Social and nonsocial environmental loss have differential effects on ventral hippocampus-dependent behavior and inhibitory synaptic markers in adult male mice

In humans, psychological loss, whether social or nonsocial, can lead to clinical depression, anxiety disorders, and social memory impairments. Researchers have modeled combined social and nonsocial loss in rodents by transitioning them from social, enriched environments (EE) to individual housing, affecting behaviors related to avoidance, stress coping, and cognitive function. However, it remains unclear if these effects are driven by social or nonsocial loss. We examined the effects of nonsocial loss by housing adult male mice in EE before moving them to standard cages, where they were pair-housed, and compared this to mice experiencing complete social loss. Continuous EE reduced social investigation time while leaving social memory intact, also decreasing avoidance behavior. Nonsocial loss restored social investigation and avoidance behavior to control levels, while social loss impaired social memory and increased avoidance. In rodents, social memory and avoidance require ventral hippocampus (vHIP) neuronal oscillations, which involve parvalbumin-positive (PV+) inhibitory interneurons. We found decreased vHIP PV intensity in the social loss group, with no differences in the nonsocial loss group. Most PV+ cells are surrounded by perineuronal nets (PNNs) concentrating GABA_A receptors in their lattice-like holes. Social loss decreased GABA_A-δ expression, a subunit associated with extrasynaptic receptors, across PNN+ soma and in PNN holes, while nonsocial loss reduced gephyrin in these regions. These findings suggest social and nonsocial losses differentially affect vHIP function and behavior, with social loss having a more pronounced impact through mechanisms involving PV+ interneurons, PNN structure, and neurotransmitter receptor expression.