Tuesday, April 1, 2025
4/1/2025
Microglial pruning of dopamine receptors and opioid abuse. - The dopaminergic “reward” circuitry undergoes significant developmental plasticity during adolescence, including the refinement of dopamine D1 and D2 (D1/D2r) receptors within the nucleus accumbens (NAc). We have recently demonstrated in male rats that microglia – the primary immune cells of the CNS that also play a role in sculpting developing circuits – engulf and eliminate D1rs during a precise window of adolescent NAc development in response to receptor “tagging” by complement protein C3; and that this developmental pruning of D1rs by microglia is critical for the development of normal reward-driven behavior (social play). Moreover, rats that receive repeated morphine during adolescence (but not young adulthood) show persistent changes in microglial function and increased reinstatement to morphine as adults; and, pre- treatment with a glial modulator during adolescent morphine exposure prevents this increased reinstatement, implicating a critical role for microglia. Microglia refine synapses based on changes in neural activity, leading us to hypothesize that, in males (1) microglia sculpt NAc D1rs during normal adolescence as a consequence of altered dopamine (DA) activity which leads to receptor tagging by the “eat me” signal C3; and (2) factors that significantly impact DA signaling within the NAc during adolescence could persistently alter reward processing - including addiction liability - by changing microglial pruning of D1rs. We will use 3 aims to test the hypothesis that dopaminergic input to the NAc leads to complement C3 “tagging” of D1r and phagocytosis by microglia and that disruptions of this normal input (e.g. by social isolation stress) will lead to dysregulated long-term reward-driven behaviors. Importantly, D1r refinement occurs via unknown mechanisms in females, independent of microglia-C3 interaction, and the implications for addiction have not been assessed. To explore putative mechanisms in females we will additionally assess changes in D2r, and examine additional putative molecular tags/ “eat-me” signals.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).