Exposure to Early Life Adversity Sensitizes Rats' Response to Stress in Later Life

Abstract

Early-life adversity (ELA), such as neglect or child maltreatment, increases an individual’s risk of developing psychopathology. However, ELA is often neither necessary nor sufficient to induce psychopathology. The two-hit hypothesis suggests that ELA might increase stress sensitivity, rendering an individual susceptible to developing psychopathology when exposed to subsequent stressors, even if the stressors are few or mild. The present study aimed to test that hypothesis. Rat dams and their litters were exposed to either standard rearing conditions (neonatal control; nCON), or ELA via the limited bedding/nesting (LBN) paradigm across the first week of life. As adolescents, offspring from both neonatal conditions either served as an adolescent no-stress control (aCON) or were exposed to a shortened, 12-day subthreshold course of chronic mild stress (CMS). When tested in adulthood, offspring exposed to both stressors (LBN-CMS) displayed heightened depression-like responding in the forced-swim test and sucrose preference test compared to the other three groups (no-stress, LBN-only, CMS-only), which did not differ from each other. Adult LBN-CMS offspring also displayed heightened aggression in a social play test compared to the other three groups, which did not differ from each other. Offspring exposed to LBN (i.e., LBN-aCON and LBN-CMS) displayed lower oxytocin-immunoreactive cell counts in the paraventricular nucleus compared to nCON offspring (i.e., nCON-aCON, nCON-CMS). This evidence suggests that LBN sensitizes offspring to later subthreshold stress, perhaps via deficits in the oxytocin system, rendering milder stress sufficient to induce depression-like responding in adulthood.