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46 reviewsDepression is one of the most common mental disorders, but its etiology remains poorly understood. Neuronal nitric oxidesynthase (nNOS) has been implicated in depression, but the role of nNOS-expressing neurons is still unknown. We usedchemogenetic strategies to show that nNOS-expressing neurons in the medial prefrontal cortex (mPFC) are essential for depressionrelated behaviors. Using electrophysiology, we determined that mPFC nNOS-expressing neurons receive projections from theposterior subregion of the paraventricular thalamic nucleus (pPVT). We show that excitatory projections from the pPVT onto mPFCnNOS-expressing neurons regulate depression-related behaviors. We further explore a mechanism in which activation of mPFCnNOS-expressing neurons leads to the subsequent release of nitric oxide (NO), which enhances the nitrosylation of cyclin1234567890();,:dependent kinase 5 (CDK5). Our data suggest a mechanism for depression involving excitatory pPVT projections onto nNOSexpressing neurons in the mPFC that represents a potential target for future treatments.Neuropsychopharmacology;