Circadian rhythms are ∼24 h fluctuations in physiology and behavior that are synchronized with the light-dark cycle. The circadian system ensures homeostatic balance by regulating multiple systems that respond to environmental stimuli including stress systems. In rats, acute exposure to a series of uncontrollable tailshocks (inescapable stress, IS) produces an anxiety and depression-like phenotype. Anxiety- and fear-related behavioral changes produced by IS are driven by sensitization of serotonergic (5-hydroxytryptamine, 5-HT) neurons in the dorsal raphe nucleus (DRN). Because the circadian and serotonergic systems are closely linked, here we tested whether the DRN-dependent behavioral and neurochemical effects of IS are time of day dependent. Exposure to IS during the light (inactive) phase elicited the expected changes in mood related behaviors. In contrast, rats that underwent IS during the dark (active) phase were buffered against stress-induced changes in juvenile social exploration and shock-elicited freezing, both DRN-dependent outcomes. Interestingly, behavioral anhedonia, which is not a DRN-dependent behavior, was comparably reduced by stress at both times of day. Neurochemical changes complimented the behavioral results: IS-induced activation of DRN 5-HT neurons was greater during the light phase compared to the dark phase. Additionally, 5-HT1AR and 5-HTT, two genes that regulate 5-HT activity were up-regulated during the middle of the light cycle. These data suggest that DRN-dependent behavioral outcomes of IS are time of day dependent and may be mediated by circadian gating of the DRN response to stress.

• Lay summary

• Here we show that the time of day at which a stressor occurs impacts the behavioral and neurochemical outcomes of the stressor. In particular, animals appear more vulnerable to a stressor that occurs during their rest phase. This work may have important implications for shift-workers and other populations that are more likely to encounter stressors during their rest phase.

昼夜节律是约24小时的生理和行为波动，与明暗周期同步。昼夜节律系统通过调节应对环境刺激的多个系统（包括压力系统）来确保体内平衡。在大鼠中，急性暴露于一系列不可控制的尾巴（不可避免的压力，IS）会产生焦虑和抑郁样表型。IS产生的与焦虑和恐惧相关的行为改变是由背缝核（DRN）中的5-羟色胺（5-羟色胺，5-HT）神经元致敏引起的。由于昼夜节律系统和血清素能系统紧密相连，因此我们在此测试了IS的DRN依赖性行为和神经化学作用是否与时间相关。在轻度（非活动）阶段暴露于IS会引起情绪相关行为的预期变化。相比之下，在黑暗（活动）阶段经历IS的大鼠被缓冲以抵抗压力诱发的青少年社会探索变化和休克引起的冻结，这都是DRN依赖的结果。有趣的是，并非每天都依赖于DRN的行为性快感缺乏症在一天中的两次压力下均得到了降低。神经化学变化与行为结果相称：与黑暗阶段相比，IS诱导的DRN 5-HT神经元激活在明亮阶段更大。另外，调节5-HT活性的两个基因5-HT1AR和5-HTT在光周期的中间被上调。这些数据表明，IS的DRN依赖性行为结局是一天中的时间依赖性，并且可能由DRN对压力反应的昼夜门控介导。在黑暗（活动）阶段经历IS的大鼠被缓冲以抵抗压力引起的青少年社会探索变化和休克引起的冻结，这都是DRN依赖的结果。有趣的是，并非每天都依赖于DRN的行为性快感缺乏症在一天中的两次压力下均得到了降低。神经化学变化与行为结果相称：与黑暗阶段相比，IS诱导的DRN 5-HT神经元激活在明亮阶段更大。另外，调节5-HT活性的两个基因5-HT1AR和5-HTT在光周期的中间被上调。这些数据表明，IS的DRN依赖性行为结局是一天中的时间依赖性，并且可能由DRN对压力反应的昼夜门控介导。在黑暗（活动）阶段经历IS的大鼠被缓冲以抵抗压力引起的青少年社会探索变化和休克引起的冻结，这都是DRN依赖的结果。有趣的是，并非每天都依赖于DRN的行为性快感缺乏症在一天中的两次压力下均得到了降低。神经化学变化与行为结果相称：与黑暗阶段相比，IS诱导的DRN 5-HT神经元激活在明亮阶段更大。另外，调节5-HT活性的两个基因5-HT1AR和5-HTT在光周期的中间被上调。这些数据表明，IS的DRN依赖性行为结局是一天中的时间依赖性，并且可能由DRN对压力反应的昼夜门控介导。

• 放置摘要

• 在这里，我们显示了应激源发生的时间会影响应激源的行为和神经化学结果。特别是，动物似乎更容易受到在其休息阶段发生的压力的影响。这项工作可能对轮班工人和其他人群产生重要影响，因为他们更可能在休息阶段遇到压力源。