Repeated stress exposure in mid-adolescence attenuates behavioral, noradrenergic, and epigenetic effects of trauma-like stress in early adult male rats

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.

Adolescent Stress Confers Resilience to Traumatic Stress Later in Life: Role of the Prefrontal Cortex

“…Timing combined with stressor modality seem to be an important factor as well. In this sense, prior work indicates adult resilience even after a single intense stressor protocol at PND37 or following 3 days of predator related stressors at PND33-35 (46). In contrast, a 3-day pre-pubertal exposure to variate stressors failed to attenuate exaggeration of fear responses in adulthood, indicating that developmental timing is critical for establishment of resilience.…”

Traumatic Stress, Chronic Ethanol Exposure, or the Combination, Alter Cannabinoid System Components in Reward and Limbic Regions of the Mouse Brain

“…In this study, we focused on the main brain regions of the reward pathway (PFC, anterior STR, NAc) as well as the two primary brain structures of the limbic system (HC and AMYG) as traumatic stress and chronic alcohol exposure are known to disrupt the function of those circuits [ 17 , 18 , 19 , 59 , 60 , 61 ], and brain regions within those pathways contain abundant levels of CB system components [ 17 , 22 , 23 , 24 ]. The PFC is one of the main reward-associated brain regions, and it plays an important role in working memory, executive function, emotional and motivational regulation, learning extinction, and decision-making [ 9 , 11 , 12 , 13 , 21 , 62 , 63 , 64 ]. Animal studies have shown that repeated restraint stress in both mice and rats decreases AEA content but increases 2-AG content in the medial PFC [ 47 , 51 ].…”

“…The STR is another main reward-associated brain region that plays an important role in regulating motivation, habitual action and learning, goal-directed behaviors, and cognition, and studies have shown that alcohol exposure alters striatal function [ 11 , 12 , 20 , 64 , 69 , 70 , 71 , 72 , 73 , 74 ]. Our results showed that both AEA and 2-AG content increased in the anterior STR after mice were exposed to both mSPS and CIE compared to mice exposed to mSPS only.…”

“…The HC, one of the primary structures in the limbic system, regulates learning and memory as well as HPA axis inhibition [ 10 , 12 , 14 , 59 , 64 , 89 , 90 , 91 , 92 , 93 ], and specifically, the dorsal HC modulates cognitive function [ 94 ]. Our results showed that mice exposed to CIE only had a higher AEA content compared to other groups (Control-Air, mSPS-Air, or mSPS-CIE) studied here, which suggests a CIE-driven effect in hippocampal AEA content.…”

“…Traumatic stress and alcohol exposure impair the function of the primary structures of the limbic system, including the hippocampus (HC) and amygdala (AMYG), which play important roles in memory and emotion [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ], as well as the primary structures in the reward pathway, including the prefrontal cortex (PFC), striatum (STR), and nucleus accumbens (NAc), which mediate motivation, reward, and executive function [ 11 , 12 , 17 , 18 , 19 , 20 , 21 ]. Although these brain regions differ in their primary function, they are similar in their enriched content of cannabinoid (CB) system components [ 17 , 22 , 23 , 24 ], suggesting a role for the CB system in the combined condition of PTSD-AUD.…”