Ventral CA3 Activation Mediates Prophylactic Ketamine Efficacy Against Stress-Induced Depressive-Like Behavior

A single prophylactic injection of ketamine (30 mg/kg) given to mice one week before social defeat stress increased ΔFosB expression in the ventral dentate gyrus and ventral CA3 of the hippocampus in stressed but not control mice. Silencing ΔFosB activity in vCA3 blocked ketamine's protective effects, while overexpressing ΔFosB mimicked and occluded those effects. Ketamine also altered memory traces representing a fear conditioning experience in vCA3. The findings suggest prophylactic ketamine may protect against stressors by modifying neural ensembles in vCA3.

Study at a glance

Abstract

BACKGROUND We previously reported that a single injection of ketamine prior to stress protects against the onset of depressive-like behavior and attenuates learned fear. However, the molecular pathways and brain circuits underlying ketamine-induced stress resilience are still largely unknown. METHODS Here, we tested if prophylactic ketamine administration altered neural activity in the prefrontal cortex (PFC) and/or hippocampus (HPC). Mice were injected with saline or ketamine (30 mg/kg) one week before social defeat (SD). Following behavioral tests assessing depressive-like behavior, mice were sacrificed and brains were processed to quantify ΔFosB expression. In a second set of experiments, mice were stereotaxically injected with viral vectors into ventral CA3 (vCA3) in order to silence or overexpress ΔFosB prior to prophylactic ketamine administration. In a third set of experiments, ArcCreERT2 mice, a line that allows for the indelible labeling of neural ensembles activated by a single experience, were used to quantify memory traces representing a contextual fear conditioning (CFC) experience following prophylactic ketamine administration. RESULTS Prophylactic ketamine administration increased ΔFosB expression in the ventral dentate gyrus (vDG) and vCA3 of SD mice but not of Ctrl mice. Transcriptional silencing of ΔFosB activity in vCA3 inhibited prophylactic ketamine efficacy, while overexpression of ΔFosB mimicked and occluded ketamine’s prophylactic effects. In the ArcCreERT2 mice, ketamine administration altered memory traces representing the CFC experience in vCA3, but not in vDG. CONCLUSIONS Our data indicate that prophylactic ketamine may be protective against a stressor by altering neural activity, specifically the neural ensembles representing an individual stressor in vCA3.