Behavioral abnormality and pharmacologic response in social isolation-reared mice

Abstract

Social isolation (SI) rearing in rodents causes a variety of behavioral changes, including hyperlocomotion, anxiety, impulsivity, aggression, and learning and memory deficits. These behavioral abnormalities in rodents may be related to the symptoms in patients with neuropsychiatric disorders, such as attention-deficit hyperactivity disorder, obsessive-compulsive disorder, autism, schizophrenia and depression. In this study, we examined the effect of long-term SI rearing after weaning on emotional behaviors and cognitive function in mice. Furthermore, the effects of methylphenidate (MPH), clozapine (CLZ) and fluoxetine (FLX) on SI-induced behavioral changes were examined to measure the predictive validity of SI-reared mice as an animal model for these neuropsychiatric disorders. MPH improved SI-induced anxiety-like behavior in the elevated-plus maze test, but had no effect on aggressive behavior. In contrast, CLZ ameliorated aggressive behavior, but not anxiety-like behavior in SI-reared mice. Repeated FLX treatment prevented SI-induced aggressive behavior and social interaction deficits. These findings suggest that SI-induced behavioral abnormality is a psychobehavioral complex relevant to various clinical symptoms observed in neuropsychiatric disorders and that SI-reared mice are a useful animal model to study the pathophysiology/pathogenesis of these diseases.

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.