Distinct abnormalities of the primate prefrontal cortex caused by ionizing radiation in early or midgestation

Abstract

Prenatal exposure of the brain to environmental insult causes different neurological symptoms and behavioral outcomes depending on the time of exposure. To examine the cellular bases for these differences, we exposed Rhesus macaque fetuses to x-rays during early gestation (E30–E42), i.e., before the onset of corticogenesis, or in midgestation (E70–E81) when superficial cortical layers are generated. Animals were delivered at term (~E165), and the size and cellular composition of prefrontal association cortex (area 46) examined in adults, using magnetic resonance imaging (MRI) and stereologic analysis. Both early and midgestational radiation exposure diminished the surface area and volume of area 46. However, early exposure spared cortical thickness and did not alter laminar composition, and due to higher cell density, neuron number was within the normal range. In contrast, exposure to x-rays at midgestation reduced cortical thickness, mainly due to elimination of neurons destined for the superficial layers. A cell-sparse gap, observed within layer III, was not filled by the later generated neurons destined for layer II, indicating that there is no subsequent replacement of the lost neurons. The distinct areal and laminar pathology consequent to temporally segregated irradiation is consistent with basic postulates of the radial unit hypothesis of cortical development. In addition, we show that an environmental disturbance inflicted in early gestation can induce subtle cytoarchitectonic alterations without loss of neurons, such as those observed in schizophrenia, whereas midgestational exposure causes selective elimination of neurons and cortical thinning as observed in some forms of mental retardation and fetal alcohol syndrome.

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

“…Thalamic neuron number overall and in the mediodorsal nucleus is reduced in fetally irradiated monkeys (FIMs) (Selemon et al, 2009); reduction of neuron number in the mediodorsal nucleus has also described in brains from schizophrenic subjects (Pakkenberg, 1990; Young et al, 2000; Popken et al, 2000). The dorsolateral prefrontal cortex in FIMs is characterized by diminished cortical surface area but not thickness (Selemon et al, 2013), as has been reported in schizophrenic subjects (Guttlerez-Galve et al, 2010). We have also found abnormally high cortical neuronal density in the dorsolateral prefrontal cortex of FIMs (Selemon et al, 2013), a finding analogous to that in postmortem studies of schizophrenic brains (Selemon et al, 1995; 1998; 2003).…”

Morphometric Differences in Planum Temporale in Schizophrenia and Bipolar Disorder Revealed by Statistical Analysis of Labeled Cortical Depth Maps

“…Estimates of neuronal and glial densities in different cortical regions have been obtained from several histopathological studies in humans and mammals. Altered measures have been suggested as explanations for cortical thinning observed at the macroscopic level in other neuroimaging studies (37, 38). …”

“…However, no definitive conclusion can be reached until LCDM analysis can be correlated with measures in histopathological MRI studies of SCZ [e.g., Ref. (38)].…”

Stem Cell–Based Tissue Replacement After Stroke

“…Despite important advances in the understanding of brain and cortical development 40, 41 , our knowledge regarding the cellular, biochemical, and electrophysiological processes directing this interplay still remains fragmentary 42 . On the other hand, even minor disturbances during this susceptible and delicate process can have significant consequences 43, 44 , and there is evidence for a strict regulation and temporal limitation of structured postnatal neurogenesis 45 . This may, at least partly, account for the observation of teratomas 46 or teratocarcinomas 47 after transplantation of pluripotent stem cells into the adult mammalian brain.…”