Sexual dimorphism and acute stress modulation of infralimbic-posterior hypothalamic synaptic transmission

Acute stress engages neural circuits that coordinate autonomic and neuroendocrine responses, including projections from the infralimbic cortex (IL) to the posterior hypothalamic nucleus (PH). Although both regions are activated during stress, the synaptic mechanisms underlying IL-to-PH communication remain poorly understood. Here, we combined optogenetics with whole-cell patch-clamp electrophysiology to determine how acute restraint stress alters excitatory synaptic transmission from IL to PH neurons in adult male and female rats. IL afferents formed functional glutamatergic synapses onto PH neurons in both sexes, characterized by short-term facilitation and a high AMPA/NMDA ratio. However, females exhibited smaller optically evoked excitatory postsynaptic currents (EPSCs) in response to single or burst stimulation across multiple holding potentials. NMDA receptor-mediated EPSCs and NMDAR-predominant spontaneous EPSCs also displayed sex differences, with females showing smaller and faster synaptic currents. When data were collapsed across sex, acute restraint stress enhanced NMDAR-mediated synaptic currents at IL-to-PH synapses while reducing the amplitude of NMDAR-predominant spontaneous EPSCs without altering their frequency. Together, these findings reveal sex-dependent differences in excitatory IL-to-PH synaptic signaling and suggest that acute stress preferentially modulates NMDAR-mediated transmission in this pathway. These results highlight dynamic postsynaptic mechanisms that shape prefrontal-hypothalamic communication during acute stress.