Abstract
Stress in adolescence can regulate vulnerability to traumatic stress in adulthood through region-specific epigenetic activity and catecholamine levels. We hypothesized that stress in adolescence would increase adult trauma vulnerability by impairing extinction-retention, a deficit in PTSD, by (1) altering class IIa histone deacetylases (HDACs), which integrate effects of stress on gene expression, and (2) enhancing norepinephrine in brain regions regulating cognitive effects of trauma. We investigated the effects of adolescent-stress on adult vulnerability to severe stress using the single-prolonged stress (SPS) model in male rats. Rats were exposed to either (1) adolescent-stress (33–35 postnatal days) then SPS (58–60 postnatal days; n = 14), or (2) no adolescent-stress and SPS (58–60 postnatal days; n = 14), or (3) unstressed conditions (n = 8). We then measured extinction-retention, norepinephrine, HDAC4, and HDAC5. As expected, SPS exposure induced an extinction–retention deficit. Adolescent-stress prior to SPS eliminated this deficit, suggesting adolescent-stress conferred resiliency to adult severe stress. Adolescent-stress also conferred region-specific resilience to norepinephrine changes. HDAC4 and HDAC5 were down-regulated following SPS, and these changes were also modulated by adolescent-stress. Regulation of HDAC levels was consistent with the pattern of cognitive effects of SPS; only animals exposed to SPS without adolescent-stress exhibited reduced HDAC4 and HDAC5 in the prelimbic cortex, hippocampus, and striatum. Thus, HDAC regulation caused by severe stress in adulthood interacts with stress history such that seemingly conflicting reports describing effects of adolescent stress on adult PTSD vulnerability may stem in part from dynamic HDAC changes following trauma that are shaped by adolescent stress history.
Highlights
Stress in adolescence can regulate vulnerability to traumatic stress in adulthood through regionspecific epigenetic activity and catecholamine levels
Among histone deacetylases (HDACs), HDAC4/5 are relevant to our inquiry because (1) several studies have linked these targets to effects of environmental context on complex cognition and (2) dysregulation of HDAC4 and HDAC5 can contribute to the development of psychopathology[28,29,31,32,33,34]
Consistent with our predictions and prior clinical evidence of decreased HDAC4 in P TSD33, our results demonstrate that singleprolonged stress (SPS) decreased HDAC4/5 in brain regions mediating cognitive effects of traumatic stress
Summary
Stress in adolescence can regulate vulnerability to traumatic stress in adulthood through regionspecific epigenetic activity and catecholamine levels. We hypothesized that stress in adolescence would increase adult trauma vulnerability by impairing extinction-retention, a deficit in PTSD, by (1) altering class IIa histone deacetylases (HDACs), which integrate effects of stress on gene expression, and (2) enhancing norepinephrine in brain regions regulating cognitive effects of trauma. HDAC regulation caused by severe stress in adulthood interacts with stress history such that seemingly conflicting reports describing effects of adolescent stress on adult PTSD vulnerability may stem in part from dynamic HDAC changes following trauma that are shaped by adolescent stress history. Broad pharmacological inhibition of class I and II HDACs can enhance fear memory reconsolidation or fear extinction, including extinction learning, following exposure to the preclinical model of severe stress called single-prolonged stress (SPS)[37,38,39,40]. Extinction retention deficits in PTSD have been linked to hypoactivation of the medial prefrontal cortex (PFC) and the hippocampus, coupled with amygdala hyperactivation[41,43]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
