Progranulin from different gliocytes in the nucleus accumbens exerts distinct roles in FTD- and neuroinflammation-induced depression-like behaviors.

BACKGROUND: Neuroinflammation in the nucleus accumbens (NAc) is well known to influence the progression of depression. However, the molecular mechanisms triggering NAc neuroinflammation in depression have not been fully elucidated. Progranulin (PGRN) is a multifunctional growth factor that is linked to the innate immune response and inflammation, and PGRN plays a key role in neurodegenerative diseases such as frontotemporal dementia (FTD). Here, the purpose of this study was to validate whether PGRN was involved in the NAc neuroinflammation-promoted depressive-like phenotype. METHODS: A NAc neuroinflammation-relevant depression-like model was established using wild-type (WT) and PGRN-knockout (KO) mice after NAc injection with lipopolysaccharide (LPS), and various behavioral tests related to cognition, social recognition, depression and anxiety were performed with WT and PGRNKO mice with or without NAc immune challenge. RT‒PCR, ELISA, western blotting and immunofluorescence staining were used to determine the expression and function of PGRN in the neuroinflammatory reaction in the NAc after LPS challenge. The morphology of neurons in the NAc from WT and PGRNKO mice under conditions of NAc neuroinflammation was analyzed using Golgi-Cox staining, followed by Sholl analyses. The potential signaling pathways involved in NAc neuroinflammation in PGRNKO mice were investigated by western blotting. RESULTS: Under normal conditions, PGRN deficiency induced FTD-like behaviors in mice and astrocyte activation in the NAc, promoted the release of the inflammatory cytokines interleukin (IL)-6 and IL-10 and increased dendritic complexity and synaptic protein BDNF levels in the NAc. However, NAc neuroinflammation enhanced PGRN expression, which was located in astrocytes and microglia within the NAc, and PGRN deficiency in mice alleviated NAc neuroinflammation-elicited depression-like behaviors, seemingly inhibiting astrocyte- and microglia-related inflammatory reactions and neuroplasticity complexity in the NAc via the p38 and nuclear factor of kappa (NF-κB) signaling pathways present in the NAc after neuroinflammation. CONCLUSIONS: Our results suggest that PGRN exerts distinct function on different behaviors, showing protective roles in the FTD-like behavior and detrimental effects on the neuroinflammation-related depression-like behavior, resulting from mediating astrocyte and microglial functions from the NAc in different status.

Dopamine D3 receptor in the nucleus accumbens alleviates neuroinflammation in a mouse model of depressive-like behavior.

We recently reported that dopamine D3 receptor (D3R) was involved in inflammation-related depression. Nucleus accumbens (NAc) inflammation is implicated in the development and progression of depression, but its regulatory mechanism remains largely unknown. In a mouse model of NAc neuroinflammation induced by bilateral NAc injection of lipopolysaccharide (LPS), we observed that NAc neuroinflammation triggered depressive-like behaviors, and D3R expression decline and microglial activation in the NAc. A selective knockdown of D3R in the NAc elicited depressive-like behaviors, while re-expression of D3R in the NAc of global D3RKO mice alleviated depressive-like behaviors induced by D3R deficiency. D3R downregulation in the NAc shifted microglia toward a proinflammatory state, which was validated with cultured mouse microglial cultures. Further in vitro results demonstrated that D3R inhibition induced microglia to enter a proinflammatory state primarily through the Akt signaling pathway. In conclusion, our results suggest that D3R expression in the NAc may inhibit microglial proinflammatory responses in the NAc, thus alleviating NAc neuroinflammation and subsequent depressive-like behaviors through the Akt signaling pathway.