Early Adolescent Emergence of Reversal Learning Impairments in Isolation-Reared Rats (original) (raw)
Related papers
Neurodevelopmental Animal Models of Schizophrenia: Effects on Prepulse Inhibition
Current Molecular Medicine, 2003
Epidemiological studies have shown increased incidence of schizophrenia in patients subjected to different forms of pre-or perinatal stress. However, as the onset of schizophrenic illness does not usually occur until adolescence or early adulthood, it is not yet fully understood how disruption of early brain development may ultimately lead to malfunction years later. In order to elucidate a possible role for neurodevelopmental factors in the pathogenesis of schizophrenia and to highlight potential new treatments, animal models are needed. Prepulse inhibition (PPI) is a model of sensorimotor gating mechanisms in the brain. It is disrupted in schizophrenia patients and the disruption can be reversed with atypical antipsychotics. It has been widely used in animal studies to explore central mechanisms possibly involved in schizophrenia. There has been a recent surge of behavioural and neurochemical animal studies on neurodevelopmental models, particularly on the effects of postweaning isolation, maternal separation and neonatal lesions of the hippocampus. In these models, long lasting alterations in behaviour and/or molecular changes in specific brain regions are observed, comparable to those seen in schizophrenia. The aim of this article is to critically review the available literature on such neurodevelopmental animal models with special focus on the effects on PPI and brain regions that are putatively involved in regulation of PPI.
Psychiatric disorders are multifactorial diseases with etiology that may involve genetic factors, early life environment and stressful life events. The neurodevelopmental hypothesis of schizophrenia is based on a wealth of data on increased vulnerability in individuals exposed to insults during the perinatal period. Maternal deprivation (MD) disinhibits the adrenocortical response to stress in neonatal rats and has been used as an animal model of schizophrenia. To test if long-term affective consequences of early life stress were influenced by maternal presence, we submitted 10-day old rats, either deprived (for 22 h) or not from their dams, to a stress challenge (i.p. saline injection). Corticosterone plasma levels were measured 2 h after the challenge, whereas another subgroup was assessed for behavior in the open field, elevated plus maze (EPM), social investigation and the negative contrast sucrose consumption test in adolescence (postnatal day 45). Maternally deprived rats exhibited increased plasma corticosterone (CORT) levels which were higher in maternally deprived and stress challenged pups. Social investigation was impaired in maternally deprived rats only, while saline injection, independently of MD, was associated with increased anxiety-like behavior in the EPM and an impaired intake decrement in the negative sucrose contrast. In the open field, center exploration was reduced in all maternally-deprived adolescents and in control rats challenged with saline injection. The most striking finding was that exposure to a stressful stimulus per se, regardless of MD, was linked to differential emotional consequences. We therefore propose that besides being a well-known and validated model of schizophrenia in adult rats, the MD paradigm could be extended to model early signs of psychiatric dysfunction, and would particularly be a useful tool to detect early signs that resemble schizophrenia.
Behavioural brain research, 2016
Social isolation of rats induces a constellation of behavioral alterations known as "isolation syndrome" that are consistent with some of the positive and cognitive symptoms observed in schizophrenic patients. In the present study we have assessed whether isolation rearing of inbred Roman high-avoidance (RHA-I) and Roman low-avoidance (RLA-I) strains can lead to the appearance of some of the key features of the "isolation syndrome", such as prepulse inhibition (PPI) deficits, increased anxious behavior, hyperactivity and memory/learning impairments. Compared to RLA-I rats, the results show that isolation rearing (IR) in RHA-I rats has a more profound impact, as they exhibit isolation-induced PPI deficits, increased anxiety, hyperactivity and long-term reference memory deficits, while isolated RLA-I rats only exhibit deficits in a spatial working memory task. These results give further support to the validity of RHA-I rats as a genetically-based model of schizophr...
Peri-pubertal maturation after developmental disturbance: A model for psychosis onset in the rat
Neuroscience, 2006
Schizophrenia is thought to be associated with abnormalities during neurodevelopment although those disturbances usually remain silent until puberty; suggesting that postnatal brain maturation precipitates the emergence of psychosis. In an attempt to model neurodevelopmental defects in the rat, brain cellular proliferation was briefly interrupted with methylazoxymethanol (MAM) during late gestation at embryonic day 17 (E17). The litters were explored at pre-and post-puberty and compared with E17 saline-injected rats. We measured spontaneous and provoked locomotion, working memory test, social interaction, and prepulse inhibition (PPI). As compared with the saline-exposed rats, the E17 MAMexposed rats exhibited spontaneous hyperactivity that emerged only after puberty. At adulthood, they also exhibited hypersensitivity to the locomotor activating effects of a mild stress and a glutamatergic N-methyl-D-aspartate receptor antagonist (MK-801), as well as PPI deficits whereas before puberty no perturbations were observed. In addition, spatial working memory did not undergo the normal peri-pubertal maturation seen in the sham rats. Social interaction deficits were observed in MAM rats, at both pre-and post-puberty. Our study further confirms that transient prenatal disruption of neurogenesis by MAM at E17 is a valid behavioral model for schizophrenia as it is able to reproduce some fundamental features of schizophrenia with respect to both phenomenology and temporal pattern of the onset of symptoms and deficits.
Early Cognitive Experience Prevents Adult Deficits in a Neurodevelopmental Schizophrenia Model
Neuron, 2012
Brain abnormalities acquired early in life may cause schizophrenia, characterized by adulthood onset of psychosis, affective flattening, and cognitive impairments. Cognitive symptoms, like impaired cognitive control, are now recognized to be important treatment targets but cognition-promoting treatments are ineffective. We hypothesized that cognitive training during the adolescent period of neuroplastic development can tune compromised neural circuits to develop in the service of adult cognition and attenuate schizophrenia-related cognitive impairments that manifest in adulthood. We report, using neonatal ventral hippocampus lesion rats (NVHL), an established neurodevelopmental model of schizophrenia, that adolescent cognitive training prevented the adult cognitive control impairment in NVHL rats. The early intervention also normalized brain function, enhancing cognition-associated synchrony of neural oscillations between the hippocampi, a measure of brain function that indexed cognitive ability. Adolescence appears to be a critical window during which prophylactic cognitive therapy may benefit people at risk of schizophrenia.
Tracing the development of psychosis and its prevention: What can be learned from animal models
Neuropharmacology, 2012
Schizophrenia (SCZ) is a neurodevelopmental disorder manifested symptomatically after puberty whose pharmacotherapy remains unsatisfactory. In recent years, longitudinal structural neuroimaging studies have revealed that neuroanatomical aberrations occur in this disorder and in fact precede symptom onset, raising the exciting possibility that SCZ can be prevented. There is some evidence that treatment with atypical antipsychotic drugs (APDs) prior to the development of the full clinical phenotype reduces the risk of transition to psychosis, but results remain controversial. It remains unknown whether progressive structural brain aberrations can be halted. Given the diagnostic, ethical, clinical and methodological problems of pharmacological and imaging studies in patients, getting such information remains a major challenge. Animal neurodevelopmental models of SCZ are invaluable for investigating such questions because they capture the notion that the effects of early brain damage are progressive. In recent years, data derived from such models have converged on key neuropathological and behavioral deficits documented in SCZ attesting to their strong validity, and making them ideal tools for evaluating progression of pathology following in-utero insults as well as its prevention. We review here our recent studies that use longitudinal in vivo structural imaging to achieve this aim in the prenatal immune stimulation model that is based on the association of prenatal infection and increased risk for SCZ. Pregnant rats were injected on gestational day 15 with the viral mimic polyriboinosinicepolyribocytidylic acid (poly I:C) or saline. Male and female offspring were imaged and tested behaviorally on postnatal days (PNDs) 35, 46, 56, 70 and 90. In other experiments, offspring of poly I:C-and saline-treated dams received the atypical antipsychotic drugs (APDs) clozapine or risperidone in two developmental windows: PND 34e47 and PND 48e61, and underwent behavioral testing and imaging at adulthood. Prenatal poly I:C-induced interference with fetal brain development led to aberrant postnatal brain development as manifested in structural abnormalities in the hippocampus, the striatum, the prefrontal cortex and lateral ventricles (LV), as seen in SCZ. The specific trajectories were region-, age-and sex-specific, with females having delayed onset of pathology compared to males. Brain pathology was accompanied by development of behavioral abnormalities phenotypic of SCZ, attentional deficit and hypersensitivity to amphetamine, with same sex difference. Hippocampal volume loss and LV volume expansion as well as behavioral abnormalities were prevented in the offspring of poly I:C mothers who received clozapine or risperidone during the asymptomatic period of adolescence (PND 34e47). Administration at a later window, PNDs 48e61, exerted sex-, region-and drug-specific effects. Our data show that prenatal insult leads to progressive postnatal brain pathology, which gradually gives rise to "symptoms"; that treatment with atypical APDs can prevent both brain and behavioral pathology; and that the earlier the intervention, the more pathological outcomes can be prevented.
Behavioural brain research, 2017
The MAM-E17 model is one of the most accepted schizophrenia rat models, which follows the neurodevelopmental theory of the disease. While symptoms of MAM-E17 rats were studied extensively, their examinations were usually restricted to adulthood and in a few cases to prepuberty. It is well known, however, that schizophrenia symptoms often start at puberty or early adulthood. Therefore the purpose of this study was to investigate the behavioral characteristics of MAM-E17 rats in various tests throughout three different age-periods, namely in prepuberty, late puberty and adulthood. In open field test, MAM-E17 rats displayed increased locomotor activity, elevated sniffing frequency and, as tendency, enhanced rearing activity. The elevated activity turned up in late puberty and remained there in adulthood, too. There was also a deficient prepulse inhibition (PPI) of startle response in late puberty and adulthood, but not before puberty. In rotarod task, MAM-treated rats performed better ...
Journal of Chemical Neuroanatomy, 2008
Neonatal ventral hippocampal (nVH) lesions in rats have been widely used as a neurodevelopmental model that mimics schizophrenia-like behaviors. Recently, we reported that nVH-lesions result in significant decreases in both length of dendrites and dendritic density of spines of pyramidal neurons of the prefrontal cortex (PFC) and in the density of dendritic spines of medium spiny neurons of the nucleus accumbens (NAcc). Moreover, postweaning social isolation induces major decreases in dendritic spiny density of PFC neurons. We investigated here the comparative dendritic morphology of PFC pyramidal neurons and NAcc medium spiny neurons in nVH rats, following social isolation after weaning (8 weeks). Morphological characteristics of dendrites were measured using the Golgi-Cox procedure followed by a Sholl analysis. Social isolation (SI) by itself induced decreases in dendritic length and dendritic spine density of the NAcc. In socially isolated nVH-lesion rats decrease in dendritic length in PFC and NAcc neurons were exacerbated whereas an increase in spine density of medium spiny neurons was observed in the NAcc. These results indicate that nVH-lesions alter dendritic morphology of NAcc and PFC neurons. These anatomical modifications in both structures may be relevant to behaviors observed in schizophrenia. #
Sensorimotor gating deficits are inheritable in an isolation-rearing paradigm in rats
Early life experience is a key etiological factor of neuropsychiatric dysfunctions and is associated with developmental origins. Impaired prepulse inhibition (PPI) following an acoustic startle response is acknowledged as a cardinal characteristic in socially deprived weanling rats, which has been employed to investigate the underlying mechanisms of sensorimotor gating abnormalities in certain mental disorders, including schizophrenia. Because impaired PPI is a postnatal malfunction, it is interesting to examine whether it can be passed to the next generation. Isolation-rearing (IR) rats had been socially deprived since weaning, which mated with social rearing rats. Next, the offspring of IR rats were reared in a normal social environment. Locomotion, PPI, monoamines, and genes in schizophrenia-relevant brain areas [medial prefrontal cortex (mPFC) and hippocampus] were later measured. To this end, we observed that the next generation of IR offspring rats appeared with impaired PPI in which the PPI deficit can be observed as early as three weeks after birth. The third generation also exhibited lower levels of dopamine and serotonin in the mPFC and hippocampus; however, higher levels of both monoamines were measured in the striatum. Finally, Slc1a2 was more highly expressed in the mPFC of the third generation male rats. The present study demonstrates a transgenerational inheritance of IR-induced character and may help to elucidate the underlying pathoetiology of schizophrenia.
2020
ABSTRACTGenetic and environmental factors interact with each other to influence the risk of various psychiatric diseases; however, the intensity and nature of their interactions remain to be elucidated. We used a maternal infection model using polyinosinic-polycytidylic acid (Poly(I:C)) to determine the relationship between the maternal breeding environment and behavioral changes in the offspring. We purchased pregnant C57BL/6J mice from three breeders and administered Poly(I:C) (2 mg/kg) intravenously in their tail vein on gestation day 15. The offspring were raised to 8-12 weeks old and subjected to the acoustic startle tests to measure their startle response intensity, prepulse inhibition levels, and degree of the adaptation of the startle response. No statistical interaction between Poly(I:C) administration and sex was observed for prepulse inhibition; thus, male and female mice were analyzed together. The Poly(I:C) challenge significantly decreased prepulse inhibition levels of...