Diazepam reduces hippocampal and behavioral plasticity, blunting environmental impact on emotional responses

Plasticity is essential for mental health, as it enables individuals to adapt to environmental changes. However, its effects are highly context-dependent. While increased plasticity can be beneficial in supportive environments, as treatments that enhance plasticity have proved more effective when paired with favorable experiences, it may promote maladaptive responses under adverse conditions. Accordingly, a reduction in plasticity is expected to be beneficial in adverse circumstances, as it can limit harmful influences on mental well-being. To test this hypothesis, we investigated whether diazepam, a benzodiazepine that reduces neural plasticity, thereby attenuates the impact of environmental conditions on behavioral and physiological endophenotypes of depression. In a first experiment, we treated C57BL/6 adult male and female mice with diazepam or vehicle, delivered either orally or intraperitoneally, and found a consistent impairment in synaptic plasticity, as indicated by reduced hippocampal long-term potentiation. In a second experiment, after inducing a depression-like phenotype, we treated C57BL/6 adult male mice for three weeks with diazepam or vehicle in either enriched or stressful conditions. The treatment had opposite effects depending on the environmental conditions. In enrichment, it was associated with no significant recovery from anhedonia, whereas under stress, it prevented a further worsening, relative to the control groups. Diazepam also affected anxiety-related behavioral outcomes and hypothalamic-pituitary-adrenal axis activation in an environment-dependent manner. Overall, we demonstrate that diazepam, impairing hippocampal plasticity, blunts the impact of environmental factors on the behavioral outcome. These findings underscore the potential of tailoring neural plasticity to environmental quality as a strategy in precision psychiatry.