nNOS-expressing neurons in the mPFC mediate depression-related behaviors in mice through pPVT-mPFC projections.

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