Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
Physiol Behav. 2012 Jul 16;106(5):707-21. doi: 10.1016/j.physbeh.2012.01.015. Epub 2012 Jan 28.
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.
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 8h 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.
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 CORT in the adult Low LG offspring was required that increased APO-gnawing and reduced PPI. This CORT-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.
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 CORT.
在本研究中，我们同时测试了精神病理学的累积应激和不匹配假说。为此，我们研究了雄性 Wistar 大鼠的早期生活逆境和后期生活压力暴露对精神病易感性行为标志物的综合影响。
实验 I：根据母鼠照顾水平的高低，将新生鼠分为低、中、高母鼠照顾组，然后在断奶后分组（实验 IA）或在社会隔离（实验 IB）中饲养，并在成年后在基础条件下或急性皮质酮（CORT）给药后进行测试。母鼠照顾水平通过测量母鼠在生命的第一周的舔舐和梳理（LG）来评估。实验 II：新生鼠在出生后第 3、4 和 5 天接受每天 8 小时的母鼠分离（MS），分别在其家庭笼中（HOME SEP）或在新环境中（NOVEL SEP）进行分离，然后在断奶后分组饲养，并在成年后在基础条件下进行测试。成年测试包括标记精神病易感性的行为：阿朴吗啡诱导的咀嚼（APO-咀嚼）、听觉惊跳反应及其被预脉冲刺激调制（PPI）。所有三个实验都以中 LG 后代的行为作为基线参考。
实验 I：单独的低母 LG 史对 Wistar 后代的行为影响有限，但观察到高的听觉惊跳反应和高的预脉冲强度水平的 PPI 增加。当低母 LG 史与断奶后社会隔离相结合时，与高 LG 和中 LG 后代相比，基础 APO-咀嚼减少，PPI 增加，这反映了精神病易感性的减弱。然而，在隔离中饲养的高 LG 后代表现出最高的 APO-咀嚼和最低的 PPI 水平，这表明精神病易感性增加。这些发现支持不匹配假说。为了证明累积应激假说，需要在成年低 LG 后代中注射 CORT，以增加 APO-咀嚼和减少 PPI。这种 CORT 诱导的 PPI 破坏在额外的隔离饲养后大大增强。高 LG 组，无论是在社会环境中饲养还是在隔离中饲养，在成年时对 CORT 的急性作用都有抵抗力。实验 II：MS 仅增加 NOVEL SEP 大鼠的精神病易感性，这些大鼠在早期社会隔离的背景下经历了 MS。如果这些个体在断奶后被饲养在与早期社会环境不匹配的条件下（即群体饲养），则表现出成年 APO-咀嚼增加和 PPI 降低。这一发现支持不匹配假说。
环境操作对精神病易感性发育编程的影响取决于早期生活逆境和后期生活应激源的相互作用，这支持了不匹配假说。然而，如果易受影响的个体在以后的生活中额外暴露于应激激素 CORT 中，那么就会出现累积应激假说的证据。
