Oxytocin (OXT) is a pleiotropic neuropeptide with diverse physiological functions, including anti-inflammatory effects. Endogenous OXT, primarily produced by neurons in hypothalamic paraventricular nucleus (PVN) and supraoptic nucleus (SON), is known to be reduced in various pathological states, particularly during peripheral inflammatory infections. However, the mechanisms by which peripheral inflammation leads to reduced OXT signaling remain poorly understood. In a mouse model of lipopolysaccharide (LPS)-induced chronic inflammation, we observed a selective reduction in the number of magnocellular (Magno) OXT-immunopositive neurons in the PVN, with no significant changes in PVN parvocellular (Parvo) or SON OXT-immunopositive neurons. Electrophysiological recordings revealed hyperexcitability of PVN OXT Magno neurons after LPS treatment, whereas Parvo neurons showed reduced activity. Microglial activation was preferentially localized to Magno neurons-dominant PVN subregions after LPS treatment. Single-cell transcriptomic analysis indicated higher expression of the Ptger4 gene in Magno OXT neurons, and bulk RNA sequencing of PVN and SON tissues highlighted enrichment of prostaglandin-related pathways following LPS challenge. Pharmacological inhibition and genetic knockdown experiments confirmed that prostaglandin E2 (PGE2)-EP4 signaling mediates the reduction of PVN OXT-immunopositive neurons and drives microglial phagocytosis of Magno OXT neurons under inflammatory conditions. Thus, these results not only identify the specific impact of peripheral inflammation on PVN Magno OXT neurons but also uncover the involvement of prostaglandin signaling in this process.
LI et al. (Tue,) studied this question.