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

Ashley M Kopec,Nathan R Ayre,Sean C Sweat,Staci D Bilbo,Caroline J Smith

doi:10.1038/s41467-018-06118-z

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.

Highlights

Adolescence is a developmental period in which the mesolimbic dopaminergic “reward” circuitry of the brain, including the nucleus accumbens (NAc), undergoes significant plasticity
The data collectively suggest that NAc D1 receptors (D1rs) are critical mediators of social behavior, but how the dopamine system in the NAc develops during adolescence, and how this development modulates social behaviors remains unclear
We focused our investigation on the dorso-medial area of the anterior NAc, as this area had robust D1r immunoreactivity (Supplementary Fig. 1)

Summary

Introduction

Adolescence is a developmental period in which the mesolimbic dopaminergic “reward” circuitry of the brain, including the nucleus accumbens (NAc), undergoes significant plasticity. A recent report showed increased association of synaptic elements (post-synaptic spines and pre-synaptic glutamatergic terminals) with microglia in the prefrontal cortex during adolescence, indicating that immunemediated synaptic pruning could be occurring in regions with protracted development[25] Taken together these data collectively suggest that microglia and immune signaling may constitute a ubiquitous developmental mechanism by which neural circuits, and theoretically behaviors mediated by these circuits, mature. Though immune processes are not regulating D1r levels in females, perturbing the complement–microglial relationship locally in the NAc alters social play behavior in females, suggesting that an as yet undetermined immune process is occurring in the female NAc during adolescence to mediate basal levels of social 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

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