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

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, 1974, 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; 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 (Brand and Rakic, 1979, 1980; Levitt and Rakic, 1982; Kordower and Rakic, 1990). Genesis of neurons in the primary visual cortex begins slightly later and extends throughout the middle third (E45-E102) of the 165-day gestational period of the rhesus monkey (Rakic, 1974, 1977b). The relatively prolonged period and temporal segregation of neurogenesis in the non-human primate is experimentally advantageous for deleting specific populations of neurons since populations that are in the final stages of mitosis are most vulnerable to the effects of ionizing irradiation. Algan and Rakic (1997) have previously shown that exposure of pregnant monkeys to multiple low doses of x-irradiation limited either to early (E33-E40) or midgestation (E70-E90) results in loss of neurons in the dorsal lateral geniculate nucleus and the primary visual cortex, respectively, in the offspring. More recently, in vivo magnetic resonance (MR) brain imaging was performed on monkeys that were prenatally exposed to x-irradiation and allowed to reach full adulthood. Analysis of the MR images indicated that volume of the whole thalamus was selectively reduced in monkeys irradiated during early gestation (E33-E42) compared to non-irradiated controls whereas midgestationally (E70-E82) irradiated monkeys had thalamic volumes indistinguishable from controls (Schindler et al., 2002). Interestingly, thalamic shape was altered in a non-uniform manner in the early irradiated group, suggesting that there might be inhomogeneity in volume reduction of individual thalamic nuclei (Schindler et al., 2002). Further analysis of cortical volumes in these same monkeys demonstrated the temporal specificity of the irradiation effects as monkeys irradiated in midgestation, but not in early gestation, showed significant reductions in cortical gray matter volume compared to controls (Selemon et al., 2005). The present study was undertaken to determine whether exposure to x-irradiation in early gestation reduces the number of neurons in associational thalamic nuclei that have been prominently implicated in the pathology of schizophrenia (Pakkenberg, 1990; Young et al., 2000; Popken et al., 2000; Byne et al., 2001, 2002; Danos et al., 2003; Kemether et al., 2003). If thalamic number were reduced by early gestational exposure to irradiation, the fetally irradiated non-human primate could be used to model the thalamic pathology of schizophrenia and to examine the morphologic and behavioral sequelae consequent to prenatal elimination of thalamic neurons.