Mechanisms of information-processing and executive deficits caused by sleep deprivation

项目总结/摘要 睡眠不足会导致认知障碍，增加患抑郁症和其他精神疾病的风险。 这些并发症造成了惊人的社会经济负担，但其生物学机制仍然很差 这限制了有效治疗干预措施的发展。 阐明睡眠不足的神经生物学效应的最佳工具之一是动物模型;然而， 大多数啮齿类动物可用的行为任务不足以捕捉所观察到的相同表现 在睡眠不足的人身上。为了克服这一障碍，我们开发了几种信息处理范式 翻译效度高。这些任务表明，在大鼠中， 急性睡眠剥夺（aSD -一种再现短期睡眠丧失的操作）是由于激活了 前额叶皮层（PFC）中的GABAA受体。 基于这一结果，我们发现aSD导致锥体神经元内氯离子的积累 这种改变逆转了GABAA受体的功能，从抑制性（超极化）， 兴奋性（去极化）。此外，我们发现aSD刺激别孕烯醇酮的合成， 神经类固醇激活PFC中的GABAA受体。 与这些数据相反，我们发现慢性睡眠限制（cSR，一种模拟延长睡眠时间的方法）， 睡眠缩短）降低PFC中的别孕烯醇酮水平，这些变化伴随着 抑郁症相关反应的出现。 这些初步的数据促使我们假设睡眠不足会通过聚合 氯稳态和神经类固醇合成的改变，这反过来又导致GABAA受体 PFC的异常 我们提案的三个目标将通过研究这些机制对 aSD和cSR引起的神经行为并发症。这些研究将有助于阐明神经生物学 信息处理缺陷和与睡眠不足相关的抑郁症状的机制。 此外，我们的研究结果可能会为这些并发症的新的，有效的干预措施的发展提供信息。

PROJECT SUMMARY / ABSTRACT Sleep loss leads to cognitive disturbances and increases the risk of depression and other psychiatric disorders. These complications pose a staggering socioeconomic burden, yet their biological mechanisms remain poorly understood, limiting the development of effective therapeutic interventions. One of the best tools to elucidate the neurobiological effects of sleep loss is afforded by animal models; however, most of the available behavioral tasks for rodents are inadequate to capture the same manifestations observed in sleep-deprived humans. To overcome this barrier, we developed several information-processing paradigms with high translational validity. These tasks revealed that, in rats, the information-processing deficits caused by acute sleep deprivation (aSD - a manipulation reproducing short-term sleep loss) were due to the activation of GABAA receptors in the prefrontal cortex (PFC). Building on this result, we found that aSD leads to the accumulation of chloride ions inside the pyramidal neurons of the PFC. This alteration reverses the function of GABAA receptors from inhibitory (hyperpolarizing) to excitatory (depolarizing). Furthermore, we found that aSD stimulates the synthesis of allopregnanolone, a neurosteroid that activates these GABAA receptors in the PFC. In contrast with these data, we found that chronic sleep restriction (cSR, a manipulation mimicking prolonged sleep curtailment) reduces allopregnanolone levels in the PFC, and these changes are accompanied by the emergence of depression-related responses. These preliminary data prompt us to hypothesize that sleep loss causes behavioral deficits through converging alterations of chloride homeostasis and neurosteroid synthesis, which in turn lead to GABAA receptor abnormalities in the PFC. The three Aims of our proposal will test this hypothesis by studying the contribution of these mechanisms to the neurobehavioral complications caused by aSD and cSR. These studies will help elucidate the neurobiological mechanisms of the information-processing deficits and depressive symptoms associated with sleep loss. Furthermore, our results may inform the development of new, effective interventions for these complications.