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NEOCORTICAL HYPERTROPHY FOLLOWING DEVELOPMENTAL HYPOTHYROIDISM IN RATS
Citation:
Briffa-Mirabella, S. A., D. P. McClosky, M. E. GILBERT, R. L. Ramos, AND J. H. Goodman. NEOCORTICAL HYPERTROPHY FOLLOWING DEVELOPMENTAL HYPOTHYROIDISM IN RATS. Presented at Society for Neuroscience Annual Meeting, San Diego, CA, November 13 - 17, 2010.
Impact/Purpose:
The present study sought to determine whether an additional consequence of developmental TH insufficiency is an alteration in neocortical volume.
Description:
Thyroid hormones (TH) are essential to the normal development of the brain. Although severe congenital hypothyroidism has long been associated with mental retardation and motor defects, it has only recently been established that even subtle decreases in maternal TH alter fetal brain development and cause impairments in intellectual function. One explanation may be altered development of the cerebral cortex, which is supported by evidence of altered migration of neurons into subcortical white matter during the period ofcorticogenesis in hypothyroid rodents (Goodman and Gilbert, 2007; Auso et al.2004). The present study sought to determine whether an additional consequence of developmental TH insufficiency is an alteration in neocortical volume. Pregnant dams were exposed to propylthiouracil (PTU; 0, 3 or 10ppm) in their drinking water from gestational day 6 through lactation, which results in significant reductions in body weight and offspring TH levels at weaning on PN30. (3ppm: 70% reduction in T4, 35% reduction in T3; 1Oppm: reduction of T4 below detection levels, 70% reduction in T3; Sui & Gilbert, 2003; 2006) One pup from each dose group (Oppm n=7; 3ppm n= 8; 10ppm n=9) was perfusion-fixed on postnatal day 23. Brains were sectioned coronally on a vibratome (50Jlm) in a stereological manner through the rostrocaudal portion ofbrain corresponding to dorsal hippocampus. Slide mounted sections were stained with cresyl violet, and images were obtained using a scarmer. Cortical and whole brain volume estimates were made on every s" section using a Calvalieri probe (Image J). A ratio ofcortex to whole brain volume was calculated to account for changes in brain volume as a result ofPTU. ANOVA revealed a significant increase in cortex to brain ratio as the concentration ofPTU was increased (p = 0.019; Mean ± SEM Oppm: 0.31 ± 0.018; 3ppm: 0.37 ± 0.014; 10ppm: 0.39 ± 0.019). Plarmed comparisons showed that the difference between 0 and 10ppm was significant, and the difference between 0 and 3ppm had a trend toward significance (p= 0.056). To determine whether this was a result of an increase in the cortex or a decrease in subcortical areas, an additional analysis of cortical thickness was conducted by making linear measurements of cortex. ANOVA confirmed that the increased ratio was a result of an increase in cortical thickness (p = 0.017; Mean ± SEM Oppm: 0.98 ± 0.015; 3ppm: 1.03 ± 0.02; 10ppm: 1.21 ± 0.03), with plarmed comparisons showing a significant difference between 0 and l Oppm, but not between 0 and 3ppm. Together, these results suggest that PTU causes a dose dependent increase in cortical volume, which may account for functional deficits following developmental TH insufficiency. (does not reflect EPA policy)