Progranulin in the Nucleus Accumbens Contributes to Neuroinflammation-Induced Depression-Like Behavior in Mice

Abstract

BackgroundNeuroin ammation in the nucleus accumbens (NAc) is well known to in uence the progression of depression. However, the molecular mechanisms triggering NAc neuroin ammation in depression have not been fully elucidated. Progranulin (PGRN) is a multifunctional growth factor that is linked to the innate immune response and in ammation, and PGRN plays a key role in neurodegenerative diseases.Here, the purpose of this study was to validate whether PGRN was involved in the NAc neuroin ammation-promoted depressive-like phenotype. MethodsA NAc neuroin ammation-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 immuno uorescence staining were used to determine the expression and function of PGRN in the neuroin ammatory reaction in the NAc after LPS challenge. The morphology of neurons in the NAc from WT and PGRNKO mice under conditions of NAc neuroin ammation was analyzed using Golgi-Cox staining, followed by Sholl analyses.The potential signaling pathways involved in NAc neuroin ammation in PGRNKO mice were investigated by western blotting. ResultsUnder normal conditions, PGRN de ciency induced frontotemoral dementia (FTD)-like behaviors in mice and astrocyte activation in the NAc, promoted the release of the in ammatory cytokines interleukin (IL)-6 and IL-10 and increased dendritic complexity and synaptic protein BDNF levels in the NAc. However, NAc neuroin ammation enhanced PGRN expression, which was located in astrocytes and microglia within the NAc, and PGRN de ciency in mice alleviated NAc neuroin ammation-elicited depression-like behaviors, seemingly inhibiting astrocyte-and microglia-related in ammatory reactions and neuroplasticity complexity in the NAc via the p38 and nuclear factor of kappa (NF-κB) signaling pathways present in the NAc after neuroin ammation. ConclusionsOur results suggest that PGRN seems to exert distinct effects on different behaviors, such as FTD-like behavior and depression-like behavior, resulting from mediating astrocyte and microglial functions from the NAc in different status.