Testing the cumulative stress and mismatch hypotheses of psychopathology in a rat model of early-life adversity
Testing the cumulative stress and mismatch hypotheses of psychopathology in a rat model of early-life adversity
复制标题
DOI：
10.1016/j.physbeh.2012.01.015
复制
发表时间：
2012-07-16
影响因子：
2.9
通讯作者：
de Kloet, E. Ronald
中科院分区：
文献类型：
--
作者：
Daskalakis, Nikolaos P.;Oitzl, Melly S.;de Kloet, E. Ronald
背景：在本研究中，我们测试了精神病理学的累积压力和不匹配假设。为了这个目的，早期生活逆境和晚年生活压力暴露对精神病易感性的行为标志物的综合影响进行了研究，在雄性Wistar rates.Method：实验一：大鼠幼崽分为低，中，高产妇护理组的基础上，他们的母亲的护理经验的水平，断奶后饲养组（实验一）。在社会隔离（Exp。IB），并在成年期在基础条件下或在急性皮质酮（CORT）施用后进行测试。母亲的护理水平进行了评估，通过测量母鼠的舔和梳理（LG）的第一个产后一周的生活。实验二：在出生后第3、4和5天，将新生大鼠暴露于每天8小时的母体分离（MS），完全在其饲养笼中（HOME SEP）或单独在新环境中（NOVEL SEP）。成年测试包括标记精神病易感性的行为：阿朴吗啡诱导的啃咬（APO-啃咬），声惊吓反应和前脉冲刺激（PPI）对其的调制。中LG后代的行为被用作基线参考所有三个experiments.Results：实验一：低母亲LG的历史只有有限的影响Wistar后代的行为，虽然增加声惊吓和增加PPI，在高前脉冲强度水平，观察。当低的母亲LG的历史相结合，断奶后的社会隔离，基础载脂蛋白O啃减少和PPI增加，相比，高LG和中LG后代。这反映了精神病易感性减弱。然而，隔离饲养的高LG后代显示，在社会隔离饲养的大鼠中，最高的载脂蛋白O-啃食和最低的PPI水平，这表明精神病易感性增加。这些发现支持错配假说。为了证明累积应力假设，需要在成年低LG后代中注射CURT，以增加APO啃食并降低PPI。在额外的隔离饲养后，这种curt诱导的PPI破坏大大增强。高LG组，无论是社会安置或饲养隔离，是耐急性CORT在adultory.Experiment II的影响：MS增加精神病的易感性，只有在NOVEL SEP大鼠经历了MS的背景下，早期的社会隔离。这些个体显示出增加的成年APO啃食和减少的PPI，如果在断奶后在与其早期生活的社会环境（即群体饲养）不匹配的条件下饲养。这一发现支持错配hypothes.Conclusion：精神病易感性的发展编程环境操作的结果取决于早期生活的逆境和晚年的压力源的相互作用的方式，支持错配假说。然而，累积压力假说的证据出现，如果脆弱的个人在以后的生活中暴露于额外的压力激素CURT过量。(C)2012 Elsevier Inc. All rights reserved.
Background: In the present study, we tested both the cumulative stress and the mismatch hypothesis of psychopathology. For this purpose the combined effects of early-life adversity and later-life stress exposure on behavioral markers of psychosis susceptibility were studied in male Wistar rats.Method: Experiment I: rat pups divided on the basis of the levels of their maternal care experience in low, medium or high maternal care groups, were reared post-weaning in groups (Exp. IA) or in social isolation (Exp. IB) and tested at adulthood under basal conditions or after an acute corticosterone (CORT) administration. Maternal care levels were assessed by measuring the dam's licking and grooming (LG) the first postnatal week of life. Experiment II: rat pups exposed as neonates to daily sessions of 8 h of maternal separation (MS) on postnatal days 3, 4 and 5 either altogether in their home cage (HOME SEP) or alone in a novel environment (NOVEL SEP). were reared post-weaning in groups and tested at adulthood under basal conditions.Adult testing included behaviors marking psychosis susceptibility: apomorphine-induced gnawing (APO-gnawing), acoustic startle response and its modulation by a prepulse stimulus (PPI). The behavior of the Medium LG offspring was used as baseline reference for all the three experiments.Results: Experiment I: Low maternal LG history alone had limited effects on the behavior of Wistar offspring, although increased acoustic startle and increased PPI, at high prepulse intensity levels, were observed. When low maternal LG history was combined with post-weaning social isolation, basal APO-gnawing was decreased and PPI increased, compared to High LG and Med LG offspring. This reflects attenuated psychosis susceptibility. High LG offspring reared in isolation displayed, however, the highest APO-gnawing and the lowest PPI levels among rats reared in social isolation, which is indicative for increased psychosis susceptibility. These findings support the mismatch hypothesis. For demonstration of the cumulative stress hypothesis an injection of CURT in the adult Low LG offspring was required that increased APO-gnawing and reduced PPI. This CURT-induced PPI disruption was greatly enhanced after additional isolation rearing. The High LG group, either socially housed or reared in isolation, was resistant to the acute effects of CORT at adulthood.Experiment II: MS increased psychosis susceptibility only in NOVEL SEP rats that had experienced MS in the context of early social isolation. These individuals displayed increased adult APO-gnawing and reduced PPI, if reared post-weaning in a condition that does not match with their early life social environment (i.e. group housing). This finding supports the mismatch hypothesis.Conclusion: The outcome of environmental manipulations on developmental programming of psychosis susceptibility depends on the interplay of early-life adversity and later-life stressors in a manner that supports the mismatch hypothesis. However, evidence for the cumulative stress hypothesis arises if vulnerable individuals are exposed in later life additionally to excess of the stress hormone CURT. (C) 2012 Elsevier Inc. All rights reserved.