Selective reduction of neuron number and volume of the mediodorsal nucleus of the thalamus in macaques following irradiation at early gestational ages

Abstract

Neurons in the macaque brain arise from progenitors located near the cerebral ventricles in a temporally segregated manner such that lethal doses of ionizing irradiation, if administered over a discrete time interval, can deplete individual nuclei selectively. A previous study showed that neuron number in the dorsal lateral geniculate nucleus is reduced following early gestational exposure to x-irradiation (Algan and Rakic, 1997). Here we examine whether similarly timed irradiation decreases neuron number in three associational thalamic nuclei: mediodorsal (MD), anterior, and pulvinar. Ten macaques were exposed to multiple doses of x-rays (total exposure: 175-350cGy) in early (E33-E42) or midgestation (E70-E90); 8 non-irradiated macaques were controls. Only the early irradiated monkeys, not the midgestationally irradiated animals, exhibited deficits in whole thalamic neuron (−15%) and glia numbers (−21%) compared to controls. Reduction of neuron number (−26%) and volume (−29%) was particularly pronounced in MD. In contrast, cell number and volume were not significantly decreased in the anterior or pulvinar nuclei following early gestational irradiation. Thus, reduced thalamic neuron number was associated specifically with irradiation in early gestation. Persistence of the thalamic neuronal deficit in adult animals indicates that prenatally deleted neurons had not been replenished during maturation or in adulthood. The selective reduction of MD neuron number also supports the protomap hypothesis that neurons of each thalamic nucleus originate sequentially from separate lines of neuronal stem cells (Rakic, 1977a). The early gestationally irradiated macaque is discussed as a potentially useful model for studying the neurodevelopmental pathogenesis of schizophrenia. Keywordsanterior nucleus; pulvinar nucleus; neurodevelopment; stereology; schizophrenia Systematic studies, based on injections of tritiated thymidine into pregnant macaque monkeys at different gestational ages, have established that each population of neurons in the developing primate brain is born, i.e., undergoes final mitotic division of the progenitor cells, during a specific and limited period (e.g. Rakic, 1974Rakic, , 2002. For example, neurons destined to become the thalamus are born during the first trimester of pregnancy with neurogenesis in the dorsal lateral geniculate nucleus (dLGN) (E36-E43) having a similar although less prolonged duration than that of the pulvinar nucleus (E36-E45) (Rakic, 1977a; Correspondence: Lynn D. Selemon, Ph.D., Department of Neurobiology, Yale University School of Medicine, PO Box 208001, New Haven, CT, 06520-8001, phone: 508-540-5306, fax: 508 540-5306, e-mail: ldselemon@aol.com Ogren and Rakic, 1981). Neurogenesis in many other subcortical structures including the neostriatum (E36-E80), nucleus accumbens (E36-E85), septal nuclei (E36-E62), basal cholinergic nuclei (E33-E48), and brain stem monoaminergic nuclei (E27-E43), begins in early gestation and overlaps with thalamogenesis Rakic, 1979, 1980;L...

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

“…Cell counts in a cohort of FIMs, not including the monkeys in this study, uncovered reduced neuron number in the thalamus as a whole and in the mediodorsal nucleus (Selemon et al, 2009). These findings mirror the reduction of neuron number in the mediodorsal nucleus of the thalamus observed in brains from schizophrenic subjects (Pakkenberg, 1990; Young et al, 2000; Popken et al, 2000).…”

“…It is unclear why fetal irradiation might lead to asymmetry of the dopamine innervation of the striatum, and unfortunately, we do not know whether there are hemispheric differences in the neuropathology in these animals. Postmortem studies of these animals have been limited to the left hemisphere (Selemon et al, 2009; 2013) and magnetic resonance imaging studies have been performed bilaterally (Aldridge et al, 2012). It is worth noting that CONs also showed selective directionality of circling although the number of circling events was much smaller.…”

“…Our previous studies have uncovered a remarkable degree of similarity between the neuropathology following early gestational exposure to radiation in the macaque and the neuropathology of schizophrenia. Widespread, but non-uniform, volume deficits have been observed most prominently in the thalamus, cortical gray matter and putamen (Schindler et al, 2002; Selemon et al, 2005; 2009; Aldridge et al, 2012). A similar global neuropathologic profile has been described in schizophrenia (Harrison, 1998; Selemon, 2001; Shenton et al, 2001; 2010).…”

“…A similar global neuropathologic profile has been described in schizophrenia (Harrison, 1998; Selemon, 2001; Shenton et al, 2001; 2010). 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).…”

Large deformation diffeomorphic metric mapping registration of reconstructed 3D histological section images and in vivo MR images

“…The procedures for sacrifice via intracardial perfusion, celloidin embedding of brain tissue, and histological processing have been described elsewhere (Selemon et al, 2009). High resolution digital photographic images (0.005534 × 0.005534 mm 2 /pixel) were acquired of each histological section.…”