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

Abstract

ABSTRACTBackgroundHippocampus can be divided along its longitudinal axis into dorsal and ventral parts. Both are usually committed to modulate different aspects of behavior and stress response. However, it is not clear whether the hippocampal subregions could 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.MethodWistar rats were fear-cued conditioned and treated chronically with fluoxetine to enhance their subsequent extinction memory. First, FLX effect on BDNF levels was assessed considering the dorsal (dHC) and ventral (vHC) hippocampus apart. Then, K252a (a functional Trk blocker) was infused either into the dHC or vHC to assay its interaction with FLX treatment over the fear response. Next, BDNF was directly infused into either the dHC or vHC to compare its behavioral effects with FLX. 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.ResultsChronic FLX treatment increased BDNF in the dHC, whereas BDNF was increased in the vHC after acute treatment only. K252a infused after the extinction protocol into either dHC or vHC was able to prevent FLX effect on fear response. BDNF directly infused 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 was observed after chronic FLX treatment specifically in the dHC CA3/CA1 and vHC CA1/DG.ConclusionBoth dHC and vHC are important for the Trk-dependent FLX effect on extinction memory, although a discrepancy on the fear response was observed with the direct infusion of BDNF into the dHC or vHC.