Chronic Intermittent Hypoxia increases EPSC Frequency in median preoptic nucleus neurons through BDNF-TrkB signaling in a sex-dependent manner

Chronic intermittent hypoxia (CIH), a hallmark of obstructive sleep apnea, produces a sustained sympathetically-mediated increase in blood pressure. The median preoptic nucleus (MnPO) contributes to CIH-induced sympathoexcitation via projections to the paraventricular nucleus of the hypothalamus (PVN). However, the synaptic mechanisms underlying CIH-induced increased activity in this pathway remain to be determined. Additionally, the impact of sex on MnPO synaptic changes in CIH exposure is unknown. We hypothesized that CIH affects MnPO synaptic activity differently between sexes and that brain-derived neurotrophic factor-tropomyosin receptor kinase B (BDNF-TrkB) signaling plays a role in CIH-mediated changes in the MnPO-PVN pathway. We performed whole-cell voltage-clamp recordings from MnPO neurons in brain slices from male and female rats exposed to either normoxia or seven days of CIH. In PVN-projecting MnPO neurons, CIH increased mEPSC frequency only in males, while females showed a reduction in mEPSC amplitude to CIH. CIH also increased BDNF expression in the MnPO of males exposed to CIH but not in females. Pharmacological studies in male rats using K252a, K252b, and ANA-12 attenuated the CIH-induced increase in mEPSC frequency, indicating that BDNF–TrkB signaling is essential for CIH. These findings highlight a sex-specific, TrkB-dependent mechanism that enhances excitatory signaling between the MnPO and PVN. In conclusion, our study shows that PVN-projecting MnPO neurons demonstrate sex-based changes in mEPSCs and that BDNF-TrkB signaling contributes to the CIH-induced increase in mEPSC frequency in neurons from males.