Hormetic pathways in environmental enrichment in animal models and humans.

Environmental Enrichment (EE), which provides enhanced sensory, cognitive, motor, and social stimulation, has emerged as a powerful paradigm for investigating neuroplasticity and stress resilience. This chapter explores how EE functions through hormetic mechanisms-where multiple mild stimuli trigger adaptive responses that promote beneficial outcomes. Since Hebb's pioneering work on neuronal ensembles, research has demonstrated that EE enhances neurogenesis, synaptic plasticity, and neurotrophic factor expression (BDNF and NGF) while modulating inflammatory processes, epigenetic pathways, and metabolic function. These adaptive responses operate according to biphasic dose-response patterns characteristic of hormesis, where moderate stimulation produces benefits that may diminish or become detrimental with excessive exposure. In animal models, EE has shown remarkable efficacy in mitigating cognitive decline, reducing anxiety-like behaviors, attenuating addiction vulnerability, and protecting against neurodegenerative diseases. The modulation of the hypothalamic-pituitary-adrenal (HPA) axis and the shifts in microglial phenotype observed with EE illustrate its role as a hormetic stimulus, as it can act as a mild stressor that promotes adaptive neuroplasticity, enhancing the organism's ability to cope with future stressors. In humans, analogous enrichments through physical exercise, cognitive challenges, social engagement, and music facilitate neuroplasticity, protect against cognitive decline, and promote stress resilience. The hormetic framework also explains why enrichment must be tailored to individual thresholds-excessive stimulation can overwhelm adaptive capacities, transforming beneficial eustress into harmful distress. By understanding EE as a hormetic intervention, this chapter bridges basic neuroscience with translational applications that may enhance resilience against neuropsychiatric disorders typically prevalent in aging.