Enduring modulation of dorsal raphe nuclei regulates (R,S)-ketamine-mediated resilient stress-coping behavior.

Prophylactic ketamine administration buffers passive stress-induced maladaptive behaviors caused by chronic stress exposure. It also prevents stress-induced disturbances of tryptophan metabolism in the dorsal raphe nuclei (DRN) and blocks the reduction of the protein p11 in that region. p11 deficiency increases susceptibility to stress-related depression-like behaviors, and these effects depend partly on p11 function in serotonergic neurons. Viral-mediated reduction of p11 in the DRN produces a stress-susceptible phenotype. The pro-resilience effect of ketamine is lost when p11 is selectively deleted in serotonergic neurons, revealing a previously unexplored role of the DRN circuit in regulating stress susceptibility and ketamine's resilience-enhancing actions.

Study at a glance

Abstract

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.