Elsevier

Schizophrenia Research

Volume 41, Issue 2, 21 January 2000, Pages 365-371
Schizophrenia Research

Lack of effect of an early stressful life event on sensorimotor gating in adult rats

https://doi.org/10.1016/S0920-9964(99)00080-8Get rights and content

Abstract

Hypotheses of the etiology of schizophrenia emphasize the important role of perinatal insults in predisposing individuals to the development of the disease, so that an animal model in which a discrete postnatal manipulation of the infant social environment yields schizophrenia-like behavior in adulthood would be valuable in terms of the study of the neural substrate and treatment of schizophrenia. Schizophrenics demonstrate a deficit in sensorimotor gating (prepulse inhibition), and a similar phenomenon has been described in adult rats following the administration of direct and indirect dopamine agonists. Recently it has been reported that a 25 h separation of rat pups from the mother results in a disruption of prepulse inhibition at adulthood. Here we report a study which investigated the same phenomenon but which, in contrast to the previous study, utilized unrelated subjects all derived from different dams. Maternal separation was conducted for 24 h with pups aged 4, 9 or 18 days and these subjects, together with non-separated controls, were tested at age 3 months in terms of their prepulse inhibition in the acoustic startle response paradigm. Maternal separation did not disrupt prepulse inhibition. Comparison of males and females (with a maximum of one opposite-sex sibling) demonstrated that acoustic startle response and prepulse inhibition of this response was enhanced in males relative to females. This study indicates that 24 h maternal separation does not provide a robust model for studying the effects of early environmental insults on the long-term abnormal development of sensorimotor gating.

Introduction

It has been consistently reported that schizophrenic patients demonstrate a disruption of prepulse inhibition (PPI) of the acoustic startle response (ASR) (American Psychiatric Association, 1994, Braff et al., 1978, Braff et al., 1992). PPI is an operational measure of sensorimotor gating. The ASR is a reflex response observed following presentation of a sudden pulse of loud noise, and PPI is a reduction in the magnitude of the ASR that typically occurs when the acoustic startle pulse is preceded by a weak acoustic prepulse. The deficit in PPI exhibited by schizophrenics has been interpreted as evidence that impaired sensorimotor gating is an important symptom of schizophrenia and that it might underlie the cognitive symptoms of this disease. PPI of the ASR has also been developed as an index of sensorimotor gating in the rat, and is measured using virtually identical techniques and parameters to those used in human subjects/patients. In the rat, several studies indicate that the brain dopamine (DA) systems are critical substrates for the mediation of ASR sensorimotor gating (see Swerdlow et al., 1992). Rat PPI is impaired by the DA agonist apomorphine and by the indirect agonist amphetamine. As these effects are obtained in the rat using essentially the same ASR–PPI paradigm as that used in humans, and as neuroleptic drugs (both typical and atypical) antagonize these DA-induced disruptions, the rat ASR–PPI paradigm has been proposed as an appropriate model of the sensorimotor gating symptoms of schizophrenia, with construct, face and predictive validity (Swerdlow et al., 1994).

Animal model studies of PPI and other schizophrenia-like symptoms have attempted to move away from pharmacological manipulations, and these studies have been influenced by the human evidence that disturbances in early normal brain development may induce schizophrenia, leading to the neurodevelopmental hypothesis of schizophrenia (Weinberger, 1987). One important animal model to have been informed by the neurodevelopmental hypothesis is that of neonatal hippocampal lesions, as developed by Lipska et al. (1993). This is based on excitotoxic lesions within the hippocampal area in 7 day old rat pups, which result in hyper-responsiveness to DA agonists, hypo-responsiveness to DA antagonists and impaired PPI; as in schizophrenia, it has been reported that the behavioral symptoms of early hippocampal lesion do not emerge until after puberty (Lipska et al., 1995). Currently there is increasing interest in the validation of animal models derived via perinatal environmental manipulation. Here the rationale is that manipulation of the rat during a sensitive phase of neurobehavioral development, involving deprivation of salient features of the normal environment, will induce important effects on development of an otherwise non-manipulated central nervous system and its functioning (Ellenbroek and Cools, 1998). If animal models based on environmental manipulations do yield robust and consistent effects on sensorimotor gating, then we are presented with the very attractive scenario of a non-pharmacological/lesioned neurodevelopmental animal model for an important aspect of schizophrenia, a disease for which environmentally-induced neurodevelopmental disturbance is one of the major hypotheses of underlying etiology (for a review see Feldon and Weiner, 1992). Two such manipulations are maternal separation performed for a single 24 h period during pup–dam dependency, and social isolation performed chronically immediately post-weaning. It has been reported that social isolation disrupts PPI in the rat (Geyer et al., 1993, Varty and Higgins, 1995, Wilkinson et al., 1994), although two recent studies conducted in our laboratory have called into question the robustness of this model, in Wistar rats at least (Domeney and Feldon, 1998, Weiss et al., in press).

It has recently been reported that 24 h maternal separation at postnatal day 3, 6 or 9 induces disruption of PPI in adult Wistar rats, and in males and females to the same extent (Ellenbroek et al., 1998). This is potentially a very important finding, for the reasons outlined above. The study by Ellenbroek et al. used a methodology in which the 8–10 pups in each control or treatment group per experiment were provided by a small number of dams and, in the case of the major experiment, by two dams only: that is, the average coefficient of relatedness of each subject to one-half of the other subjects in its experimental group was 0.5. Treating subjects from the same litter as independent samples will decrease within-treatment variance and thereby increase the likelihood of obtaining treatment effects (Denenberg, 1977, Spear and File, 1996). Such ‘litter effect’ has been reported for the great majority of behavioral paradigms in which it has been tested for to-date, including auditory startle habituation (Buelke-Sam et al., 1985). For example, it has been demonstrated that treating just two pups per litter as independent observations nearly triples the likelihood of obtaining statistically significant effects with prenatal treatments (Holson and Pearce, 1992). Against this background, the aim of the study described here was to analyze the effects of 24 h maternal separation on PPI in subjects that were unrelated. If we observed a decrease in PPI of the ASR as a result of 24 h maternal separation under conditions that used independent samples, then this would add considerably to the proposal that this represents a robust environmental animal model of PPI disruption in schizophrenia. However, if 24 h maternal separation did not yield a decrease in PPI, this would strongly suggest that this environmental manipulation is inappropriate for the modelling of disrupted PPI.

Section snippets

Animals

The experiment was carried out with male and female Wistar rats, all bred in-house (Zur:WIST[HanIbm], Animal Services, Swiss Federal Institute of Technology Zürich, Schwerzenbach) and under constant husbandry conditions of reversed cycle lighting (lights on: 1900–0700 h) in a temperature (21±1°C) and humidity (55±5%) controlled animal facility. Subjects were derived from 48 different litters produced by 48 different dams; that is, each of 48 dams contributed one male (total n=48) and one female (

Results

The 2×4×16 ANOVA did not yield either a main effect or an interaction involving the factor of maternal separation on ASP (p>0.73). There was a significant main effect of sex (F1,88=81.79; p<0.001) and of the repeated measurement factor of startle pulse (F15,1320=14.1; p<0.0001), and a significant sex×startle pulse interaction (F15,1320=3.4; p<0.0001). As presented in Fig. 1, these analyses reflect the absolute sex difference in ASR and the sex-dependent habituation of ASR across trials. Females

Discussion

In this experiment, designed to study the effects on prepulse inhibition of a single 24 h period of maternal separation, we have demonstrated that sensorimotor gating is not influenced by this environmental manipulation. Unrelated adult rats, male and female, were unaffected in terms of the development of PPI relative to controls, following 24 h of maternal deprivation at day 4, 9 or 18. This negative finding contradicts a recent report that a 24 h maternal separation does yield a PPI deficit in

Acknowledgments

This work was supported by a grant from the Swiss Federal Institute of Technology Zürich. We thank Animal Services for the maintenance and care of the animals.

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