Nociceptin/OrphaninFQ Receptor Modulates the Maturation of Adult-Born Neurons in the Mouse Dentate Gyrus Under Physiological Conditions and in a Chronic Stress Model

Neurogenesis persists in the adult dentate gyrus (DG) of the hippocampus, playing a critical role in memory and stress adaptation. Dysregulation of this process is implicated in cognitive deficits and depressive behaviors induced by chronic stress, while classical antidepressants are known to enhance neurogenesis. The Nociceptin/Orphanin FQ (N/OFQ) system, comprising N/OFQ and its NOP receptor, modulates memory and the stress response, yet its role in adult neurogenesis remains underexplored. Here, we investigated the impact of N/OFQ signaling on neurogenesis in the mouse DG using genetic and pharmacological approaches under basal and chronic stress conditions. In constitutive NOP receptor knockout (KO) mice, adult neurogenesis was only mildly altered, with subtle changes in neuronal maturation. However, spine density in 4-week-old adult-born DG neurons increased following conditional NOP Receptor KO in the DG. The increase was specific to stubby and thin spines, while mature mushroom spine density decreased. When NOP KO was restricted to newly born neurons, no significant differences were observed in spine density suggesting that the absence of NOP receptors in mature DG neurons influences the local environment to regulate spinogenesis in adult-born neurons indirectly. Finally, chronic corticosterone exposure impaired spinogenesis in immature neurons, and this was mitigated by systemic administration of a NOP antagonist. Our findings suggest that N/OFQ signaling indirectly regulates the maturation and connectivity of adult-born neurons through modulation of local and distal inputs. This regulation may contribute to the antidepressant and pro-cognitive effects of NOP receptor antagonists.