导致TBI的睡眠-觉醒碎片，在睡眠-觉醒回路中对谷氨酸的药理学操作可能会产生从TBI中恢复的新方法。 我们计划通过追求以下三个具体目标来测试我们的中心假设：1。描述TBI中睡眠-觉醒功能障碍的区域模式。 2.评估TBI患者睡眠和觉醒期间谷氨酸和GABA的变化。 3.检查饮食疗法对脑外伤后谷氨酸、GABA和局部睡眠-觉醒功能障碍的影响。 为了实现这些目标，我们将首先在自由行为的脑损伤小鼠的不同皮层皮层神经元区域进行慢性体内电生理记录，分析睡眠和清醒时的定量EEG测量，并将这些指标与行为相关联。接下来，我们将在脑损伤小鼠中结合EEG进行体内微透析，以确定睡眠和清醒状态下下丘脑中的细胞外谷氨酸和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，鉴于我们的饮食疗法将神经末梢输入中的谷氨酸含量增加到下丘脑中的唤醒活性神经元上的假设，将对脑损伤的小鼠施用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）以及睡眠-唤醒测量（EEG）的恢复。 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EEG指标，以预测功能恢复，并检查TBI中睡眠-觉醒回路的兴奋性和抑制性输入，这些输入可接受治疗干预。这些结果预计将对我们理解TBI和脑震荡后症状产生深远的影响，通过加深我们对TBI诱导的睡眠-觉醒障碍中皮质-下丘脑相互作用的理解，并评估具有巨大潜力的治疗，以优化觉醒，从而从TBI中恢复。

 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.