Background

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 are implicated in susceptibility-related dysregulation of motivational and emotional behaviors, their effects on sleep are unclear.

Methods

We used chemogenetics (DREADDs [designer receptors exclusively activated by designer drugs]) to examine the effects of selective alterations in activity of nucleus accumbens medium spiny neurons expressing dopamine D₁ receptors (D1-MSNs) or dopamine D₂ receptors (D2-MSNs) on sleep-related end points. Mice were implanted with wireless transmitters enabling continuous collection of data to quantify vigilance states over a 20-day test period. Parallel cohorts were examined in behavioral tests assessing stress susceptibility.

Results

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 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 rapid eye movement sleep.

Conclusions

In addition to regulation of motivational and emotional behaviors, the nucleus accumbens also influences sleep, an end point with high translational relevance. These findings provide a neural basis for comorbidity in key features of stress-related illness.

中文翻译：

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伏隔核中等多刺神经元亚型差异调节睡眠结构中与压力相关的变化

背景

压力与重度抑郁症和创伤后应激障碍的病理生理学有关。这些病症具有共同的核心特征，包括动机缺陷、高度焦虑和睡眠失调。慢性压力会在啮齿动物中产生这些相同的特征，其中一些个体易感或有弹性，如人类所见。虽然伏隔核内压力诱导的神经适应与易感性相关的动机和情绪行为失调有关，但它们对睡眠的影响尚不清楚。

方法

我们使用化学遗传学（DREADDs [由设计药物专门激活的设计受体]）来检查选择性改变表达多巴胺 D ₁受体 (D1-MSNs) 或多巴胺 D ₂受体 (D2-MSNs)的伏隔核中等棘神经元活动的影响关于睡眠相关的终点。小鼠被植入无线发射器，能够连续收集数据以量化 20 天测试期间的警觉状态。在评估压力敏感性的行为测试中检查了平行队列。

结果

D1-和 D2-MSN 在睡眠调节中发挥着可分离的作用。在 D1-MSN 中表达的抑制性或兴奋性 DREADD 的刺激仅影响快速眼动睡眠，而靶向 D2-MSN 会影响慢波睡眠。D1-MSN 抑制和 D2-MSN 激活对睡眠的综合影响类似于慢性社交失败压力。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-MSN 内 CREB（cAMP 反应元件结合蛋白）的升高足以对快速眼动睡眠产生类似压力的影响。

结论

除了调节动机和情绪行为外，伏隔核还影响睡眠，这是一个具有高度转化相关性的终点。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。