Microglial dopamine receptor elimination defines sex-specific nucleus accumbens development and social behavior in adolescent rats

Abstract

Adolescence is a developmental period in which the mesolimbic dopaminergic “reward” circuitry of the brain, including the nucleus accumbens (NAc), undergoes significant plasticity. Dopamine D1 receptors (D1rs) in the NAc are critical for social behavior, but how these receptors are regulated during adolescence is not well understood. In this report, we demonstrate that microglia and complement-mediated phagocytic activity shapes NAc development by eliminating D1rs in male, but not female rats, during adolescence. Moreover, immune-mediated elimination of D1rs is required for natural developmental changes in male social play behavior. These data demonstrate for the first time that microglia and complement-mediated immune signaling (i) participate in adolescent brain development in a sex-specific manner, and (ii) are causally implicated in developmental changes in behavior. These data have broad implications for understanding the adolescent critical period of development, the molecular mechanisms underlying social behavior, and sex differences in brain structure and function.

Microglia and sexual differentiation of the developing brain: A focus on ontogeny and intrinsic factors

“…While early microglia research focused on these cells' roles in the innate immune response, microglia are increasingly recognized for their importance in shaping early brain development. For example, they are heavily involved in the sculpting of neural circuitry in the developing visual system through the refinement of projections from the retina to the lateral geniculate nucleus (LGN) in activity‐ and complement‐dependent manners (Schafer, Kautzman, et al, ; Schafer, Lehrman, & Stevens, ), in the laminar positioning of interneurons in upper layers of the cortex (Squarzoni et al, ), and play an important role in the organization of social behavior (Kopec et al, ; VanRyzin et al, ). Recent studies show robust sex differences in microglial morphology, maturation, and function (Hanamsagar et al, ; Schwarz, Sholar, & Bilbo, ; Thion et al, ; Villa et al, ).…”

“…Microglia may also play a key and sex‐specific role in the shaping of brain development during the highly plastic developmental time period that is adolescence. Microglial and complement‐dependent processes mediate elimination of dopamine D1 receptors in adolescent male rats, which shapes social behavior changes occurring during the adolescent period (Kopec et al, ). Although D1 receptors are eliminated in females, these changes do not appear to be dependent upon the microglial complement system (Kopec et al, ), suggesting a differential role for microglial sculpting of social behavior in developing male versus female rats.…”

“…Microglial and complement‐dependent processes mediate elimination of dopamine D1 receptors in adolescent male rats, which shapes social behavior changes occurring during the adolescent period (Kopec et al, ). Although D1 receptors are eliminated in females, these changes do not appear to be dependent upon the microglial complement system (Kopec et al, ), suggesting a differential role for microglial sculpting of social behavior in developing male versus female rats. Of course, microglia could still be involved in the organization of female social play behaviors in a manner other than the direct elimination of receptors.…”

“…(iii) CD68+ microglial lysosomes containing co‐localized C3 and D1R peak in males at PN30, with a minor dip seen in females at PN38. This figure is based on data presented in Kopec et al ()…”

Microglia and sexual differentiation of the developing brain: A focus on extrinsic factors

“…Microglia not only organize the circuitry required for the expression of sex‐typical social play, but they also reorganize brain circuitry in a sex‐specific manner to reduce play at the end of the juvenile period. By pruning dopamine D1 receptor‐containing synapses in the nucleus accumbens selectively in males, microglia promote the natural decline in play behavior by rats as the animal transitions into puberty (Kopec, Smith, Ayre, Sweat, & Bilbo, ).…”