Prefrontal circuit mechanisms underlying antidepressant effects of sleep deprivation: a role for metabotropic glutamate receptors

睡眠剥夺抗抑郁作用的前额叶回路机制：代谢型谷氨酸受体的作用

• 批准号: 9888208
• 负责人: Puja Parekh
• 金额: $ 6.53万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-20 至 2022-02-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888208
• 关键词: Acute; Affect; Anhedonia; Animals; Antidepressive Agents; Attenuated; Automobile Driving; Behavior; Behavioral; Brain region; Calcium; Cells; Chemosensitization; Chronic; Chronic stress; Cognitive deficits; Cost-Benefit Analysis; Cues; Decision Making; Dendritic Spines; Depressive Syndromes; Development; Disease remission; Dorsal; Economic Burden; Exposure to; Functional disorder; Glutamates; Growth; Head; Homeostasis; Image; Implant; Influentials; Lead; Major Depressive Disorder; Measurement; Medial; Mediating; Mental Depression; Metabotropic Glutamate Receptors; Modeling; Moods; Neurons; Nucleus Accumbens; Optics; Patients; Prefrontal Cortex; Process; Proteins; Quality of life; Receptor Signaling; Recovery; Research; Rewards; Role; Signal Pathway; Signal Transduction; Sleep; Sleep Deprivation; Sleep disturbances; Spinal Manipulation; Stress; Symptoms; Synapses; Synaptic plasticity; System; Testing; Therapeutic; Vertebral column; Wakefulness; antidepressant effect; base; cognitive function; disability; effective therapy; frontal lobe; functional restoration; glutamatergic signaling; hippocampal pyramidal neuron; in vivo; insight; interest; metabotropic glutamate receptor type 1; monoamine; neurobiological mechanism; neuropsychiatry; neurotransmission; new technology; novel; pleasure; postsynaptic; programs; receptor; relating to nervous system; response; social; social defeat; therapeutic target; two-photon

Project Summary Stress-related neuropsychiatric illnesses including major depressive disorder (MDD) are increasingly prevalent and impose a great social and economic burden. Conventional monoamine antidepressants can be slow to achieve efficacy and remission rates are low, highlighting the need for novel, rapid therapeutic treatments. While sleep disturbance is associated with MDD, interestingly, one night of sleep deprivation (SD) produces a dramatic albeit temporary reduction in symptoms. Understanding the neurobiological mechanisms underlying the effects of this counterintuitive strategy can help enhance and prolong its treatment potential. Sleep and wake states are marked by changes in cortical homeostatic synaptic plasticity including within the medial prefrontal cortex (mPFC) a region critically involved in mood and cognitive functions associated with MDD. Anhedonia, or diminished pleasure from previously rewarding activities is a core feature of MDD and mPFC neurons are known to encode effort valuation, or cost-benefit analyses for motivated reward seeking. The neural projection from the dorsal mPFC (dmPFC) to the core region of the nucleus accumbens (NAcc) is especially critical for effortful reward seeking and accumbens-projecting neurons are tuned to encode reward- predictive cues, suggesting that this circuit may be particularly relevant for chronic-stress induced anhedonia- related behavior. The effects of SD on effort valuation and the role of this circuit have not been specifically investigated. SD is known to promote glutamatergic signaling and prolonged wakefulness increases cortical excitability, which may in turn lead to enhanced inducibility of synaptic plasticity. Group 1 metabotropic glutamate receptors including mGluR5 are promising candidates to study antidepressant actions of SD as mGluR5 signaling is decreased the frontal cortex in MDD and increased following one night of SD. Functional mGluR5 is also necessary for maintaining sleep/wake homeostasis and behavioral adaptability to sleep deprivation. For this proposal, I will use cutting-edge in vivo approaches including two-photon (2P) calcium imaging of dmPFC-NAcc neurons during a novel head-fixed effort valuation task (Aim 1), in vivo measurement and manipulation of spine dynamics (Aim 2), and cell-specific photoswitchable control of mGluRs (Aim 3) to test the hypothesis that SD reverses stress-induced deficits in effort valuation by increasing mGluR5 signaling in dmPFC-NAcc projection neurons, which in turn enhances their excitability, restores lost spines, and rescues stress effects on reward-predictive cue encoding. The completion of these aims will provide valuable insight into neurobiological mechanisms of sleep deprivation as a rapid antidepressant strategy. My findings could also inform therapeutic targets to attenuate cognitive deficits associated with MDD and optimize the efficacy of SD.

项目摘要 与压力相关的神经精神疾病，包括重度抑郁障碍(MDD)，越来越普遍 并造成巨大的社会和经济负担。传统的单胺类抗抑郁药可以缓慢地 有效率和缓解率都很低，突出表明需要新的、快速的治疗方法。 虽然睡眠障碍与MDD有关，但有趣的是，一晚的睡眠剥夺(SD)会产生 症状虽然是暂时的，但戏剧性的减少。了解潜在的神经生物学机制 这种违反直觉的策略的效果可以帮助增强和延长其治疗潜力。睡眠和 觉醒状态的标志是皮质内稳态突触可塑性的变化，包括内侧 前额叶皮质(MPFC)是与MDD相关的情绪和认知功能的关键区域。 快感缺乏，或从以前有回报的活动中获得的快乐减少，是MDD和mPFC的核心特征 众所周知，神经元编码努力评估，或用于动机奖励寻求的成本效益分析。这个 从背侧mPFC(DmPFC)到伏核核心区(NAcc)的投射是 对于努力寻求奖励和伏隔神经投射的神经元来说尤其关键--神经元被调整为编码奖励-- 预测性线索，表明这一回路可能与慢性应激诱导的快感缺失特别相关。 相关行为。SD对努力评价的影响以及这一回路的作用还没有具体说明 调查过了。已知SD促进谷氨酸能信号传递，长时间清醒可增加大脑皮层 兴奋性，这反过来可能导致突触可塑性的增强。第1组代谢性 谷氨酸受体包括mGluR5是研究SD AS抗抑郁作用的有前途的候选药物 MDD患者额叶皮质mGluR5信号减弱，SD一夜后mGluR5信号增强。功能性 MGluR5也是维持睡眠/觉醒动态平衡和对睡眠的行为适应所必需的 剥夺。对于这项提议，我将使用体内的尖端方法，包括双光子(2P)钙 在一项新的头部固定努力评估任务(目标1)中dmPFC-NAcc神经元的成像，活体测量 和脊柱动力学的操纵(目标2)，以及mGluRs的细胞特异性光切换控制(目标3)，以 测试SD通过增加mGluR5信号来逆转应激导致的努力评估缺陷的假设 在dmPFC-NAcc投射神经元中，这反过来又增强了它们的兴奋性，恢复了丢失的脊柱，并拯救了 压力对奖赏预测线索编码的影响。这些目标的实现将提供有价值的见解 睡眠剥夺作为一种快速抗抑郁策略的神经生物学机制。我的发现可能 还提供治疗目标，以减轻与MDD相关的认知障碍，并优化 标清。