Chronic stress can produce reward system deficits (i.e. anhedonia) and other common symptoms associated with depressive disorders, as well as neural circuit hypofunction in the medial prefrontal cortex (mPFC). However, the molecular mechanisms by which chronic stress promotes depressive-like behavior and hypofrontality remain unclear. We show here that the neuronal activity-regulated transcription factor, NPAS4, in the mPFC is regulated by chronic social defeat stress (CSDS), and it’s required in this brain region for CSDS-induced changes in sucrose preference and natural reward motivation. Interestingly, NPAS4 is not required for CSDS-induced social avoidance or anxiety-like behavior. We also find that mPFC NPAS4 is required for CSDS-induced reduction of pyramidal cell dendritic spine density, revealing a relationship between mPFC dendritic spine changes and anhedonia-like behavior, but not social avoidance behavior. Finally, transcriptomic analysis from the mPFC revealed that NPAS4 influences expression of numerous genes linked to glutamatergic synapses and ribosomal function, as well as many dysregulated genes observed in common neuropsychiatric disorders, including depression. Together our findings reveal an essential role for the activity-regulated transcription factor, NPAS4, in chronic stress-induced mPFC hypofunction and anhedonia.

中文翻译：

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内侧前额叶皮层中的 NPAS4 介导慢性社交失败压力引起的快感缺乏和树突棘丢失

慢性应激能产生奖励系统缺陷（我。Ë. 快感缺乏）和其他与抑郁症相关的常见症状，以及内侧前额叶皮层 (mPFC) 的神经回路功能减退。然而，慢性压力促进抑郁样行为和前额不足的分子机制尚不清楚。我们在这里展示了 mPFC 中神经元活动调节的转录因子 NPAS4 受慢性社会失败压力 (CSDS) 的调节，并且它是 CSDS 诱导的蔗糖偏好和自然奖励动机变化的大脑区域所必需的。有趣的是，CSDS 引起的社交回避或类似焦虑的行为不需要 NPAS4。我们还发现 mPFC NPAS4 是 CSDS 诱导的锥体细胞树突棘密度降低所必需的，揭示了 mPFC 树突棘变化与快感缺乏样行为之间的关系，但不是社交回避行为。最后，mPFC 的转录组学分析显示，NPAS4 影响与谷氨酸能突触和核糖体功能相关的众多基因的表达，以及在常见神经精神疾病（包括抑郁症）中观察到的许多失调基因的表达。我们的研究结果共同揭示了活性调节转录因子 NPAS4 在慢性应激诱导的 mPFC 功能减退和快感缺乏中的重要作用。