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

睡眠剥夺引起的信息处理和执行缺陷的机制

基本信息

批准号：
10886925
负责人：
Marco Bortolato
金额：
$ 51.14万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-10 至 2024-08-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10886925
关键词：
5 Alpha-Reductase Inhibitor Acute Allopregnanolone Animal Model Antidepressive Agents Attention Back Behavioral Behavioral Mechanisms Biological Biology Chloride Ion Chlorides Chronic Clinical Cognitive Cognitive deficits Data Development Economic Burden Electrophysiology (science)Enzymes Homeostasis Human Image Impaired cognition Impairment Isoenzymes Mental Depression Mental disorders Molecular Neurobiology Neurons Outcome Oxidoreductase Physiological Play Prefrontal Cortex Process Property Rattus Risk Risk Factors Rodent Role Sleep Sleep Deprivation Sleep Disorders Testing Therapeutic Intervention Time Translating antagonist associated symptom behavioral outcome biophysical properties depressive symptoms economic impact effective intervention effective therapy emotion regulation executive function gamma-Aminobutyric Acid hippocampal pyramidal neuron information processing mood regulation neurobehavioral neurobiological mechanism neurosteroids receptor response side effect socioeconomics therapeutically effective tool

项目摘要

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.

项目概要/摘要睡眠不足会导致认知障碍，并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理解，限制了有效治疗干预措施的发展。动物模型提供了阐明睡眠不足对神经生物学影响的最佳工具之一。然而，大多数啮齿动物可用的行为任务不足以捕获观察到的相同表现在睡眠不足的人类中。为了克服这个障碍，我们开发了几种信息处理范例具有较高的翻译效度。这些任务表明，在大鼠中，由以下因素引起的信息处理缺陷急性睡眠剥夺（aSD - 一种再现短期睡眠不足的操作）是由于激活前额皮质 (PFC) 中的 GABAA 受体。在此结果的基础上，我们发现 aSD 会导致锥体神经元内氯离子的积累 PFC 的。这种改变将 GABAA 受体的功能从抑制性（超极化）转变为兴奋性（去极化）。此外，我们发现 aSD 会刺激四氢孕酮的合成，这是一种激活 PFC 中 GABAA 受体的神经类固醇。与这些数据相反，我们发现慢性睡眠限制（cSR，一种模仿长时间睡眠的操作）睡眠减少）降低了 PFC 中的异孕酮水平，这些变化伴随着出现与抑郁相关的反应。这些初步数据促使我们假设睡眠不足通过收敛导致行为缺陷氯稳态和神经类固醇合成的改变，进而导致 GABAA 受体 PFC 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与睡眠不足相关的信息处理缺陷和抑郁症状的机制。此外，我们的结果可能为针对这些并发症开发新的、有效的干预措施提供信息。