Nucleus Accumbens Medium Spiny Neuron Subtypes Differentially Regulate Stress-Associated Alterations in Sleep Architecture.
Nucleus Accumbens Medium Spiny Neuron Subtypes Differentially Regulate Stress-Associated Alterations in Sleep Architecture.
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DOI：
10.1016/j.biopsych.2020.12.030
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发表时间：
2021-06-15
影响因子：
10.6
通讯作者：
Carlezon WA Jr
中科院分区：
文献类型：
--
作者：
McCullough KM;Missig G;Robble MA;Foilb AR;Wells AM;Hartmann J;Anderson KJ;Neve RL;Nestler EJ;Ressler KJ;Carlezon WA Jr
压力与重度抑郁症和创伤后应激障碍的病理生理学有关。这些疾病有着共同的核心特征，包括动机缺陷、高度焦虑和睡眠失调。慢性压力在啮齿类动物中产生了同样的特征，一些个体易受影响或有弹性，就像在人类中看到的那样。虽然压力诱导的神经适应性核（NAc）内的参与易感性相关的失调的动机和情绪行为，他们对睡眠的影响还不清楚。我们使用化学遗传学（DREADDs）来研究选择性改变表达多巴胺-1受体（D1-MSNs）或多巴胺-2受体（D2-MSNs）的NAc中棘神经元（MSNs）活性对睡眠相关终点的影响。在小鼠体内植入无线发射器，使其能够连续收集脑电图（EEG）数据，以量化20天测试期内的警惕状态。在评估压力敏感性的行为测试中检查平行队列。D1-和D2-MSNs在睡眠调节中起着不可分离的作用。刺激D1-MSNs中表达的抑制性或兴奋性DREADD只影响快速眼动（REM）睡眠，而靶向D2-MSNs则影响慢波睡眠。D1-MSN抑制和D2-MSN激活对睡眠的综合影响类似于慢性社会失败压力。D1-MSN功能的改变也会影响社会行为测试中的压力敏感性。D1-MSNs内CREB（cAMP反应元件结合蛋白）的升高足以对REM睡眠产生应激样作用。除了调节动机和情绪行为外，NAc还影响睡眠，这是一个具有高度翻译相关性的终点。这些发现为压力相关疾病的关键特征的共病提供了神经基础。
Stress is implicated in the pathophysiology of major depression and posttraumatic stress disorder. These conditions share core features, including motivational deficits, heighted anxiety, and sleep dysregulation. Chronic stress produces these same features in rodents, with some individuals being susceptible or resilient, as seen in humans. While stress-induced neuroadaptations within the nucleus accumbens (NAc) are implicated in susceptibility-related dysregulation of motivational and emotional behaviors, their effects on sleep are unclear. We used chemogenetics (DREADDs) to examine the effects of selective alterations in activity of NAc medium spiny neurons (MSNs) expressing dopamine-1 receptors (D1-MSNs) or dopamine-2 receptors (D2-MSNs) on sleep-related endpoints. Mice were implanted with wireless transmitters enabling continuous collection of electroencephalography (EEG) data to quantify vigilance states over a 20-day test period. Parallel cohorts were examined in behavioral tests assessing stress susceptibility. D1- and D2-MSNs play dissociable roles in sleep regulation. Stimulation of inhibitory or excitatory DREADDs expressed in D1-MSNs exclusively affects rapid eye movement (REM) sleep, whereas targeting D2-MSNs affects slow wave sleep. The combined effects of D1-MSN inhibition and D2-MSN activation on sleep resemble those of chronic social defeat stress. Alterations in D1-MSN function also affect stress susceptibility in social behavior tests. Elevation of CREB (cAMP response element binding protein) within D1-MSNs is sufficient to produce stress-like effects on REM sleep. In addition to regulation of motivational and emotional behaviors, the NAc also influences sleep, an endpoint with high translational relevance. These findings provide a neural basis for comorbidity in key features of stress-related illness.
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