Optogenetic stimulation of the median preoptic nucleus: Effects on hypothalamic paraventricular nucleus magnocellular neurons after chronic intermittent hypoxia exposure

Abstract

Median preoptic nucleus (MnPO) neurons projecting to the hypothalamic paraventricular nucleus (PVN) are linked to hypertension induced by chronic intermittent hypoxia (CIH), a model of obstructive sleep apnea. The modulation of MnPO-driven synaptic activity in PVN magnocellular neurons (MNCs) by CIH remains unexamined. We hypothesized that single and repetitive activation of MnPO-PVN projections causes differential synaptic plasticity in MnPO-PVN synapses with and without CIH exposure. Adult male rats were prepared using an intersectional viral approach to induce Cre-dependent channelrhodopsin expression in PVN-projecting MnPO neurons. Two weeks after stereotaxic surgery, some rats were exposed to 7 days of CIH. All rats were anesthetized and their brains were prepared for in vitro electrophysiological recording from PVN MNCs and optogenetic stimulation of the MnPO. We observed distinct EPSC and IPSC response patterns to the optogenetic stimulation of the MnPO. Low-frequency optogenetic stimulation (15 Hz) resulted in short-term potentiation manifested in increased poststimulatory spontaneous EPSC (sEPSC) frequency without altering amplitude while gradually increasing poststimulatory sIPSC frequency and amplitude, shifting some neurons to a more inhibitory state. CIH increased the amplitude of both sEPSCs and stimulation-evoked EPSCs while reducing their frequency. In contrast, CIH enhanced both the amplitude and frequency of sIPSCs and stimulation-evoked IPSC. Stimulation-evoked currents recorded during train protocols reflected a mixture of spontaneous and evoked events. Optogenetic stimulation increased the intrinsic excitability of MNCs in rats exposed to CIH. Activation of the MnPO-PVN pathway recruits both excitatory and inhibitory synaptic circuits converging onto PVN MNCs. CIH induces metaplasticity within this pathway, manifested as strengthened excitatory synaptic drive and heightened intrinsic excitability of PVN MNCs, which is counterbalanced by an adaptive increase in inhibitory tone. These parallel changes could explain why CIH is not associated with increased neurohypophysial hormone release.

Keywords: chronic intermittent hypoxia; hypothalamus; optogenetics; plasticity; preoptic area.