Testing the cumulative stress and mismatch hypotheses of psychopathology in a rat model of early-life adversity.
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.


METHODS
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.


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 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.


CONCLUSIONS
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.
Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, Einsteinweg 55, 2333 CC, Leiden, The Netherlands. n.daskalakis@lacdr.leidenuniv.nl
Nikolaos P
NP
Daskalakis
Melly S
MS
Oitzl
Hartmut
H
Schächinger
Danielle L
DL
Champagne
E Ronald
ER
de Kloet
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001058:Apomorphine / Q000008:administration & dosage; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000187:drug effects; D003345:Corticosterone / Q000008:administration & dosage; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000008:administration & dosage; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005123:Eye / Q000187:drug effects; D007266:Inhibition, Psychological; D011599:Psychopathology; D051381:Rats; D017208:Rats, Wistar; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D055139:Sensory Gating / Q000187:drug effects / Q000502:physiology; D012934:Social Isolation; D013315:Stress, Psychological / Q000209:etiology* / Q000523:psychology*; D014886:Weaning
D018491:Dopamine Agonists; D001058:Apomorphine; D003345:Corticosterone