Wells Audrey M, Ridener Elysia, Bourbonais Clinton A, Kim Woori, Pantazopoulos Harry, Carroll F Ivy, Kim Kwang-Soo, Cohen Bruce M, Carlezon William A
Basic Neuroscience Division, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts 02478.
Pfizer, Cambridge, Massachusetts 02139, and.
J Neurosci. 2017 Aug 9;37(32):7656-7668. doi: 10.1523/JNEUROSCI.0885-17.2017. Epub 2017 Jul 3.
Stress plays a critical role in the neurobiology of mood and anxiety disorders. Sleep and circadian rhythms are affected in many of these conditions. Here we examined the effects of chronic social defeat stress (CSDS), an ethological form of stress, on sleep and circadian rhythms. We exposed male mice implanted with wireless telemetry transmitters to a 10 day CSDS regimen known to produce anhedonia (a depressive-like effect) and social avoidance (an anxiety-like effect). EEG, EMG, body temperature, and locomotor activity data were collected continuously during the CSDS regimen and a 5 day recovery period. CSDS affected numerous endpoints, including paradoxical sleep (PS) and slow-wave sleep (SWS), as well as the circadian rhythmicity of body temperature and locomotor activity. The magnitude of the effects increased with repeated stress, and some changes (PS bouts, SWS time, body temperature, locomotor activity) persisted after the CSDS regimen had ended. CSDS also altered mRNA levels of the circadian rhythm-related gene within brain areas that regulate motivation and emotion. Administration of the κ-opioid receptor (KOR) antagonist JDTic (30 mg/kg, i.p.) before CSDS reduced stress effects on both sleep and circadian rhythms, or hastened their recovery, and attenuated changes in Our findings show that CSDS produces persistent disruptions in sleep and circadian rhythmicity, mimicking attributes of stress-related conditions as they appear in humans. The ability of KOR antagonists to mitigate these disruptions is consistent with previously reported antistress effects. Studying homologous endpoints across species may facilitate the development of improved treatments for psychiatric illness. Stress plays a critical role in the neurobiology of mood and anxiety disorders. We show that chronic social defeat stress in mice produces progressive alterations in sleep and circadian rhythms that resemble features of depression as it appears in humans. Whereas some of these alterations recover quickly upon cessation of stress, others persist. Administration of a kappa-opioid receptor (KOR) antagonist reduced stress effects or hastened recovery, consistent with the previously reported antistress effects of this class of agents. Use of endpoints, such as sleep and circadian rhythm, that are homologous across species will facilitate the implementation of translational studies that better predict clinical outcomes in humans, improve the success of clinical trials, and facilitate the development of more effective therapeutics.
应激在情绪和焦虑障碍的神经生物学中起着关键作用。在许多此类病症中，睡眠和昼夜节律都会受到影响。在此，我们研究了慢性社会挫败应激（CSDS）这种行为学形式的应激对睡眠和昼夜节律的影响。我们将植入无线遥测发射器的雄性小鼠暴露于一种已知会产生快感缺失（类似抑郁的效应）和社交回避（类似焦虑的效应）的10天CSDS方案中。在CSDS方案期间和5天的恢复期内，持续收集脑电图（EEG）、肌电图（EMG）、体温和运动活动数据。CSDS影响了众多指标，包括异相睡眠（PS）和慢波睡眠（SWS），以及体温和运动活动的昼夜节律。随着应激的反复，这些影响的程度增加，并且在CSDS方案结束后，一些变化（PS发作次数、SWS时间、体温、运动活动）仍然存在。CSDS还改变了调节动机和情绪的脑区内与昼夜节律相关基因的mRNA水平。在CSDS之前给予κ-阿片受体（KOR）拮抗剂JDTic（30毫克/千克，腹腔注射）可减轻应激对睡眠和昼夜节律的影响，或加速其恢复，并减弱[此处原文缺失部分内容]的变化。我们的研究结果表明，CSDS会导致睡眠和昼夜节律的持续紊乱，模拟人类出现的与应激相关病症的特征。KOR拮抗剂减轻这些紊乱的能力与先前报道的抗应激作用一致。研究跨物种的同源指标可能有助于开发针对精神疾病的改进治疗方法。应激在情绪和焦虑障碍的神经生物学中起着关键作用。我们表明，小鼠的慢性社会挫败应激会导致睡眠和昼夜节律的渐进性改变，类似于人类出现的抑郁症特征。虽然其中一些改变在应激停止后会迅速恢复，但其他改变会持续存在。给予κ-阿片受体（KOR）拮抗剂可减轻应激影响或加速恢复，这与先前报道的这类药物的抗应激作用一致。使用跨物种同源的指标，如睡眠和昼夜节律，将有助于开展转化研究，从而更好地预测人类的临床结果、提高临床试验的成功率并促进更有效治疗方法的开发。
