Ketamine may be a novel pharmacologic approach to enhance resilience and protect against stress-related disorders, but the molecular targets underlying this response remain to be fully characterized. The multifunctional protein p11 is crucial in the pathophysiology of depression and antidepressant responses. However, it is still unclear whether p11 plays a role in the pro-resilience effects induced by ketamine. Here, we demonstrated that prophylactic administration of ketamine buffers passive stress-induced maladaptive phenotypes induced by chronic stress exposure. Spatial neurotransmitter and metabolite analysis revealed that prophylactic ketamine was also effective in blunting stress-induced disturbances of tryptophan metabolism in dorsal raphe nuclei (DRN). Additionally, we demonstrated that ketamine prevented chronic restraint stress-induced p11 reduction in DRN, a highly p11-enriched region. Furthermore, we provide novel evidence indicating that p11 deficiency regulates susceptibility to stress-induced depression-related phenotypes, and these behavioral maladaptations are dependent, at least in part, on p11 function in serotonergic neurons. Spatial neurotransmitter and metabolite analysis also showed a reduction of tryptophan and dopamine metabolism in DRN of serotonergic p11-deficient mice. Viral-mediated downregulation of p11 within DRN induced a stress-susceptible phenotype. Finally, our results also unveiled that the ability of ketamine to elicit a pro-resilience response against stress-induced maladaptive phenotypes was occluded when p11 was selectively deleted in serotonergic neurons. Altogether, we showed a previously unexplored role of the DRN circuit in regulating stress susceptibility and resilience-enhancing actions of ketamine.

氯胺酮可能是一种增强恢复力和预防压力相关疾病的新型药理学方法，但这种反应背后的分子靶点仍有待充分表征。多功能蛋白 p11 在抑郁症和抗抑郁反应的病理生理学中起着至关重要的作用。然而，目前尚不清楚 p11 是否在氯胺酮诱导的促恢复作用中发挥作用。在这里，我们证明了氯胺酮缓冲剂的预防性给药会引起慢性压力暴露诱导的被动应激诱导的适应不良表型。空间神经递质和代谢物分析显示，预防性氯胺酮也可有效减弱应力诱导的中缝背核 （DRN） 色氨酸代谢紊乱。此外，我们证明氯胺酮可防止慢性约束压力诱导的 DRN p11 减少，DRN 是一个高度富含 p11 的区域。此外，我们提供了新的证据表明，p11 缺陷调节对压力诱导的抑郁相关表型的易感性，而这些行为适应不良至少部分依赖于 5-羟色胺能神经元中的 p11 功能。空间神经递质和代谢物分析还显示，5-羟色胺能 p11 缺陷小鼠 DRN 中的色氨酸和多巴胺代谢减少。DRN 中病毒介导的 p11 下调诱导了应激敏感表型。最后，我们的结果还揭示了当 p11 在血清素能神经元中选择性缺失时，氯胺酮引发针对压力诱导的适应不良表型的促恢复反应的能力被遮挡。总而言之，我们展示了 DRN 回路在调节氯胺酮的应激易感性和弹性增强作用中以前未探索的作用。