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

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.