Background and purpose Activation of indoleamine 2,3-dioxygenase (IDO) in prefrontal cortex (PFC) is closely related to depression. It has been proved that prelimbic (PrL) and infralimbic (IL) regions of medial PFC are involved in emotion regulation, and may play distinct roles in regulation of depression. However, the mechanism of how IDO in PrL or IL affects depressive behaviors remains unclear. Experimental approach IDO inhibitor 1-MT was directly injected into PrL and IL of depressive rats induced by ICV-STZ, respectively. Depressive- and anxiety-behaviors were evaluated in forced swim test, sucrose preference test, novelty-suppressed feeding test, novel object recognition test and open field test. HPLC‒MS/MS detected kynurenine metabolites, ELISA detected cytokines, Western blot examined protein expression and Golgi staining assessed synaptic plasticity. Immunofluorescence staining was used to observe the expression and morphology of glial cells. Key results Dissimilar abnormalities were observed in PrL and IL of ICV-STZ depressed rats. In PrL, astrocyte defects were manifested, including reduced GFAP-positive cells, glial transporters and kynurenic acid, and morphological damage. In IL, microglial overactivation was manifested by increased cytokines, Iba1-positive cells and 3-hydroxy-kynurenine, accompanied by morphological alterations. Meanwhile, synaptic plasticity was decreased in both subregions. Microinjection of 1-MT at PrL or IL may improve depressive behaviors by reversing these different abnormalities in PrL and IL, respectively, without influencing anxiety behavior. Conclusions and implications Overall, the antidepressant effects of 1-MT by inhibiting IDO in PrL or IL are realized through different pathways, that is, by enhancing neuroprotective effects in PrL and attenuating neurotoxic response in IL.

Background and Purpose: Mineralocorticoid receptors (MRs), glucocorticoid receptors (GRs) and corticotropin-releasing factor (CRF) in the paraventricular nucleus of the hypothalamus (PVN) are implicated in the stress response. The present study investigated the role of GRs and MRs in the PVN in regulating depressive and anxiety-like behaviors. Experimental Approach: To model chronic stress, rats were exposed to chronic corticosterone treatment via drinking water for 21 days, and the GR antagonist RU486 and MR antagonist spironolactone, alone and combined, were directly injected in the PVN daily for 7 days before the behavioral tests. Depressive- and anxiety-like behaviors were evaluated in forced swim test, sucrose preference test, novelty-suppressed feeding test and social interaction test. The expression of GRs, MRs and CRF were detected by Western-Blot. Key Results: The rats exposed to corticosterone exhibited depressive- and anxiety-like behaviors. The expression of GRs and MRs decreased, and CRF levels increased in the PVN. The intra-PVN administration of RU486 increased the levels of GRs and CRF without influencing depressive- or anxiety-like behaviors. The spironolactone-treated group exhibited an increase in MRs without influencing GRs and CRF in the PVN, and improved anxiety-like behaviors. Interestingly, the intra-PVN administration of RU486 and spironolactone combined restored the expression of GRs, MRs, and CRF and improved depressive- and anxiety-like behaviors. Conclusion and Implications: These results suggest that the simultaneous restoration of GRs, MRs, and CRF in the PVN in this rat model of stress might play an important role in the treatment of depression and anxiety.