| Summary: | Abstract Stress is a primary risk factor for psychiatric disorders. However, it is not fully understood why some stressed individuals are more vulnerable to psychiatric disorders than others. Here, we investigated whether multigenerational ancestral stress produces phenotypes that are sensitive to depression-like symptoms in rats. We also examined whether social isolation reveals potentially latent sensitivity to depression-like behaviours. F4 female rats born to a lineage of stressed mothers (F0-F3) received stress in adulthood while housed in pairs or alone. Social isolation during stress induced cognitive and psychomotor retardation only in rats exposed to ancestral stress. Social isolation also hampered the resilience of the hypothalamic-pituitary-adrenal axis to chronic stress and reduced hippocampal volume and brain-derived neurotrophic factor (BDNF) expression. Thus, synergy between social isolation and stress may unmask a latent history of ancestral stress, and raises vulnerability to mental health conditions. The findings support the notion that social support critically promotes stress coping and resilience.
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