Optogenetic stimulation of medial prefrontal cortex excites GABAergic cells in the nucleus accumbens and hippocampus of Wistar-Kyoto rats exposed to chronic mild stress

Abstract

Background: High frequency optogenetic stimulation (OGS) of prelimbic cortex (PLC) has been reported to exert antidepressant-like effects in the chronic mild stress model of depression in Wistar Kyoto (WKY) rats, which are non-responsive to antidepressant drugs. Here we have examined the effect of OGS on activity in the PLC and in two other regions implicated in depression, the nucleus accumbens (NAc) and hippocampus (HPC).

Method: OGS was applied to the PLC of WKY rats using the same stress schedule, and the identical placement, virus infection and stimulation parameters, used in the earlier behavioural experiments. Confocal microscopy was used to identify cells co-expressing the immediate early gene c-Fos and markers of GABAergic (GAD) and glutamatergic (CaMKII) neurons.

Results: Stress decreased sucrose intake, which was restored by OGS. Stress also caused an overall decrease in Fos expression in the structures examined. In stressed animals, but not in non-stressed controls, OGS in mPFC increased the number of Fos⁺ cells in both the core and shell of the NAc (where the vast majority of cells are GABAergic), and increased the number and proportion of active GABAergic, but not glutamatergic, cells in dorsal and ventral HPC and dentate gyrus.

Conclusions: We conclude that OGS of PLC has a net excitatory effect on outputs from the PLC, leading to an overall inhibitory effect in structures innervated (NAc and HPC).

Keywords: Chronic mild stress; Confocal microscopy; GABAergic neurons; Glutamatergic neurons; Hippocampus; Nucleus accumbens; Optogenetic stimulation; Prelimbic cortex; Wistar-Kyoto rat.