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H.M. Petry, B. Chen, G.L. Yarbrough; Temporal Progression of Ethanol Triggered Apoptosis in the Developing Tree Shrew Visual System . Invest. Ophthalmol. Vis. Sci. 2004;45(13):3547.
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Purpose: The purpose of this research was to determine whether the tree shrew (Tupaia) would provide a useful model to study the visual system components of Alcohol Related Neurodevelopmental Disorders, including Fetal Alcohol Syndrome. A specific goal was to assess the time course of ethanol–induced apoptopic cell death in central visual structures of the tree shrew brain within the early post–natal brain growth spurt period of synaptogenesis. Methods: We assessed apoptotic cell death in the visual systems of 7–day–old tree shrew pups 4–, 8–, 12– or 24–hrs following injection with saline or ethanol (2.5g/kg ip, given twice over a 2–hr period). Standard immunocytochemical procedures were used to localize activated caspase–3, a critical apoptotic protease. Results: The brains of ethanol–treated shrews revealed widespread caspase–3 IR+ neurons in central visual structures. In contrast, saline–treated control brains showed only sparsely distributed caspase–3 IR+ neurons, presumably revealing normal apoptosis during this stage of neural development. Caspase–3 IR+ in the dorsal lateral geniculate nucleus peaked at 12 hrs, with IR+ neurons mostly in layer 3 and in interlaminar zones. At 4–, 8– and 24–hrs only a few IR+ neurons were scattered throughout the nucleus. In the dorsal–medial pulvinar, the number of IR+ neurons increased from 4– to 8– to 12– to 24–hrs at which time a whirl–like pattern was observed. In ventral–medial pulvinar, less numerous and scattered IR+ cells were observed at each time period. In the superior colliculus, IR+ neurons were scattered throughout the nucleus and peaked at 24 hrs. The SZ and SGS were labeled less than the SO. In area 17 and area 18 of visual cortex, little IR+ occurred at 4–hrs, but at 8 hrs and 12 hrs significant IR+ was differentiated by layer (especially layers II, III and V) and by area (17 vs 18). Only scattered IR+ cells were present there at 24–hrs. Conclusions: A single exposure to ethanol during the brain growth spurt period triggers widespread neuronal apoptosis in the developing tree shrew visual system. Different visual structures and cell groups/layers within those structures show different patterns of caspase–3 activation over time. This result may indicate the differential susceptibility of these neurons to ethanol and/or a combination of cell vulnerability at this stage of neuronal development coupled with the transitory 2–3 hour time course of caspase–3 activation. This widespread apoptotic cell death likely underlies many of the visual performance deficits that accompany Alcohol Related Neurodevelopmental Disorders.
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