NgR-Dependent plasticity in a dCA3CaMKIIα → VTADA → NAc circuit underlies stress resilience and susceptibility

The Nogo receptor (NgR), a core receptor for myelin-derived axon growth inhibitors, has been implicated not only in the regulation of synaptic plasticity but also in the pathogenesis of various neuropsychiatric disorders. However, its specific role and the underlying circuit mechanisms in the development of depression remain elusive. This study used a chronic unpredictable mild stress (CUMS) model in male mice and found that the expression of the NgR in the dorsal CA3 (dCA3) region of the hippocampus was significantly increased in depressive-like mice, and it was mainly enriched in glutamatergic neurons with reduced excitability. Downregulation of NgR in dCA3 or enhancement of glutamatergic neuronal excitability significantly alleviated depressive-like behaviors, while upregulation of NgR or inhibition of glutamatergic neuronal excitability promoted stress-induced depressive-like behaviors. Notably, dCA3 glutamatergic neurons specifically project to the dopaminergic neuronal pathway in the ventral tegmental area (VTA) and its downstream dopaminergic projections to the nucleus accumbens (NAc). The inhibition of D1/D2 receptors in the NAc is required for mediating depressive-like behaviors. Furthermore, downregulation of NgR in dCA3 exerts antidepressant-like effects by disinhibiting the neurons projecting to the VTA → NAc pathway. This study systematically reveals the role of NgR in dCA3 glutamatergic neurons and the dCA3CaMKIIα → VTADA → NAc circuit in depressive-like behaviors, providing a new theoretical basis for developing potential therapeutic strategies targeting myelin-related signaling pathways for depression.