Background

The reward system regulates motivated behavior, and repeated practice of specific motivated behavior might conversely modify the reward system. However, the detailed mechanisms by which they reciprocally regulate each other are not clearly understood.

Methods

Mice subjected to chronic restraint stress show long-lasting depressive-like behavior, which is rescued by continual engagement with playable objects. A series of molecular, pharmacological, genetic, and behavioral analyses, combined with microarray, liquid chromatography, and chemogenetic tools, are used to investigate the neural mechanisms of antidepressive effects of playable objects.

Results

Here, we show that repeated restraint induces dopamine surges into the nucleus accumbens–lateral shell (NAc-lSh), which cause upregulation of the neuropeptide PACAP in the NAc-lSh. As repeated stress is continued, the dopamine surge by stressors is adaptively suppressed without restoring PACAP upregulation, and the resulting enhanced PACAP inputs from NAc-lSh neurons to the ventral pallidum facilitate depressive-like behaviors. Continual engagement with playable objects in mice subjected to chronic stress remediates reduced dopamine response to new stressors, enhanced PACAP upregulation, and depressive-like behaviors. Overactivation of dopamine D₁ receptors over the action of D₂ receptors in the NAc-lSh promotes depressive-like behaviors. Conversely, inhibition of D₁ receptors or PACAP upregulation in the NAc-lSh confers resilience to chronic stress–induced depressive-like behaviors. Histochemical and chemogenetic analyses reveal that engagement with playable objects produces antidepressive effects by reshaping the ventral tegmental area–to–NAc-lSh and NAc-lSh–to–ventral pallidum circuits.

Conclusions

These results suggest that behavioral engagement with playable objects remediates depressive-like behaviors by resolving stress-induced maladaptive changes in the reward system.

中文翻译：

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与可玩对象的行为参与通过重塑奖励系统来解决压力引起的自适应变化

背景

奖励系统调节动机行为，特定动机行为的重复实践可能反过来改变奖励系统。然而，它们相互调节的详细机制尚不清楚。

方法

受到慢性约束压力的小鼠表现出持久的抑郁样行为，这种行为可以通过与可玩物体的持续接触来拯救。一系列分子、药理学、遗传和行为分析，结合微阵列、液相色谱和化学遗传学工具，用于研究可玩对象的抗抑郁作用的神经机制。

结果

在这里，我们展示了反复的约束诱导多巴胺涌入伏隔核-侧壳 (NAc-lSh)，这导致 NAc-lSh 中的神经肽 PACAP 上调。随着重复压力的持续，压力源引起的多巴胺激增被适应性抑制而不恢复PACAP上调，由此产生的从NAc-lSh神经元到腹侧苍白球的增强的PACAP输入促进了抑郁样行为。在遭受慢性压力的小鼠中，与可玩物体的持续接触可以缓解多巴胺对新压力源的反应、增强 PACAP 上调和抑郁样行为。NAc-lSh中多巴胺 D ₁受体的过度激活对 D ₂受体的作用促进了抑郁样行为。相反，抑制 D ₁NAc-lSh 中的受体或 PACAP 上调赋予了对慢性压力诱导的抑郁样行为的恢复力。组织化学和化学遗传学分析表明，与可玩物体的接触通过重塑腹侧被盖区-到-NAc-lSh 和 NAc-lSh-到-腹侧苍白球回路来产生抗抑郁作用。

结论

这些结果表明，与可玩对象的行为参与通过解决奖励系统中压力引起的适应不良变化来纠正抑郁样行为。