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... Show moreBackground: 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. Show less
Horst, J. ter; Kloet, E.R. de; Schachinger, H.; Oitzl, M.S. 2012
There are clear sex differences in incidence and onset of stress-related and other psychiatric disorders in humans. Yet, rodent models for psychiatric disorders are predominantly based on male... Show moreThere are clear sex differences in incidence and onset of stress-related and other psychiatric disorders in humans. Yet, rodent models for psychiatric disorders are predominantly based on male animals. The strongest argument for not using female rodents is their estrous cycle and the fluctuating sex hormones per phase which multiplies the number of animals to be tested. Here, we will discuss studies focused on sex differences in emotionality and cognitive abilities in experimental conditions with and without stress. First, female sex hormones such as estrogens and progesterone affect emotions and cognition, contributing to sex differences in behavior. Second, females respond differently to stress than males which might be related to the phase of the estrous cycle. For example, female rats and mice express less anxiety than males in a novel environment. Proestrus females are less anxious than females in the other estrous phases. Third, males perform in spatial tasks superior to females. However, while stress impairs spatial memory in males, females improve their spatial abilities, depending on the task and kind of stressor. We conclude that the differences in emotion, cognition and responses to stress between males and females over the different phases of the estrous cycle should be used in animal models for stress-related psychiatric disorders. Show less
Strelzyk, F.; Hermes, M.; Naumann, E.; Oitzl, M.S.; Schachinger, H. 2010
Impairing effects of cortisol on learning performance have been shown in human trace eyeblink conditioning As the effect is observed from 30 min to hours after administration a genomic action of... Show moreImpairing effects of cortisol on learning performance have been shown in human trace eyeblink conditioning As the effect is observed from 30 min to hours after administration a genomic action of cortisol is assumed Here we report rapid cortisol effects that were observed during the first 10 min after cortisol administration in humans Young healthy males (n = 24) received the cortisol synthesis inhibitor metyrapone (1 5 g per os) to avoid Interference of the endogenous pulsatile secretion of cortisol Next 2 mg cortisol or placebo was infused intravenously immediately before the trace conditioning task The probability of the conditioned eyeblink responses was assessed electromyographically during the trace eyeblink conditioning task (unconditioned stimulus corneal air puff 10 psi 50 ms conditioned stimulus binaural pure tone 75 dB 1000 Hz 400 ms empty interval between CS and US 550 ms) Cortisol resulted in a faster increase of conditioning (p = 02) reaching a comparable level to placebo later on This result extends the well-known effects of stress on the quality and amount of learning by showing that cortisol also affects the speed of learning We propose that cortisol accelerates trace eyeblink conditioning via a fast non-genomic mechanism This fast action of cortisol is part of the adaptive strategy during the early stress response (C) 2010 Elsevier Inc All rights reserved Show less
Schwabe, L.; Schachinger, H.; Kloet, E.R. de; Oitzl, M.S. 2010
Recent evidence indicates that stress modulates multiple memory systems, favoring caudate nucleus-based stimulus-response learning at the expense of hippocampus-based spatial learning. Whether this... Show moreRecent evidence indicates that stress modulates multiple memory systems, favoring caudate nucleus-based stimulus-response learning at the expense of hippocampus-based spatial learning. Whether this is due to a facilitating effect of stress on stimulus-response learning, an impairing effect on spatial learning, or both, is not known. To answer this question, mice were either subjected to restraint stress, injected with vehicle or corticosterone or left untreated before training in two circular hole board tasks that could discriminate spatial and stimulus-response strategies. Stress, vehicle and corticosterone injection all impaired learning performance in the spatial task. Conversely, performance in the stimulus-response task was not affected by stress or corticosterone injection, although performance was generally lower than in the spatial task. Irrespective of the treatment, mice had to overcome the preference to use their spatial memory system to achieve the stimulus-response task. These findings suggest that (i) the caudate nucleus-based memory system is less stress sensitive than the hippocampus-based system and may thus dominate behavior in situations of stress and (ii) that multiple memory systems may compete for control of behavior even in tasks that can solely be solved by one system. (C) 2010 Elsevier B.V. All rights reserved. Show less
Schwabe, L.; Schachinger, H.; Kloet, E.R. de; Oitzl, M.S. 2010
Stress and corticosteroid hormones are known to affect learning and memory processes. In this study, we examined whether stress and corticosteroids are capable of facilitating the switch between... Show moreStress and corticosteroid hormones are known to affect learning and memory processes. In this study, we examined whether stress and corticosteroids are capable of facilitating the switch between multiple memory systems in mice. For this purpose, we designed a task that allowed measurement of nucleus caudate-based stimulus-response and hippocampus-based spatial learning strategies. Naive mice used spatial strategies to locate an exit hole on a circular hole board at a fixed location flagged by a proximal stimulus. When the mice were either stressed or administered corticosterone before the task, 30-50% of the mice switched to a stimulus-response strategy. This switch between learning strategies was accompanied by a rescue of performance, whereas performance declined in the stressed mice that kept using the spatial strategy. Pretreatment with a mineralocorticoid receptor antagonist prevented the switch toward the stimulus-response strategy but led to deterioration of hippocampus-dependent performance. These findings (i) show that corticosteroids promote the transition from spatial to stimulus-response memory systems, (ii) provide evidence that the mineralocorticoid receptor underlies this corticosteroid-mediated switch, and (iii) suggest that a stress-induced switch from hippocampus-based to nucleus caudate-based memory systems can rescue performance. Show less
