Insufficient thyroid hormone (TH) during development results in permanent neurological deficits. These deficits are the result of neuroanatomical defects that include smaller brain, fewer parvalbumin neurons, and hypomyelination. Interestingly, insufficient insulin-like growth factor 1 (Igf-1) during development results in similar neuroanatomical defects to those reported for developmental hypothyroidism. Thyroid hormone is known to indirectly influence serum Igf-1 levels through its regulation of pituitary growth hormone (GH) secretion which stimulates hepatic Igf-1 production. Our lab and others have observed decreases of local brain-derived Igf-1 in the developing hypothyroid mouse brain. This observation suggests that deficits associated with low TH during development may be the result of altered brain-derived Igf-1. Considering this, we sought to determine whether ectopically expressing Igf-1 in the developing brain could rescue neuroanatomical defects associated with TH. To accomplish this, the tet-off transgenic system was used where mice harboring tetracycline transactivator protein driven by the human GFAP promoter (tTA-GFAP) were crossed with mice containing the human Igf-1cDNA under the control the TET response element (Igf1-pTRE) transgene. Double transgenic (dTg) offspring carrying both the tTA-GFAP and Igf1-TRE genes overexpress Igf-1 specifically in brain astrocytes. The timed-pregnant mice were treated with thyroid gland inhibitors from embryonic day 14.5 (E14.5) until postnatal day 14 (P14) to induce a hypothyroid state in pups. At P14, pups were weighed and sacrificed, trunk blood was collected, and brains were dissected, weighed, and immediately frozen. Hippocampal structure, known be disrupted by developmental hypothyroidism, was assessed by fluorescent imaging using DAPI staining. Our initial results indicate that ectopic expression of Igf-1 in the brain (dTg mice) rescues hypothyroidism-induced reductions in brain weight without increasing body weight. In addition, the ectopic expression of Igf-1 restored hypothyroidism-induced perturbations in dentate gyrus size. Ongoing studies are using quantitative real-time PCR on micro-dissected cortical and hippocampal samples, to quantify myelin associated glycoprotein and parvalbumin mRNAs. Taken together, our findings support the idea that ectopic brain-derived Igf-1 rescues neuroanatomical defects caused by hypothyroidism and implicates TH in the regulation of brain Igf-1.
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Acute Sleep Disruption Does Not Diminish Pulsatile Growth Hormone Secretion in Pubertal Children
Abstract Context In children, growth hormone (GH) pulses occur after sleep onset in association with slow-wave sleep (SWS). There have been no studies in children to quantify the effect of disrupted sleep on GH secretion. Objective This study aimed to investigate the effect of acute sleep disruption on GH secretion in pubertal children. Methods Fourteen healthy individuals (aged 11.3-14.1 years) were randomly assigned to 2 overnight polysomnographic studies, 1 with and 1 without SWS disruption via auditory stimuli, with frequent blood sampling to measure GH. Results Auditory stimuli delivered during the disrupted sleep night caused a 40.0 ± 7.8% decrease in SWS. On SWS-disrupted sleep nights, the rate of GH pulses during N2 sleep was significantly lower than during SWS (IRR = 0.56; 95% CI, 0.32-0.97). There were no differences in GH pulse rates during the various sleep stages or wakefulness in disrupted compared with undisrupted sleep nights. SWS disruption had no effect on GH pulse amplitude and frequency or basal GH secretion. Conclusion In pubertal children, GH pulses were temporally associated with episodes of SWS. Acute disruption of sleep via auditory tones during SWS did not alter GH secretion. These results indicate that SWS may not be a direct stimulus of GH secretion.
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- NSF-PAR ID:
- 10409028
- Date Published:
- Journal Name:
- Journal of the Endocrine Society
- Volume:
- 6
- Issue:
- 11
- ISSN:
- 2472-1972
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1210/jendso/bvac146
