Remission after stress via enriched environment increases hippocampal dendritic spine density independent of microglia

Major depressive disorder (MDD) is a common disease of the central nervous system that leads to high socio-economic and clinical challenges. Chronic stress is a major risk factor for MDD, yet the underlying mechanisms remain unclear. Recent studies suggest that microglia play a role in synaptic dysfunction, crucial in the ethology and progression of depression. Our research focuses on the hippocampal microglia-synapse interaction during both the induction and remission phases following stress in a mouse model. We induced a depression-like state in adult male mice using chronic mild stress in the automated IntelliCage system and assessed behavioral phenotypes. We induced a depression-like state in adult male mice using chronic mild stress in the automated IntelliCage system and assessed behavioral phenotypes. Simultaneously, we monitor structural changes of dendritic spines and microglia in the hippocampus using chronic in vivo two-photon microscopy. To determine microglia's role in spine density and behavior changes, we depleted them with the CSF1-R antagonist BLZ945. Stress led to an increased spine density on hippocampal CA1-neurons dependent on the presence of microglia. As previously shown, enriched environment resulted in increased spine density and was able to ameliorate stress-dependent behavior phenotypes. Surprisingly, enriched environment related dendritic spine increase was independent of microglia. The microglia fine process motility decreased upon stress induction and increased upon exposure to the enriched environment. Our multimodal approach, combining chronic in vivo imaging with behavioral analysis, enabled us to elucidate the relationship between dendritic spine changes and microglia under stress conditions in the hippocampus.