The “play transcriptome� is sex-specific in the juvenile rat medial amygdala: a role for inhibitory neurons

Social play is a well-conserved, dynamic behavior known to be sexually differentiated. In most species, males play more than females, a sex difference largely driven by the medial amygdala (MeA) yet the full mechanism establishing this bias is unknown. Here, we explore “the transcriptome of playfulness� in both sexes for the first time, demonstrating that the transcriptomic profile in the juvenile rat MeA associated with playfulness is markedly distinct in males and females. Parallel single-cell RNA-sequencing experiments from newborn rats suggest that inhibitory neurons drive this sex difference. Furthermore, we show that inhibitory neurons comprise the majority of play-active cells in the juvenile MeA, with males having more play-active cells than females, of which a greater proportion are GABAergic. Through integrative bioinformatic analyses, we further explore the expression, function, and cell-type specificity of key play-associated gene modules, providing valuable insight into the sex-biased mechanisms underlying this fundamental social behavior.