Chronic activation of the vHipp-mPFC pathway reduces depression-like behavior but impairs spatial memory

The hippocampus and medial prefrontal cortex (mPFC) have been implicated in depression pathology and antidepressant response. Brain imaging studies suggest that a dysfunctional connection between these two structures underlies depression symptomatology. Previous studies demonstrated that the ventral hippocampus (vHipp) sends specific excitatory projections to the mPFC (the vHipp-mPFC pathway), which have been implicated in several psychiatric disorders. Here, we investigated whether chronic activation of the vHippo-mPFC pathway using chemogenetic approach elicits antidepressant effects and enhances hippocampal function. Retrograde adenovirus (AAV) driving the expression of Cre recombinase was injected in the mPFC (prelimbic and infralimbic regions) of adult C57BL/6J mice, whereas AAV driving the expression of the human muscarinic Gq-coupled receptor 3 (hM3Dq) under the human synapsin gene promoter (hSyn) was injected in the vHipp. Animals were treated with clozapine N-oxide (CNO, 0.3 mg/kg, i.p.) to selectively activated the targeted vHippo-mPFC pathway for 14 consecutive days, followed by a battery of behavioral tests to assess depressive phenotypes and immunohistochemical analysis for neuronal activation using antibodies against c-Fos. Our preliminary data showed a significant reduction in depression-like behavior in forced swim test, but impaired hippocampal-dependent spatial memory in Y maze test. This memory impairment is in association with reduced number of proliferating progenitor cells and immature neurons (Ki-67 and DCX positive cells, respectively) in the hippocampal dentate gyrus and reduced neuronal activation in the mPFC. The results may suggest that a vHippo-mPFC pathway is involved in reducing depression-like behavior, however, chronic activation of this pathway can lead to impairment in spatial memory.