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

• 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
• 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

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.

项目摘要 /摘要 睡眠损失会导致认知障碍，并增加抑郁症和其他精神疾病的风险。 这些并发症构成了惊人的社会经济负担，但它们的生物学机制仍然很差 理解，限制了有效的治疗干预措施的发展。 动物模型提供了阐明睡眠损失神经生物学作用的最佳工具之一；然而， 啮齿动物的大多数可用行为任务不足以捕获相同的表现 在睡眠不足的人类中。为了克服这一障碍，我们开发了几个信息处理范例 具有高转化有效性。这些任务表明，在大鼠中，是由 急性睡眠剥夺（ASD-繁殖短期睡眠损失的操作）是由于激活 前额叶皮层（PFC）中的GABAA受体。 在此结果的基础上，我们发现ASD导致氯离子在锥体神经元内的积累 pfc。这种改变逆转了GABAA受体从抑制（超极化）的功能 兴奋性（去极化）。此外，我们发现ASD刺激了Allopregnanolone的合成，A 神经类固醇激活PFC中的这些GABAA受体。 与这些数据相反，我们发现慢性睡眠限制（CSR，一种模仿延长的操纵 睡眠减少）降低了PFC中的异烷酮水平，这些变化伴随着 与抑郁相关的反应的出现。 这些初步数据促使我们假设睡眠损失通过收敛会导致行为缺陷 氯化物稳态和神经固醇合成的改变，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该假设的贡献来检验这一假设。 由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 信息处理缺陷的机制和与睡眠损失相关的抑郁症状。 此外，我们的结果可能会为这些并发症的新有效干预措施开发。