Effect of dynamic interaction of estrous cycle and stress on synaptic transmission and neuronal excitability in the lateral habenula

The prevalence of depressive disorders in women has been reported in many countries. However, the cellular mechanisms mediating such sex differences in stress susceptibility remain largely unknown. Previously, we showed that lateral habenula (LHb) neurons are more activated in female mice than in male mice by restraint stress. Given the important role of LHb in depressive disorders, we aimed to investigate the synaptic differences between male and female LHb and to examine the possible impact of the estrous cycle on neurotransmission in LHb. We found that the passive and active properties of LHb neurons differed according to the estrous cycle. Spontaneous excitatory postsynaptic currents exhibited higher amplitudes during the diestrus stage and lower frequencies in females than in males, whereas inhibitory postsynaptic currents showed no significant differences. Acute stress-induced hyperpolarization of resting membrane potentials (RMP) was observed in both sexes, with notable changes in female silent and tonic neurons. Stress exposure eliminated estrous cycle-dependent RMP differences and introduced cycle-specific excitability changes, especially in the metestrus and diestrus stages, suggesting that the hormonal cycle may set the synaptic tone of the LHb, thus modulating stress responses in females. Our study provides invaluable groundwork for understanding the detailed interaction between the estrous cycle and stress exposure in female LHb.