Research reportBehavioral abnormality and pharmacologic response in social isolation-reared mice
Introduction
Adverse early life experiences, such as maternal separation or social isolation (SI) affect structural and functional brain development and adult behaviors in rodents [22], [31], [38]. Behavioral changes induced by SI rearing have been characterized, including enhanced locomotor activity under a novel environment [47], [49], anxiety-like behavior [23], [48], aggressive behavior [24], [29], [50], and impairment of prepulse inhibition of the acoustic startle response [9] and spatial learning and memory in the Morris water maze [24], [28].
The social environment in early life significantly influences not only the behavioral organization but also neurochemical and anatomical development of the brain. For instance, dopamine and serotonin systems are affected by SI in the nucleus accumbens [20], prefrontal cortex [21] and hippocampus [33]. The neuroanatomical consequences of isolation rearing include decreased spine density of pyramidal neurons in the prefrontal cortex and hippocampus [41], fewer hippocampal synapses [46] and the decreased survival of newly divided cells and neurogenesis in the dentate gyrus of hippocampus [24].
The behavioral, neurochemical and anatomical changes in SI-reared mice may be related to clinical symptoms and pathophysiology in patients with neuropsychiatric disorders [15] in which anxiety, impulsivity and aggression are commonly observed. To address this issue, we measured the predictive validity in SI-reared mice by examining the effects of methylphenidate (MPH), clozapine (CLZ) and fluoxetine (FLX) on SI-induced behavioral abnormality. A clinical report has shown that attention-deficit/hyperactivity disorder (ADHD) occurred with disruptive disorders (oppositional defiant disorder or conduct disorder), internalizing disorder (anxiety and/or depression), or both [25]. MPH is one of the most commonly used drugs to treat ADHD [4] and is effective to improve attention and behavior, including impulsivity and aggression [34], [43]. CLZ, atypical antipsychotic, is effective to reduce aggressive or violent acts in schizophrenia and neuroleptic-resistant schizophrenia patients [17], [42]. FLX, a selective serotonin reuptake inhibitor (SSRI), is used to treat depression. In addition, FLX reduces impulsive aggressive behavior in personality-disordered subjects [7]. Our findings suggest that SI-induced behavioral abnormality is a psychobehavioral complex relevant to various clinical symptoms observed in neuropsychiatric disorders, including ADHD, schizophrenia and depression, and that SI-reared mice are a useful animal model to study the pathophysiology/pathogenesis of these diseases.
Section snippets
Animals
Male ICR mice 3 and 7 weeks old (Japan SLC Inc., Hamamatsu, Japan) were purchased and used for the experiments. They were housed under a standard 12-h light/dark cycle (lights on 9:00 am) at a constant temperature of 23 ± 1 °C with free access to food and water throughout the experiments. The animals were handled in accordance with the guidelines established by the Institutional Animal Care and Use Committee of Nagoya University, the Guiding Principles for the Care and Use of Laboratory Animals
SI rearing induced behavioral abnormality
There was no significant difference in spontaneous locomotor activity between GH and SI mice under novel environmental conditions (Fig. 1a). In the elevated-plus maze test, the time spent in the open and closed arms was significantly different between GH and SI mice. SI mice spent significantly less time exploring the open arms and longer time in the closed arms than GH mice (Fig. 1b). In the forced swim test, one-way repeated ANOVA revealed a significant effect of the rearing condition on the
Discussion
The behavioral, neurochemical and anatomical changes in SI-reared mice may be relevant to the clinical symptoms and pathophysiology in patients with neuropsychiatric disorders, such as ADHD and schizophrenia. To address this issue, we examined the response to drugs used to treat these neuropsychiatric disorders.
First, we investigated the effect of SI rearing after weaning on emotional behavior and recognition memory. SI rearing after weaning induced anxiety-like behavior, aggressive behavior,
Acknowledgments
This study was supported in part by a Grant-in-Aid for Scientific Research (no.19390062) from the JSPS, the global COE program from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Academic Frontier Project for Private Universities; matching fund subsidy from MEXT, 2007–2011, the Research on Risk of Chemical Substances, Health and Labour Science Research Grants supported by Ministry of Health, Labour and Welfare, Takeda Science Foundation, AstraZeneca Research
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