BACKGROUND Anhedonia, the diminished ability to experience pleasure, is an important dimensional entity linked to depression, schizophrenia, and other emotional disorders, but its origins and mechanisms are poorly understood. We have previously identified anhedonia, manifest as decreased sucrose preference and social play, in adolescent male rats that experienced chronic early-life adversity/stress (CES). Here we probed the molecular, cellular, and circuit processes underlying CES-induced anhedonia and tested them mechanistically. METHODS We examined functional brain circuits and neuronal populations activated by social play in adolescent CES and control rats. Structural connectivity between stress- and reward-related networks was probed using high-resolution diffusion tensor imaging, and cellular/regional activation was probed using c-Fos. We employed viral-genetic approaches to reduce corticotropin-releasing hormone (Crh) expression in the central nucleus of the amygdala in anhedonic rats, and tested for anhedonia reversal in the same animals. RESULTS Sucrose preference was reduced in adolescent CES rats. Social play, generally considered an independent measure of pleasure, activated brain regions involved in reward circuitry in both control and CES groups. In CES rats, social play activated Crh-expressing neurons in the central nucleus of the amygdala, typically involved in anxiety/fear, indicating aberrant functional connectivity of pleasure/reward and fear circuits. Diffusion tensor imaging tractography revealed increased structural connectivity of the amygdala to the medial prefrontal cortex in CES rats. Crh-short hairpin RNA, but not control short hairpin RNA, given into the central nucleus of the amygdala reversed CES-induced anhedonia without influencing other emotional measures. CONCLUSIONS These findings robustly demonstrate aberrant interactions of stress and reward networks after early-life adversity and suggest mechanistic roles for Crh-expressing amygdala neurons in emotional deficits portending major neuropsychiatric disorders.

中文翻译：

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早年逆境后的快感缺失涉及奖励和焦虑回路的异常相互作用，并通过杏仁核促肾上腺皮质激素释放激素基因的部分沉默逆转

背景快感缺失，即体验快乐的能力减弱，是与抑郁、精神分裂症和其他情绪障碍相关的重要维度实体，但其起源和机制知之甚少。我们之前已经在经历过慢性早期生活逆境/压力 (CES) 的青春期雄性大鼠中发现快感缺乏症，表现为蔗糖偏好和社交活动减少。在这里，我们探讨了 CES 诱导的快感缺乏症的分子、细胞和电路过程，并对其进行了机械测试。方法我们检查了青少年 CES 和对照大鼠的功能性脑回路和由社交游戏激活的神经元群。使用高分辨率扩散张量成像探测压力和奖励相关网络之间的结构连接，并使用 c-Fos 探测细胞/区域激活。我们采用病毒遗传方法来减少快感缺失大鼠杏仁核中央核中促肾上腺皮质激素释放激素 (Crh) 的表达，并在相同的动物中测试快感缺失逆转。结果 青少年 CES 大鼠的蔗糖偏好降低。社交游戏，通常被认为是快乐的独立衡量标准，激活了控制组和 CES 组中参与奖励回路的大脑区域。在 CES 大鼠中，社交游戏激活了杏仁核中央核中表达 Crh 的神经元，通常与焦虑/恐惧有关，表明愉悦/奖励和恐惧回路的功能连接异常。扩散张量成像纤维束成像显示 CES 大鼠杏仁核与内侧前额叶皮层的结构连通性增加。Chr-短发夹RNA，但不是对照短发夹RNA，给予杏仁核中央核逆转 CES 引起的快感缺乏，而不影响其他情绪测量。结论这些发现有力地证明了在早期生活逆境后压力和奖励网络的异常相互作用，并表明表达 Crh 的杏仁核神经元在预示主要神经精神疾病的情绪缺陷中的机制作用。