Sex differences in biophysical signatures across molecularly defined medial amygdala neuronal subpopulations.

The medial amygdala (MeA) is essential for processing innate social and non-social behaviors, such as territorial aggression and mating, which display in a sex-specific manner. While sex differences in cell numbers and neuronal morphology in the MeA are well established, if and how these differences extend to the biophysical level remain unknown. Our previous studies revealed that expression of the transcription factors, Dbx1 and Foxp2 during embryogenesis defines separate progenitor pools destined to generate different subclasses MeA inhibitory output neurons. We have also previously shown that Dbx1- and Foxp2-lineage neurons display different responses to innate olfactory cues and in a sex specific manner. To examine if these neurons also possess sex specific biophysical signatures, we conducted a multi-dimensional analysis of the intrinsic electrophysiological profiles of these transcription factor defined neurons in the male and female MeA. We observed striking differences in the action potential spiking patterns across lineages, and across sex within each lineage, properties known to be modified by different voltage-gated ion channels. To identify the potential mechanism underlying the observed lineage- and sex-specific differences in spiking adaptation, we conducted a phase plot analysis to narrow down putative ion channel candidates. Of these candidates, we found a subset expressed in a lineage- and/or sex-biased manner. Thus, our results uncover neuronal subpopulation and sex differences in the biophysical signatures of developmentally-defined MeA output neurons, providing a potential physiological substrate for how the male and female MeA may process social and non-social cues that trigger innate behavioral responses. Significance Statement The amygdala is a major brain center for processing environmental cues for social, emotional and survival behaviors. Furthermore, the amygdala is one of a handful of sexually dimorphic regions of the brain. Focusing on the medial sub-nucleus of the amygdala (MeA), which regulates innate social and non-social behaviors, here we studied neuronal subpopulation and sex differences in the intrinsic biophysical properties of two developmentally and molecularly identifiable subpopulations of MeA output neurons. We find dramatic lineage- and sex differences in a variety of intrinsic biophysical properties and provide insight into potential molecular mechanisms underlying these differences. These sex-specific neural substrates may help us understand how the amygdala processes innate social and non-social behaviors differently across sex.