Univ. Maryland, USA
Glia as sculptors of sex differences in the social brain
Rough-and-tumble play is a highly conserved, sexually differentiated behavior that is more frequent and vigorous in juvenile male rats than females. The behavioral difference is reflected in higher neuronal activation in males in a critical node of the social behavior circuit: the medial amygdala (MeA). However, while neurons in the MeA are differentially active between the sexes during play, the entire process arises from sex differences in MeA architecture mediated not by neurons, but by microglia and astrocytes.
During postnatal development, masculinization of the MeA is androgen-dependent and driven by microglia phagocytosis. These brain-resident macrophages engulf more newborn astrocytes in the male amygdala which, by the juvenile age, results in fewer astrocytes than females. Blocking phagocytosis postnatally in the male amygdala increases astrocyte number and correspondingly decreases neuronal activation and playfulness to female levels. Simultaneously, microglia mediate the feminization of MeA astrocyte number by promoting newborn cell survival through TNFalpha/NF-kB signaling. Microglia are the primary source of TNFalpha in the developing amygdala, and either depleting microglia or inhibiting NF-kB during this critical period increases female play to male levels as juveniles.
The sex difference in juvenile astrocyte number has significant implications for play behavior, as chemogenetic activation or inhibition of MeA astrocytes either decreases or increases play, respectively. Thus, our data demonstrate that the organization and activation of the neural circuitry of play is both established and regulated by non-neural cells. Microglia mediate both the masculinization and feminization of astrocyte number in the MeA, while astrocyte number and activity controls neuronal activity which in turn mediates play behavior.
Jonathan VanRyzin is a postdoctoral fellow in the lab of Dr. Margaret McCarthy in the Department of Pharmacology, University of Maryland School of Medicine. Jon received his PhD in Neuroscience in 2018 at the University of Maryland School of Medicine, where he studied neuroimmune mechanisms of sexual differentiation of the brain in a rodent model. His research currently focuses on understanding the mechanisms by which non-neuronal cells, mainly microglia and astrocytes, organize and regulate developing neural circuits underlying social behaviors.