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，包括重度抑郁症（MDD）越来越普遍 并造成巨大的社会和经济负担。传统的单胺抗抑郁药可以缓慢地 达到疗效和缓解率低，突出了对新的，快速的治疗方法的需要。 虽然睡眠障碍与MDD相关，但有趣的是，一晚的睡眠剥夺（SD）会产生一个 虽然暂时的症状急剧减少。了解其背后的神经生物学机制 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 清醒状态的特点是皮质稳态突触可塑性的变化，包括在内侧皮层内， 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。 快感缺失，或从先前有益的活动中减少的快乐是MDD和mPFC的核心特征 已知神经元编码努力评估，或用于有动机的奖励寻求的成本效益分析。的 从背侧mPFC（dmPFC）到延髓核核心区（NAcc）的神经投射是 特别是对努力寻求奖励至关重要，并且投射神经元被调整为编码奖励， 预测线索，这表明这一电路可能是特别相关的慢性压力诱导的快感缺失- 相关行为。SD对努力评价的影响和这个回路的作用还没有被具体地 研究了已知SD促进神经元能信号传导，并且长时间的觉醒增加皮质神经元的兴奋性。 兴奋性，这反过来又可能导致突触可塑性的增强。组1代谢型 包括mGluR 5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， mGluR 5信号在MDD中的额叶皮层减少，并且在SD一晚后增加。功能 mGluR 5也是维持睡眠/觉醒稳态和睡眠行为适应性所必需的 剥夺对于这个建议，我将使用尖端的体内方法，包括双光子（2 P）钙 在一种新的头部固定努力评价任务（Aim 1）期间，dmPFC-NAcc神经元的成像，体内测量 和脊柱动力学的操纵（目标2），以及mGluRs的细胞特异性光开关控制（目标3）， 测试SD通过增加mGluR 5信号转导逆转压力诱导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，恢复了失去的脊髓，并挽救了 应激对奖赏预测线索编码的影响。这些目标的完成将提供宝贵的见解 睡眠剥夺作为一种快速抗抑郁策略的神经生物学机制。我的发现可以 还告知治疗靶点，以减轻与MDD相关的认知缺陷，并优化 SD.