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: 9760839
• 负责人: Puja Parekh
• 金额: $ 6.12万
• 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/9760839
• 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.

项目概要 包括重度抑郁症 (MDD) 在内的与压力相关的神经精神疾病越来越普遍 并造成巨大的社会和经济负担。传统的单胺类抗抑郁药可能会缓慢起效 达到疗效和缓解率较低，凸显了对新颖、快速治疗方法的需求。 虽然睡眠障碍与抑郁症有关，但有趣的是，一晚睡眠不足 (SD) 会产生一种 症状虽然暂时但显着减轻。了解潜在的神经生物学机制 这种违反直觉的策略的效果有助于增强和延长其治疗潜力。睡眠和 唤醒状态的标志是皮质稳态突触可塑性的变化，包括内侧 前额叶皮层 (mPFC) 是与 MDD 相关的情绪和认知功能密切相关的区域。 快感缺乏，或从先前有益的活动中获得的乐趣减少，是 MDD 和 mPFC 的核心特征 众所周知，神经元可以对努力评估或动机奖励寻求的成本效益分析进行编码。这 从背侧 mPFC (dmPFC) 到伏隔核核心区域 (NAcc) 的神经投射为 对于努力寻求奖励尤其重要，伏隔核投射神经元被调整为编码奖励 预测线索，表明该回路可能与慢性压力引起的快感缺乏特别相关 相关行为。 SD 对努力评估的影响以及该电路的作用尚未具体说明 调查了。众所周知，SD 可以促进谷氨酸信号传导，长时间清醒会增加皮质功能 兴奋性，这可能反过来导致突触可塑性的诱导能力增强。第 1 组代谢型 包括 mGluR5 在内的谷氨酸受体是研究 SD 抗抑郁作用的有希望的候选者 MDD 患者额叶皮层的 mGluR5 信号传导减弱，而 SD 患者一晚后额叶皮层 mGluR5 信号传导减弱。功能性 mGluR5 对于维持睡眠/觉醒稳态和睡眠行为适应性也是必需的 剥夺。对于这个提案，我将使用尖端的体内方法，包括双光子（2P）钙 在新型头部固定努力评估任务（目标 1）期间对 dmPFC-NAcc 神经元进行成像，体内测量 和操纵脊柱动力学（目标 2），以及 mGluR 的细胞特异性光开关控制（目标 3） 检验 SD 通过增加 mGluR5 信号传导逆转压力引起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，恢复失去的脊柱，并挽救 压力对奖励预测线索编码的影响。完成这些目标将提供宝贵的见解 研究睡眠剥夺的神经生物学机制作为快速抗抑郁策略。我的发现可以 还告知治疗目标，以减轻与 MDD 相关的认知缺陷并优化治疗效果 标准差。