Juvenile social play behavior is a shared trait across a wide variety of mammalian species. When play is characterized by the frequency or duration of physical contact, males usually display more play relative to females. The endocannabinoid system contributes to the development of the sex difference in social play behavior in rats. Treating newborn pups with a non-specific endocannabinoid agonist, WIN55,212-2, masculinizes subsequent juvenile rough-and-tumble play behavior by females. Here we utilize specific drugs to target signaling through either the CB1 or CB2 endocannabinoid receptors (CB1R or CB2R) to determine which modulates the development of sex differences in play. Our data reveal that signaling through both CB1R and CB2R must be altered neonatally to modify development of neural circuitry regulating sex differences in play. Neonatal co-agonism of CB1R and CB2R masculinized play by females, while co-antagonism of these receptors feminized rates of male play. Because of a known role for the medial amygdala in the sexual differentiation of play, we reconstructed Golgi-impregnated neurons in the juvenile medial amygdala and used a factor analysis to identify morphological parameters that were sexually differentiated and responsive to dual agonism of CB1R and CB2R during the early postnatal period. Our results suggest sex differences in the medial amygdala are modulated by the endocannabinoid system during early development. Sex differences in play behavior are loosely correlated with differences in neuronal morphology.
Significance Statement: Juvenile social play behavior is a critical component for proper brain development and the acquisition of social competence in the majority of mammalian species. In juvenile rats, males exhibit higher numbers of rough-and-tumble play events relative to females. This difference in rat play behavior is programmed by the actions of steroid hormones during the early postnatal sensitive period for sexual differentiation of the brain. Here we demonstrate a requirement for combined activation or inhibition of both endocannabinoid receptors for masculinization or feminization of the neural circuitry for play, respectively. Furthermore, our findings suggest a correlation between playfulness and neuronal morphology in the medial amygdala.
Authors report no conflict of interest.
This work was funded by RO1MH052716-020 and RO1DA039062-01 to MMM.