Input-specific properties of excitatory synapses on oxytocin receptor-expressing neurons in the lateral septum

Oxytocin receptor (OXTR) is expressed in a distinct population of neurons in the lateral septum (LS), among other brain regions, and is responsible for regulating various social and nonsocial behaviors, including reward processing, feeding, social memory, anxiety, and fear. The LS serves as a key link between the cortical and subcortical regions, yet the synaptic inputs that drive the OXTR-expressing LS neurons have not been characterized. Here, we established retrograde and anterograde viral tracing in the mouse brain to map the input connections of the intermediate part of the LS where OXTR neurons are concentrated. Utilizing pathway-specific optogenetic activation, we identified that the strongest cortical inputs to LS OXTR neurons are from the posteromedial amygdala cortex (PMCo) and the ventral hippocampus (vHipp). We further determined that these excitatory inputs exhibit distinct presynaptic and postsynaptic properties, with PMCo synapses displaying a lower release probability and smaller α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-to-N-methyl-d-aspartate (NMDA) receptor-mediated excitatory postsynaptic current (EPSC) ratio compared to vHipp synapses. Our results also demonstrated that both vHipp and PMCo inputs establish a direct excitatory and a disynaptic inhibitory circuit on LS OXTR neurons. These findings deepen our understanding of the synaptic control of LS OXTR neurons by cortical regions, carrying significant implications for the affective behaviors in which these neurons are involved.NEW & NOTEWORTHY This is the first identification and characterization of the cortical synaptic inputs that drive the oxytocin receptor (OXTR)-expressing neurons in the lateral septum (LS), which are involved in diverse affective behavior. The strongest cortical inputs to LS OXTR neurons are from the posteromedial amygdala cortex, an understudied cortical region that is beginning to gain prominence for its role in social behavior. The synapses from these projections show differences in properties compared to inputs from the ventral hippocampus.