Nucleus Accumbens Dopamine D3 Receptor Regulates Microglial M1 Polarization Through Akt Signaling Pathway in the Depressive-Like Behavior
Abstract Background: Nucleus accumbens (NAc) inflammation is implicated in the development and progression of depression but the underlying mechanism remains largely unclear. We previously reported that dopamine D3 receptor (D3R) expressed in the NAc strongly correlated with inflammation-related depression. The objective of the present study is to determine the exact mechanism of D3R in the NAc inflammation relevant depression.Methods: Bilateral NAc injection of Lipopolysaccharide (LPS)-induced NAc inflammation mouse model was used to explore the relationship between NAc inflammation and depressive-like behaviors. Either conditional knockout of D3R in the NAc in the adult mice or restoration of D3R expression in the NAc in D3R mutant mice was applied to investigate the effects of D3R in the NAc on depressive disorders. The exact molecular mechanism of D3R in the NAc inflammation-induced depressive-like phenotype was ascertained by in vivo and in vitro studies. Results: NAc inflammation induced by intra-NAc LPS triggered a series of depressive-like disorders, and the interaction of D3R and microglia activation involved in the NAc inflammation-induced depressive-like phenotype. We observed that selective knock-down of D3R in the NAc elicited the depressive-like behaviors, but re-expression of D3R in the NAc alleviated the depressive-like behaviors established by D3R mutation. Finally, D3R in the NAc mediated microglial polarization to M1 phenotype mainly through Akt signaling pathway. Conclusions: These findings provide direct evidence that not only NAc inflammation but also down-regulation of D3R in the NAc has a role in regulation the initiation and development of depression, and indicate that D3R negatively regulated microglial M1 polarization mainly via Akt signaling pathway that may be involved in the NAc inflammation and thereby depressive-like behaviors.
