E.W.P.M. Daenen

The effects of neonatal lesions in the amygdala or ventral hippocampus on social behaviour later in life

Disruption of normal social behaviour is seen in psychiatric neurodevelopmental disorders like schizophrenia or autism. In a rat model of neurodevelopmental disorders we investigated the social behavioural changes after damage of limbic brain areas, at two early stages of life. The effects of ibotenic acid lesions made on day 7 or 21 of life in the amygdala (AM) ((baso)lateral/medical) or ventral hippocampal area on social play behaviour, social behaviour unrelated to social play behaviour early in life, and social behaviour in adulthood were assessed. Lesions of the AM, but not lesions of the ventral hippocampal area, resulted in decreased social play behaviour, and no differences were found between lesions made on day 7 or 21 of life. Social behaviour unrelated to social play behaviour early in life and in adulthood was decreased in animals lesioned in the AM on day 7 but not in animals lesioned on day 21 of life. This effect was particularly present in animals with an additional lesion in the medial nuclei of the AM. Lesions in the ventral hippocampal area did not affect social behaviour. It is concluded that the AM is an important structure for social play behaviour. The effects on social behaviour that are dependent on the day of lesioning (day 7 vs. 21) are an indication of a neurodevelopmental deficit of structures connected to the (medial part) of the AM.

Adaptation and habituation to an open field and responses to various stressful events in animals with neonatal lesions in the amygdala or ventral hippocampus

A rat model of neurodevelopmental psychopathological disorders, designed to determine neurodevelopmental deficits following damage to the brain early in life, was used to investigate behavioural changes in adaptation and habituation to an open field and responses to different kinds of stressful events. Animals with bilateral ibotenic acid lesions in the amygdala or ventral hippocampus on day 7 or 21 of life were compared to sham-operated animals. According to the model it was assumed that behavioural changes in animals lesioned on day 7, but not in animals lesioned on day 21 of life, were caused by maldevelopment of one or more structures connected to the damaged area. Animals lesioned in the amygdala or ventral hippocampus on day 7, but not animals lesioned in these structures on day 21 of life, displayed decreased (within-session) adaptation and (between-session) habituation to the open field and a decrease in immobility in the forced swim test, whereas only animals lesioned in the amygdala displayed enhanced general activity. These results were indicative of neurodevelopmental deficits. No changes in stress-induced hyperthermia were found, while animals lesioned in the amygdala both on day 7 or 21 of life exhibited decreased conditioned ultrasonic vocalizations. These latter results suggest that the amygdala is implicated in the conditioned stress-induced response. The contribution of the present findings to the animal model of neurodevelopmental disorders like schizophrenia and possible brain structures and neurotransmitter systems involved in the neurodevelopmental deficits are discussed.

Neonatal lesions in the amygdala or ventral hippocampus disrupt prepulse inhibition of the acoustic startle response; implications for an animal model of neurodevelopmental disorders like schizophrenia

Prepulse inhibition of the acoustic startle response is a behavioural tool applied to assess sensorimotor gating processes in humans and rats. Schizophrenic patients show deficits in prepulse inhibition of the acoustic startle response. The animal model of neurodevelopmental disorders such as schizophrenia, as purported in earlier reports and the present study, is based on the assumption that damage to brain structures early in life (on day 7) disrupts brain maturation of structures connected to the damaged areas, measurable by behavioural changes, whereas similar damage later in life (on day 21) does not result in these behavioural changes. Locomotor activity, the acoustic startle response and its prepulse inhibition were investigated in adult rats lesioned in the amygdala or ventral hippocampus on day 7 or 21 of life. The acoustic startle response was increased in animals lesioned in the amygdala on day 7 or 21 of life, but not in animals lesioned in the ventral hippocampus. Prepulse inhibition was impaired and locomotor activity enhanced in animals lesioned in the amygdala or ventral hippocampus on day 7, but not in animals lesioned in these structures on day 21 of life. The results on the acoustic startle response are suggestive of amygdaloid influences on modulation of the acoustic startle response. The effects of early postnatal lesions on prepulse inhibition and locomotor activity are in support of the animal model of neurodevelopmental disorders like schizophrenia.

Amygdala or ventral hippocampal lesions at two early stages of life differentially affect open field behaviour later in life; an animal model of neurodevelopmental psychopathological disorders

Psychiatric disorders like schizophrenia or autism are thought to result from disruption of the normal pattern of brain development. Abnormalities in the amygdaloid complex and hippocampus have been reported in these disorders. In the present study rats were lesioned in the amygdala or ventral hippocampus on day 7 of life (immature brain) or day 21 of life (almost mature brain) and open field behaviour was determined later in life before and after puberty. Lesioning on day 7 resulted in behavioural changes, interpreted as locomotor stereotypy and decreased anxiety in case of amygdala or hippocampus, respectively. These effects were more profoundly present after puberty. Lesioning on day 21 did not result in these behavioural changes, which subscribes to the importance of the stage of brain maturation on functional development. The results suggest that the behavioural changes in rats lesioned on day 7 may due to a malfunctioning of structures connected to the amygdala or ventral hippocampus. Brain lesions made on day 7 of life may serve as a potential model of psychopathological neurodevelopmental disorders.

Hyperresponsiveness to phencyclidine in animals lesioned in the amygdala on day 7 of life. Implications for an animal model of schizophrenia.

Phencyclidine (PCP) has been described to exacerbate psychotic symptoms in patients suffering from schizophrenia. In rats, PCP, dose-dependently, induces hyperactivity, stereotyped behaviour and social isolation, postulated to represent the positive (hyperactivity, stereotypy) and negative (social isolation) symptoms of schizophrenia. Based on previous studies, ibotenic acid lesions in the amygdala on day 7 of life have been proposed as an animal model of psychiatric neurodevelopmental disorders like schizophrenia. The purpose of the present study was to determine whether the responsiveness to PCP on locomotor activity in animals lesioned in the amygdala on day 7 of life is different from the response to this drug in sham-operated animals. The effect of graded doses of PCP on behaviour was assessed in a small open field. Animals lesioned in the amygdala on day 7 of life appeared to be hyperresponsive to PCP compared to sham-operated animals. The hyperresponsiveness to PCP in rats lesioned in the amygdala on day 7 of life further contributes to the validation of this putative animal model of schizophrenia.

Animal models for schizophrenia

Over the years a variety of animal models for schizophrenia have been developed. Initially, these models were predominantly pharmacological in nature, based on the effects of drugs used in the treatment of the disease. With increasing knowledge of the disturbances in the schizophrenic brain, and better methodologies to perform research in both patients and animals, animal models with face, predictive and construct validity have been set up. The present paper reviews a number of animal models that have been and still are used to uncover the mechanisms underlying the psychopathological processes leading to schizophrenia.