Repeated stress exposure in mid-adolescence attenuates behavioral, noradrenergic, and epigenetic effects of trauma-like stress in early adult male rats.
Repeated stress exposure in mid-adolescence attenuates behavioral, noradrenergic, and epigenetic effects of trauma-like stress in early adult male rats.
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DOI：
10.1038/s41598-020-74481-3
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发表时间：
2020-10-21
影响因子：
4.6
通讯作者：
Perrine SA
中科院分区：
文献类型：
--
作者：
Chaby LE;Sadik N;Burson NA;Lloyd S;O'Donnel K;Winters J;Conti AC;Liberzon I;Perrine SA
青春期的压力可以通过特定区域的表观遗传活动和儿茶酚胺水平调节成年期对创伤性压力的脆弱性。我们假设，青春期的压力会通过以下方式增加成人创伤的脆弱性：（1）改变IIa类组蛋白脱乙酰酶（HDAC），从而损害创伤后应激障碍中的一种缺陷，（2）增强调节创伤认知效应的大脑区域中的去甲肾上腺素。本研究采用单次长时间应激（SPS）雄性大鼠模型，探讨了慢性应激对成年大鼠严重应激易感性的影响。将大鼠暴露于（1）应激（出生后33-35天），然后SPS（出生后58-60天; n = 14），或（2）无应激和SPS（出生后58-60天; n = 14），或（3）无应激条件（n = 8）。然后，我们测量了排尿保留、去甲肾上腺素、HDAC 4和HDAC 5。正如预期的那样，SPS暴露引起的防御保留赤字。青春期的压力之前SPS消除了这一赤字，这表明双相压力赋予弹性成年严重的压力。青少年压力也赋予了特定区域的去甲肾上腺素变化的弹性。HDAC 4和HDAC 5在SPS后下调，这些变化也受到干旱胁迫的调节。HDAC水平的调节与SPS的认知效应模式一致;只有暴露于SPS而不受应激的动物在前边缘皮层、海马和纹状体中表现出HDAC 4和HDAC 5降低。因此，HDAC调节所造成的严重压力在成年期与压力的历史相互作用，这样似乎相互矛盾的报告描述的青少年压力对成人创伤后应激障碍的脆弱性的影响可能源于动态HDAC的变化，创伤后，青少年的压力历史的形状。
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.
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