Microglia sculpt dopamine receptor-mediated adolescent behaviors in a social experience dependent manner

Adverse childhood experiences like social isolation (SI) contribute to long term negative health outcomes and the development of severe psychiatric disorder. Adolescence is a unique period of coordinated social and motivational system development driven by dopamine (DA) signaling. Microglia, immune cells of the brain, may play a unique role in regulating SI-induced DA system changes and associated behavioral dysfunction. Male microglia refine dopamine D1 receptors (D1rs) in the nucleus accumbens (NAc) of adolescent male rats shaping play behavior. Here we characterized the molecular developmental impacts of postweaning SI from P21-P38, with a resocialization period to P54. We tested the role of microglial engulfment of D1rs in mediating behavioral consequences of SI using neutrophil inhibitory factor (NIF) to block complement-mediated engulfment required for D1r pruning. We found sex specific impacts of SI on brain development and the DA system. In SI males, microglia engulf more NAc D1rs than group housed (GH) controls. Within GH animals, NAc D1r density is positively correlated to play and allogrooming. In SI animals, NAc D1r density is negatively correlated to biting behavior, and is not correlated to play or allogrooming. Pharmacologically inhibiting microglial engulfment of D1r via bilateral NAc NIF injection prevents observed D1r:behavior correlations in GH and SI animals. NIF treatment interacts with SI, exaggerating aggressive-like behavior, showing a role for microglia in regulating aggressive-like behavior via complement pruning in adolescence. Microglia may play a unique role in regulating behavior that drive negative health outcomes in the face of developmental stress, including SI.