Fluoxetine acts concomitantly on dorsal and ventral hippocampus to Trk-dependently modulate the extinction of fear memory

Background: Hippocampus can be divided along its longitudinal axis into dorsal and ventral parts, which play different roles in modulating the behavioral responses to stress. However, it is not clear whether the hippocampal subregions could also differently modulate the effect of antidepressant drugs. Since fluoxetine (FLX) effect on extinction of aversive memory is well known to depend on hippocampal BDNF levels, we hypothesized that the hippocampal subregions might play different roles in fluoxetine efficacy in decreasing fear response. Method: Wistar rats were fear-cued conditioned and treated chronically with FLX to subsequently investigate their extinction memory. BDNF levels were assessed separately in the dorsal (dHC) and ventral (vHC) hippo campus in animals chronically treated with FLX. An independent group received K252a (a functional Trk blocker) infusion into the dHC or vHC to assay its interaction with FLX treatment along the fear response. Next, BDNF was directly infused into either the dHC or vHC to the behavior be compared with those induced by chronic FLX treatment. Finally, FLX effect on c-Fos expression was evaluated also considering the dHC and vHC apart, along with subareas of amygdala and medial prefrontal cortex. Results: BDNF levels were increased in the vHC after acute FLX, and in the dHC after chronic FLX treatment. FLX effect on fear response was blocked by K252a administration into either dHC or vHC, after the extinction protocol. BDNF administration into the dHC increased fear response, however its administration into the vHC induced an opposite effect. Besides, a negative correlation between the fear response and c-Fos expression in the dHC CA3/CA1 and vHC CA1/DG was observed after chronic FLX treatment. Conclusion: Both dHC and vHC are essential for the Trk-dependent effect of FLX on extinction memory, although a discrepancy in the fear response was observed with the infusion of BDNF into the dHC or vHC.

Automated summary

The study demonstrates that the dorsal and ventral subregions of the hippocampus play different roles in modulating the effects of the antidepressant drug fluoxetine in decreasing fear response. This suggests a discrepancy in fear response when BDNF is infused into the dorsal or ventral hippocampus.