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 包括重度抑郁症（MDD）在内的与压力有关的神经精神疾病越来越普遍 并施加巨大的社会和经济负担。常规的单胺抗抑郁药可能会很慢 达到功效和缓解率很低，突出了对新型快速治疗治疗的需求。 尽管睡眠障碍与MDD有关，但有趣的是，睡眠剥夺（SD）会产生 尽管症状暂时减轻，但急剧减轻。了解神经生物学机制 这种违反直觉策略的影响可以帮助增强和延长其治疗潜力。睡觉和 唤醒状态标志着皮质稳态突触可塑性的变化，包括内侧 前额叶皮层（MPFC）与MDD相关的情绪和认知功能至关重要的区域。 Anhedonia，或从以前奖励的活动中减少乐趣是MDD和MPFC的核心特征 众所周知，神经元可以编码努力估值或成本效益分析，以寻求积极的奖励。这 从背MPFC（DMPFC）到伏隔核区域（NACC）的神经投射 对于寻求努力的奖励和振荡的神经元特别重要的是要编码奖励 - 预测提示，表明该电路可能与慢性压力诱导的Anhedonia- 相关行为。 SD对努力估值的影响和该电路的作用尚未具体 调查。已知SD可促进谷氨酸能信号传导和长时间的清醒增加皮质 兴奋性，这可能导致突触可塑性的诱导性增强。第1组代谢型 包括MGLUR5在内 MGLUR5信号传导降低了MDD的额叶皮层，并在SD晚上增加了。功能 MGLUR5对于维持睡眠/唤醒稳态和行为适应性也是必需的 剥夺。对于此提案，我将使用包括两光子（2p）钙在内的尖端的体内方法 在新颖的头部固定努力估值任务中，DMPFC-NACC神经元的成像（AIM 1），体内测量 以及对脊柱动力学的操纵（AIM 2）和细胞特异性的光开关控制MGLURS（AIM 3） 测试SD通过增加MGLUR5信号传导来逆转压力引起的努力估值缺陷的假设 在DMPFC-NACC投射神经元中，它又增强了其兴奋性，恢复脊椎丢失并营救 压力对奖励预测性提示编码的影响。这些目标的完成将提供宝贵的见解 作为一种快速的抗抑郁药策略，进入睡眠剥夺的神经生物学机制。我的发现可以 还要告知治疗靶标，以减轻与MDD相关的认知缺陷并优化 SD。