Lipska BK, Weinberger DR. Genetic variation in vulnerability to the behavioral effects of neonatal hippocampal damage in rats. Proc Natl Acad Sci USA 92: 8906-8910

Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health, Washington, DC 20032, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/1995; 92(19):8906-10. DOI: 10.1073/pnas.92.19.8906
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We explored how two independent variables, one genetic (i.e., specific rat strains) and another environmental (i.e., a developmental excitotoxic hippocampal lesion), contribute to phenotypic variation. Sprague-Dawley (SD), Fischer 344 (F344), and Lewis rats underwent two grades of neonatal excitotoxic damage: small and large ventral hippocampal (SVH and LVH) lesions. Locomotion was tested before puberty [postnatal day 35 (P35)] and after puberty (P56) following exposure to a novel environment or administration of amphetamine. The behavioral effects were strain- and lesion-specific. As shown previously, SD rats with LVH lesions displayed enhanced spontaneous and amphetamine-induced locomotion as compared with controls at P56, but not at P35. SVH lesions in SD rats had no effect at any age. In F344 rats with LVH lesions, enhanced spontaneous and amphetamine-induced locomotion appeared early (P35) and was exaggerated at P56. SVH lesions in F344 rats resulted in a pattern of effects analogous to LVH lesions in SD rats--i.e., postpubertal onset of hyperlocomotion (P56). In Lewis rats, LVH lesions had no significant effect on novelty- or amphetamine-induced locomotion at any age. These data show that the degree of genetic predisposition and the extent of early induced hippocampal defect contribute to the particular pattern of behavioral outcome. These results may have implications for modeling interactions of genetic and environmental factors involved in schizophrenia, a disorder characterized by phenotypic heterogeneity, genetic predisposition, a developmental hippocampal abnormality, and vulnerability to environmental stress.

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Available from: Barbara K Lipska, Aug 19, 2014
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    • "Comparing strains may provide an avenue to investigate how polygenetic vulnerability interacts with environmental conditions to produce deficits relevant to neuropsychiatric disorders [21]. For example, a comparison of Sprague-Dawley (SD), Lewis and Fischer 344 rat strains demonstrated that F344 rats, which are more responsive to stress [16] had the greatest vulnerability to a neonatal ventral hippocampal lesion [22] which is used as a neurodevelopmental animal model of schizophrenia. "
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    ABSTRACT: Genetic (G) and environmental (E) manipulations are known to alter behavioural outcomes in rodents, however many animal models of neuropsychiatric disorders only use a restricted selection of strain and housing conditions. The aim of this study was to examine GxE interactions comparing two outbred rat strains, which were housed in either standard or enriched cages. The strains selected were the albino Sprague-Dawley rat, commonly used for animal models, and the other was the pigmented Long Evans rat, which is frequently used in cognitive studies. Rats were assessed using a comprehensive behavioural test battery and included well-established tests frequently employed to examine animal models of neuropsychiatric diseases, measuring aspects of anxiety, exploration, sensorimotor gating and cognition. Selective strain and housing effects were observed on a number of tests. These included increased locomotion and reduced pre-pulse inhibition in Long Evans rats compared to Sprague Dawley rats; and rats housed in enriched cages had reduced anxiety-like behaviour compared to standard housed rats. Long Evans rats required fewer sessions than Sprague Dawley rats to learn operant tasks, including a signal detection task and reversal learning. Furthermore, Long Evans rats housed in enriched cages acquired simple operant tasks faster than standard housed Long Evans rats. Cognitive phenotypes in animal models of neuropsychiatric disorders would benefit from using strain and housing conditions where there is greater potential for both enhancement and deficits in performance.
    PLoS ONE 03/2014; 9(3):e93411. DOI:10.1371/journal.pone.0093411 · 3.23 Impact Factor
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    • "The increased locomotion reflects a single reaction to a complex situation where a diversity of factors have to be considered such as novelty, stress, animal housing and handling conditions, as well as many other experimental parameters (light and noise). It depended even on the strain and the sex of the rats (Lipska and Weinberger, 1995; Beninger et al., 2009). We shall not comment this point further because our aim was to analyze the reaction to drugs, not the baseline differences. "
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    ABSTRACT: Rats with a neonatal ventral hippocampal lesion (NVHL) are used to model schizophrenia. They show enhanced locomotion and difficulties in learning after puberty. Such behavioral modifications are strengthened by dopaminergic psychostimulant drugs, which is also relevant for schizophrenia because illustrating its dopaminergic facet. But it remains questionable that only dopaminergic drugs elicit such effects. The behavioral effects could simply represent a non specific arousal, in which case NVHL rats should also be hyper-responsive to other vigilance enhancing drugs. We administered an adenosine (caffeine) or an adrenaline receptor antagonist, (RX821002) at doses documented to modify alertness of rats, respectively 5 mg/kg and 1 mg/kg. Rats were selected prior to the experiments using magnetic resonance imaging (MRI). Each group contained typical and similar NVHL lesions. They were compared to sham lesioned rats. We evaluated locomotion in a new environment and the capacity to remember a visual or acoustic cue that announced the occurrence of food. Both caffeine and RX82100 enhanced locomotion in the novel environment, particularly in NVHL rats. But, RX82100 had a biphasic effect on locomotion, consisting of an initial reduction preceding the enhancement. It was independent of the lesion. Caffeine did not modify the learning performance of NVHL rats. But, RX821002 was found to facilitate learning. Patients tend to intake much more caffeine than healthy people, which has been interpreted as a means to counter some cognitive deficits. This idea was not validated with the present results. But adrenergic drugs could be helpful for attenuating some of their cognitive deficits.
    Frontiers in Behavioral Neuroscience 01/2014; 8:15. DOI:10.3389/fnbeh.2014.00015 · 3.27 Impact Factor
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    • "Thus, stress responsivity is a critical consideration both for models utilising stressful manipulations and for the interpretation of behavioral results from different strains (Faraday, 2002). Spontaneous and amphetamine-induced hyper locomotion varied across development with strain, indicating genetic predisposition has a critical role in determining the phenotype derived from this neurodevelopmental model, although cognitive outcomes were not assessed in this study (Lipska and Weinberger, 1995). "
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    ABSTRACT: Schizophrenia is associated with many genetic and environmental risk factors and there is growing evidence that the interactions between genetic and environmental "hits" are critical for disease onset. Animal models of schizophrenia have traditionally used specific strain and housing conditions to test potential risk factors. As the field moves towards testing gene (G) x environment (E) interactions the impact of these choices should be considered. Given the surge of research focused on cognitive deficits, we have examined studies of cognition in rodents from the perspective of GxE interactions, in which strain or housing manipulations have been varied. Behavior is clearly altered by these factors, yet few animal models of schizophrenia have investigated cognitive deficits using different strain and housing conditions. It is important to recognise the large variation in behavior observed when using different strain and housing combinations because GxE interactions may mask or exacerbate cognitive outcomes. Further consideration will improve our understanding of GxE interactions and the underlying neurobiology of cognitive impairments in neuropsychiatric disorders.
    Frontiers in Behavioral Neuroscience 07/2013; 7:97. DOI:10.3389/fnbeh.2013.00097 · 3.27 Impact Factor
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