Motor stereotypies and cognitive perseveration in non-human primates exposed to early gestational irradiation

Selemon, Lynn D.; Friedman, Harriet R.

doi:10.1016/j.neuroscience.2013.06.006

Cited by 14 publications

(7 citation statements)

References 68 publications

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“…The broadest performance difference between the two groups was demonstrated at the re-reversal phase, which suggests that the control animals learned to adapt to the task’s changing rules while the irradiated animals lacked the cognitive flexibility necessary to do so. Similar increased perseverative errors were reported in a study of juvenile and adult macaques that were exposed to radiation in utero (39). In addition, survivors of pediatric cranial lymphoid malignancies showed deficits in cognitive flexibility 25 years after receiving radiotherapy (35).…”

Section: Discussionsupporting

confidence: 83%

Long-Term Cognitive Functioning in Single-Dose Total-Body Gamma-Irradiated Rhesus Monkeys (Macaca mulatta)

et al. 2016

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In this study, the effects of a potentially lethal radiation exposure on the brain for long-term cognitive sequelae were investigated using Rhesus macaques (Macaca mulatta) adopted from other facilities after analysis of acute radiation response via the Centers for Medical Countermeasures against Radiation (CMCR) network. Fifty-nine animals were given the opportunity to participate in cognitive cage-side testing. The animals that received single-dose gamma irradiation were significantly less likely to engage in cognitive testing than the controls, suggesting that irradiated animals may have differences in cognitive ability. Five irradiated (6.75–8.05 Gy) and three naïve control animals self-selected, were extensively trained and administered a simple visual discrimination with reversal (SVD+R) task 2–3 times per week for 11–18 months. Each session consisted of 30 trials in which the animals were required to choose the correct visual stimulus for a food reward. After the initial presentation, the stimulus that signaled the presence of food was twice reversed once the animal reached criterion (90% accuracy across four consecutive sessions). While the limited sample size precluded definitive statistical analysis, irradiated animals took longer to reach the criterion subsequent to reversal than did control animals, suggesting a relative deficiency in cognitive flexibility. These results provide preliminary data supporting the potential use of a nonhuman primate model to study radiation-induced, late-delayed cognitive deficits.

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Section: Discussionsupporting

confidence: 83%

Long-Term Cognitive Functioning in Single-Dose Total-Body Gamma-Irradiated Rhesus Monkeys (Macaca mulatta)

et al. 2016

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“…Previous research indicated that behavioural defects after in utero radiation exposure highly depend upon the evident morphological changes, such as brain volume decrease, ventricular enlargement and cortical thinning [ 71 ]. This is further evidenced in non-human primates, in which morphological effects induced by prenatal radiation exposure are thought to be responsible for neurological symptoms [ 72 , 73 ]. Here, we observed both abnormalities in neurogenesis as well as morphological aberrations.…”

Section: Discussionmentioning

confidence: 99%

A multidisciplinary approach unravels early and persistent effects of X-ray exposure at the onset of prenatal neurogenesis

Verreet

Quintens

Dam

et al. 2015

J Neurodevelop Disord

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BackgroundIn humans, in utero exposure to ionising radiation results in an increased prevalence of neurological aberrations, such as small head size, mental retardation and decreased IQ levels. Yet, the association between early damaging events and long-term neuronal anomalies remains largely elusive.MethodsMice were exposed to different X-ray doses, ranging between 0.0 and 1.0 Gy, at embryonic days (E) 10, 11 or 12 and subjected to behavioural tests at 12 weeks of age. Underlying mechanisms of irradiation at E11 were further unravelled using magnetic resonance imaging (MRI) and spectroscopy, diffusion tensor imaging, gene expression profiling, histology and immunohistochemistry.ResultsIrradiation at the onset of neurogenesis elicited behavioural changes in young adult mice, dependent on the timing of exposure. As locomotor behaviour and hippocampal-dependent spatial learning and memory were most particularly affected after irradiation at E11 with 1.0 Gy, this condition was used for further mechanistic analyses, focusing on the cerebral cortex and hippocampus. A classical p53-mediated apoptotic response was found shortly after exposure. Strikingly, in the neocortex, the majority of apoptotic and microglial cells were residing in the outer layer at 24 h after irradiation, suggesting cell death occurrence in differentiating neurons rather than proliferating cells. Furthermore, total brain volume, cortical thickness and ventricle size were decreased in the irradiated embryos. At 40 weeks of age, MRI showed that the ventricles were enlarged whereas N-acetyl aspartate concentrations and functional anisotropy were reduced in the cortex of the irradiated animals, indicating a decrease in neuronal cell number and persistent neuroinflammation. Finally, in the hippocampus, we revealed a reduction in general neurogenic proliferation and in the amount of Sox2-positive precursors after radiation exposure, although only at a juvenile age.ConclusionsOur findings provide evidence for a radiation-induced disruption of mouse brain development, resulting in behavioural differences. We propose that alterations in cortical morphology and juvenile hippocampal neurogenesis might both contribute to the observed aberrant behaviour. Furthermore, our results challenge the generally assumed view of a higher radiosensitivity in dividing cells. Overall, this study offers new insights into irradiation-dependent effects in the embryonic brain, of relevance for the neurodevelopmental and radiobiological field.Electronic supplementary materialThe online version of this article (doi:10.1186/1866-1955-7-3) contains supplementary material, which is available to authorized users.

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“… 8 As adults, fetally irradiated monkeys exhibit motor stereotypies, cognitive perseveration and profound working memory deficits, indicating that the prefrontal cortical and corticostriatal loop functions are impaired by fetal exposure to irradiation. 102 , 103 Most intriguingly, the same fetally irradiated animals that exhibit severe cognitive deficits and motor stereotypies as adults were indistinguishable from their normal counterparts as juveniles. 102 , 103 These observations indicate that the ‘lesion' incurred by fetal irradiation in the prefrontal cortex remains dormant and is expressed only as the animals mature to adulthood, perhaps when late adolescent developmental processes unmask the underlying ‘lesion.'…”

Section: Cell Proliferation: a Vulnerable Developmental Process In Eamentioning

confidence: 99%

Schizophrenia: a tale of two critical periods for prefrontal cortical development

2015

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Schizophrenia is a disease of abnormal brain development. Considerable evidence now indicates that environmental factors have a causative role in schizophrenia. Elevated incidence of the disease has been linked to a wide range of disturbances in the prenatal environment and to social factors and drug intake during adolescence. Here we examine neurodevelopment of the prefrontal cortex in the first trimester of gestation and during adolescence to gain further insight into the neurodevelopmental processes that may be vulnerable in schizophrenia. Early embryonic development of the prefrontal cortex is characterized by cell proliferation, including renewal of progenitor cells, generation of early transient cell populations and neurogenesis of subcortical populations. Animal models show that curtailing early gestational cell proliferation produces schizophrenia-like pathology in the prefrontal cortex and mimics key behavioral and cognitive symptoms of the disease. At the other end of the spectrum, elimination of excitatory synapses is the fundamental process occurring during adolescent maturation in the prefrontal cortex. Adverse social situations that elevate stress increase dopamine stimulation of the mesocortical pathway and may lead to exaggerated synaptic pruning during adolescence. In a non-human primate model, dopamine hyperstimulation has been shown to decrease prefrontal pyramidal cell spine density and to be associated with profound cognitive dysfunction. Development of the prefrontal cortex in its earliest stage in gestation and in its final stage in adolescence represents two critical periods of vulnerability for schizophrenia in which cell proliferation and synaptic elimination, respectively, may be influenced by environmental factors.

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Motor stereotypies and cognitive perseveration in non-human primates exposed to early gestational irradiation

Cited by 14 publications

References 68 publications

Long-Term Cognitive Functioning in Single-Dose Total-Body Gamma-Irradiated Rhesus Monkeys (Macaca mulatta)

Long-Term Cognitive Functioning in Single-Dose Total-Body Gamma-Irradiated Rhesus Monkeys (Macaca mulatta)

A multidisciplinary approach unravels early and persistent effects of X-ray exposure at the onset of prenatal neurogenesis

Schizophrenia: a tale of two critical periods for prefrontal cortical development

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