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Long-term Effects of Multiple Glucocorticoid Exposures in Neonatal Mice
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA
Department of Pharmacology and Toxicology and Life Span Institute, University of Kansas, Lawrence, KS 66045, USA
Department of Psychiatry, Box 8134, 660 S. Euclid Ave., Washington University School of Medicine, St. Louis, MO 63110, USA
These authors contributed equally
* Author to whom correspondence should be addressed.
Received: 10 December 2011; in revised form: 27 December 2011 / Accepted: 28 December 2011 / Published: 30 December 2011
Abstract: Glucocorticoids (GCs) such as dexamethasone (DEX) or betamethasone are repeatedly administered for up to a month to prematurely born infants as a treatment for chronic lung dysfunction. Results of clinical trials have shown that the use of GCs in these infants induces long-term deficits in neuromotor function and cognition. We have previously shown that a single exposure to clinically relevant doses of DEX or other GCs in the mouse during a period corresponding to the human perinatal period produces a dramatic increase in apoptotic cell death of neural progenitor cells in the developing cerebellum. To provide a model approximating more chronic clinical dosing regimens, we evaluated possible behavioral effects resulting from repeated exposures to DEX and subsequent GC-induced neuronal loss where neonatal mouse pups were injected with 3.0 mg/kg DEX or saline on postnatal days 7, 9, and 11 (DEX3 treatment). Adult, DEX3-treated mice exhibited long-term, possibly permanent, neuromotor deficits on a complex activity wheel task, which requires higher-order motor co-ordination skills. DEX3 mice exhibited impaired performance on this task relative to saline controls in each of two independent studies involving separate cohorts of mice. Histopathology studies utilizing stereological neuronal counts conducted in behaviorally-tested mice showed that the DEX3 treatment resulted in a significant decrease in the number of neurons in the internal granule layer (IGL) of the cerebellum, although the number of neurons in the Purkinje cell layer were unchanged. The results suggest that multiple neonatal DEX exposures can produce chronic deficits in fine motor co-ordination that are associated with cerebellar IGL neuronal loss.
Keywords: glucocorticoid; dexamethasone; neuromotor deficits; motor co-ordination; complex activity wheel; cerebellum; internal granule layer; neuron loss; apoptotic cell death
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Maloney, S.E.; Noguchi, K.K.; Wozniak, D.F.; Fowler, S.C.; Farber, N.B. Long-term Effects of Multiple Glucocorticoid Exposures in Neonatal Mice. Behav. Sci. 2011, 1, 4-30.
Maloney SE, Noguchi KK, Wozniak DF, Fowler SC, Farber NB. Long-term Effects of Multiple Glucocorticoid Exposures in Neonatal Mice. Behavioral Sciences. 2011; 1(1):4-30.
Maloney, Susan E.; Noguchi, Kevin K.; Wozniak, David F.; Fowler, Stephen C.; Farber, Nuri B. 2011. "Long-term Effects of Multiple Glucocorticoid Exposures in Neonatal Mice." Behav. Sci. 1, no. 1: 4-30.