Elevated dorsal medial prefrontal cortex to lateral habenula pathway activity mediates chronic stress-induced depressive and anxiety-like behaviors.

The medial prefrontal cortex (mPFC) sends projections to numerous brain regions and is believed to play a significant role in depression and anxiety. One of the key downstream targets of the mPFC, the lateral habenula (LHb), is essential for chronic stress (CS)-induced depressive and anxiety-like behaviors. Nevertheless, whether the mPFC-LHb pathway mediates the co-occurrence of depression and anxiety and the underlying mechanism remain incompletely understood. Here, using chemogenetics, we first determined that activation of LHb-projecting mPFC neurons is essential for the development of depressive and anxiety-like behaviors induced by CS. Subsequently, we identify the extent and distribution of LHb-projecting neurons originating from the mPFC subregion. Through circuit-specific in vivo fiber photometry, we found that Ca activity in dorsal mPFC (dmPFC) axon terminals within the LHb was increased during exposure to stressful and anxiety-related stimuli, highlighting the potential role of LHb-projecting dmPFC neurons in conveying stressful and anxiety-related information to the LHb. Finally, we observed that activation of both LHb-projecting dmPFC neurons and their postsynaptic counterparts in the LHb was necessary for CS-induced depressive and anxiety-like behaviors. Overall, this study provides multiple lines of evidence demonstrating that activation of the dmPFC-LHb pathway is a crucial neural circuitry for CS-induced depressive and anxiety-like behaviors.