Early Cognitive Experience Prevents Adult Deficits in a Neurodevelopmental Schizophrenia Model (original) (raw)
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Cognitive Effects of Neonatal Hippocampal Lesions in a Rat Model of Schizophrenia
Neuropsychopharmacology, 1996
Lesioning the ventral hippocampus of neonatal rats has been proposed as an experimental model of schizophrenia. This lesion causes a syndrome of hyperresponsivity to the stimulant effects of amphetamine, impaired grooming and disrupted social interactions, effects that emerge during adolescence, much like schizophrenia. Persisting cognitive effects of neonatal ventral hippocampal lesions were assessed in the current study, because the hippocampus is critically important far a variety of cognitive functions and cognitive impairment and because it is an important feature of schizophrenia. Spatial learning and working memory were assessed in the radial-arm maze, which is sensitive to the adverse effects of hippocampal lesions made in adults. Lesioned rats showed pronounced deficits in radial-arm maze choice accuracy that persisted throughout training. Deficits were seen during the prepubertal period as well as in adulthood. Even though the lesioned rats performed mare poorly, they were significantly less sensitive to the amnestic
A neurodevelopmental model of schizophrenia: Neonatal disconnection of the hippocampus
Neurotoxicity Research, 2002
In the context of our current knowledge about schizophrenia, heuristic models of psychiatric disorders may be used to test the plausibility of theories developed on the basis of new emerging biological findings, explore mechanisms of schizophrenia-like phenomena, and develop potential new treatments. In a series of studies, we have shown that neonatal excitotoxic lesions of the rat ventral hippocampus (VH) may serve as a heuristic model. The model appears to mimic a spectrum of neurobiological and behavioral features of schizophrenia, including functional pathology in presumably critical brain regions interconnected with the hippocampal formation and targeted by antipsychotic drugs--the striatum/nucleus accumbens and the prefrontal cortex, and leads in adolescence or early adulthood to the emergence of abnormalities in a number of dopamine related behaviors. Moreover, our data show that even transient inactivation of the VH during a critical period of development, that produces subtle, if any, anatomical changes in the hippocampus, may be sufficient to disrupt normal maturation of the prefrontal cortex (and perhaps, other interconnected late maturing regions) and trigger behavioral changes similar to those observed in animals with the permanent excitotoxic lesion. These results represent a potential new model of aspects of schizophrenia without a gross anatomical lesion.
Prevention of schizophrenia deficits via non-invasive adolescent frontal cortex stimulation in rats
Molecular Psychiatry, 2019
Schizophrenia is a severe neurodevelopmental psychiatric affliction manifested behaviorally at late adolescence/early adulthood. Current treatments comprise antipsychotics which act solely symptomatic, are limited in their effectiveness and often associated with side-effects. We here report that application of non-invasive transcranial direct current stimulation (tDCS) during adolescence, prior to schizophrenia-relevant behavioral manifestation, prevents the development of positive symptoms and related neurobiological alterations in the maternal immune stimulation (MIS) model of schizophrenia.
Annual Review of Clinical Psychology, 2013
Several important paradigm shifts have occurred in the field of schizophrenia treatment, including an increased focus on early detection, the development of preemptive interventions, and the view of schizophrenia as a neurodevelopmental disease characterized by decreased efficiency and abnormal connectivity in cortical and subcortical neural networks. In this review, we briefly describe some of the neural impairments that contribute to the development of schizophrenia, with an emphasis on the impact of stress and trauma on cognitively vulnerable neural systems. We then present current data on two behavioral interventions that target these critical risk factors and that aim to preempt the onset of schizophrenia in vulnerable individuals or improve the clinical course in recent-onset schizophrenia: cognitive therapy and computerized cognitive training.
Developmental abnormalities of the hippocampus in First-Episode schizophrenia
Biological Psychiatry, 2003
Background: The human hippocampus becomes visible during the first trimester and folds to form the hippocampal fissure (HF) in the second trimester. The walls of this fissure fuse by 30 weeks, although small residual cavities can occur if development is disrupted. The primary purpose of this study was to determine if hippocampal fissures are evident in schizophrenia. A second goal was to assess the association between HF size and premorbid and clinical features of the illness. Methods: Magnetic resonance imaging scans were obtained on 33 patients with first-episode schizophrenia and 19 healthy volunteers. Hippocampal fissures were measured using semi-automated procedures, and hippocampi were manually traced. Birth history and premorbid functioning were assessed using maternal report. Results: Patients had a significantly larger mean HF volume and a nonsignificantly smaller hippocampal volume. Hippocampal fissure size was significantly associated with poor educational achievement and with anxietydepression symptoms during the onset of illness. Smaller hippocampal size was associated with poor premorbid adjustment. Conclusions: Larger HF size and an association between low educational achievement and enlarged HFs suggest abnormal neurodevelopment in schizophrenia. The association between HF size and anxiety-depression symptoms suggests that hippocampal abnormalities underlying HF dilatation may be a predisposing factor for increased stress sensitivity. Biol Psychiatry 2003;53: 555-561
Dynamic mapping of hippocampal development in childhood onset schizophrenia
Schizophrenia research, 2007
Prior cross-sectional anatomic brain imaging studies of the hippocampus in schizophrenia have generally shown loss in total hippocampal volume although the progressive course of these changes remains unknown. We report the first prospective subregional maps of hippocampal development in childhood onset schizophrenia (COS), reconstructed from serial brain MRI scans of 29 children with COS scanned every 2 years (87 scans) and compared to 31 controls matched for age, sex, and scan interval (94 scans). As expected, the COS subjects showed significant bilateral deficits (9-10%) in total hippocampal volume which remained consistent between age 9 and 26. However sub-regional maps showed heterogeneous changes with loss of hippocampal volume in both anterior as well as posterior ends while the body of the hippocampus gained in volume suggesting that hippocampal subunits are differentially affected in schizophrenia. Published by Elsevier B.V.
Neuroscience, 2006
This experiment assessed the effect of neonatal ventral hippocampus lesions in rats, a heuristic approach to model schizophrenia, on continuous delayed alternation and conditional discrimination learning performance before and after complete cerebral maturation. Delays (0, 5, 15, and 30 s) were introduced in the tasks to help dissociate between a hippocampal and a prefrontal cortex dysfunction. At postnatal day (PND) 6 or 7, rats received bilateral microinjections of ibotenic acid or phosphate-buffered saline in the ventral hippocampus. From PND 26 to PND 35, rats were tested on the alternation task in a T-maze; from PND 47 to PND 85, the same rats were tested in the discrimination task where a stimulus and a response location had to be paired. Deficits in ventral hippocampus-lesioned rats were observed in both tasks whether a delay was introduced before a response or not. Impaired performance regardless of delay length, combined with high rates of perseverative errors, suggested a ...
Cognitive performance of the MAM-E17 schizophrenia model rats in different age-periods
Behavioural Brain Research, 2019
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Schizophrenia Bulletin, 2014
Neurodevelopmental and neurodegenerative theories may be viewed as incompatible accounts that compete to explain the pathogenesis of schizophrenia. However, it is possible that neurodevelopmental and neurodegenerative processes could both reflect common underlying causal mechanisms. We hypothesized that cognitive dysfunction would gradually deteriorate over time in schizophrenia and the degree of this deterioration in adulthood would be predicted by an infant measure of neurodevelopment. We aimed to examine the association between age of learning to stand in infancy and deterioration of cognitive function in adulthood. Participants were nonpsychotic control subjects (n = 76) and participants with schizophrenia (n = 36) drawn from the Northern Finland 1966 Birth Cohort study. The schizophrenia group showed greater deterioration in abstraction with memory than controls, but there were no differences between schizophrenia and controls in rate of change of other cognitive measures. Age of learning to stand in infancy significantly inversely predicted later deterioration of abstraction with memory in adult schizophrenia (later infant development linked to greater subsequent cognitive deterioration during adulthood), possibly suggesting a link between abnormal neurodevelopmental and neurodegenerative processes in schizophrenia.