Maladaptation to stress is a critical risk factor in stress-related disorders, such as major depression and post-traumatic stress disorder (PTSD). Dopamine signaling in the nucleus accumbens (NAc) has been shown to modulate behavior by reinforcing learning and evading aversive stimuli, which are important for the survival of animals under environmental challenges such as stress. However, the mechanisms through which dopaminergic transmission responds to stressful events and subsequently regulates its downstream neuronal activity during stress remain unknown. To investigate how dopamine signaling modulates stress-coping behavior, we measured the subsecond fluctuation of extracellular dopamine concentration and pH using fast scanning cyclic voltammetry (FSCV) in the NAc, a postsynaptic target of midbrain dopaminergic neurons, in male mice engaged in a tail suspension test (TST). The results revealed a transient decrease in dopamine concentration and an increase in pH levels when the animals changed behaviors, from being immobile to struggling. Interestingly, optogenetic inhibition of dopamine release in NAc, potentiated the struggling behavior in animals under the TST. We then addressed the causal relationship of such a dopaminergic transmission with behavioral alterations by knocking out both the dopamine receptors, i.e., D1 and D2, in the NAc using viral vector-mediated genome editing. Behavioral analyses revealed that male D1 knock-out mice showed significantly more struggling bouts and longer struggling durations during the TST, while male D2 knock-out mice did not. Our results therefore indicate that D1 dopaminergic signaling in the NAc plays a pivotal role in the modulation of stress-coping behaviors in animals under tail suspension stress.

SIGNIFICANCE STATEMENT The tail suspension test (TST) has been widely used as a despair-based behavioral assessment to screen the antidepressant so long. Despite its prevalence in the animal studies, the neural substrate underlying the changes of behavior during the test remains unclear. This study provides an evidence for a role of dopaminergic transmission in the modulation of stress-coping behavior during the TST, a despair test widely used to screen the antidepressants in rodents. Taking into consideration the fact that the dopamine metabolism is upregulated by almost all antidepressants, a part of which acts directly on the dopaminergic transmission, current results would uncover the molecular mechanism through which the dopaminergic signaling mediates antidepressant effect with facilitation of the recovery from the despair-like behavior in the TST.

对压力的适应不良是与压力有关的疾病（例如严重抑郁症和创伤后应激障碍（PTSD））的关键危险因素。已显示伏伏核（NAc）中的多巴胺信号传导通过增强学习和逃避厌恶性刺激来调节行为，这对于动物在环境挑战（例如压力）下的生存至关重要。然而，多巴胺能传递对应激事件作出反应并随后在应激过程中调节其下游神经元活动的机制仍未知。为了研究多巴胺信号传导如何调节应激反应行为，我们使用快速扫描循环伏安法（FSCV）在NAc（中脑多巴胺能神经元的突触后靶标）中测量了细胞外多巴胺浓度和pH的亚秒波动，在进行尾部悬吊测试（TST）的雄性小鼠中。结果表明，当动物从不活动状态变为挣扎状态时，多巴胺浓度会暂时降低，pH值会升高。有趣的是，光遗传学抑制NAc中多巴胺的释放增强了TST下动物的挣扎行为。然后，我们通过使用病毒载体介导的基因组编辑敲除NAc中的多巴胺受体（即D1和D2）来解决这种多巴胺能传播与行为改变之间的因果关系。行为分析显示，在TST期间，雄性D1基因敲除小鼠表现出更多的挣扎和更长的挣扎持续时间，而雄性D2基因敲除小鼠则没有。

重要性声明拖尾测试（TST）已被广泛用作基于绝望的行为评估，以筛选抗抑郁药已有很长时间。尽管在动物研究中很普遍，但尚不清楚测试过程中行为变化背后的神经基质。这项研究提供了多巴胺能传递在调节TST过程中应激反应行为的作用中的证据，该试验是广泛用于筛选啮齿类动物抗抑郁药的绝望测试。考虑到几乎所有的抗抑郁药都会上调多巴胺的代谢，而其中的一部分直接作用于多巴胺能的传递，因此目前的结果将揭示多巴胺能信号传导介导抗抑郁作用并促进从绝望中恢复的分子机制。 TST中的类似行为。