Harris Hannah, Woods Avery, Chen Yixin, Del Arco Alberto
Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, Mississippi 38677.
Computer and Information Science, University of Mississippi, Oxford, Mississippi 38677.
eNeuro. 2025 Jul 25;12(7). doi: 10.1523/ENEURO.0229-25.2025. Print 2025 Jul.
Previous research suggests that stress predisposes individuals to develop substance use disorders by disrupting the brain processing of rewards. Yet, how stressful experiences disrupt the brain processing of reward-related cues at the neuronal level is poorly understood. Intermittent social defeat (ISD) is a stress animal model that increases reward-seeking behavior, drug self-administration, and choice impulsivity up to several weeks after stress. We tested the hypothesis that ISD disrupts the neuronal encoding of reward cues in key areas of the brain that regulate reward-seeking. We examined in vivo neuronal dynamics in response to reward cues in the dorsal medial prefrontal cortex (dmPFC) and the ventral tegmental area (VTA) simultaneously, and longitudinally, in control and stressed Long-Evans male rats during a discriminative stimulus reward-seeking task. In the dmPFC, ISD decreased cue-evoked neuronal activity 1 and 15 d after stress, which indicates a long-term degradation of outcome anticipation-related processing. In the VTA, ISD increased cue-evoked neuronal activity 1 d after stress but decreased cue-evoked activity 15 d after stress. Moreover, decoding analysis in single neurons and populations showed parallel increases and decreases in reward discrimination accuracy in the VTA which points to time-dependent changes in incentive salience after stress. These results demonstrate that ISD differently disrupts the neuronal encoding of reward cues in the dmPFC and the VTA and identify novel neurofunctional signatures that underlie a higher predisposition to seek out rewards after stress.
先前的研究表明，压力会破坏大脑对奖励的处理过程，使个体更容易患上物质使用障碍。然而，压力经历如何在神经元水平上干扰大脑对奖励相关线索的处理，目前还知之甚少。间歇性社会挫败（ISD）是一种应激动物模型，它会增加寻求奖励的行为、药物自我给药以及选择冲动性，这种影响在应激后的几周内都存在。我们测试了这样一个假设：ISD会破坏大脑中调节寻求奖励行为的关键区域对奖励线索的神经元编码。我们在辨别性刺激奖励寻求任务中，同时并纵向地检测了对照和应激的雄性Long-Evans大鼠背内侧前额叶皮质（dmPFC）和腹侧被盖区（VTA）中对奖励线索做出反应的体内神经元动态。在dmPFC中，ISD在应激后1天和15天降低了线索诱发的神经元活动，这表明与结果预期相关的处理过程出现了长期退化。在VTA中，ISD在应激后1天增加了线索诱发的神经元活动，但在应激后15天降低了线索诱发的活动。此外，对单个神经元和神经元群体的解码分析表明，VTA中奖励辨别准确性同时出现了增加和降低，这表明应激后动机显著性存在时间依赖性变化。这些结果表明，ISD以不同方式破坏了dmPFC和VTA中奖励线索的神经元编码，并确定了新的神经功能特征，这些特征是应激后寻求奖励倾向增加的基础。
