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Leptin is a hormone produced by the small intestines and adipose tissue that promotes feelings of satiety. Leptin receptors (LepRs) are highly expressed in the hypothalamus, enabling central neural control of hunger. Interestingly, LepRs are also expressed in several other regions of the body and brain, notably in the cerebral cortex and hippocampus. These brain regions mediate higher-order sensory, motor, cognitive, and memory functions, which can be profoundly altered during periods of hunger and satiety. However, LepR expression in these regions has not been fully characterized on a cell-type-specific basis, which is necessary to begin assessing their potential functional impact. Consequently, we examined LepR expression on neurons and glia in the forebrain using a LepR-Cre transgenic mouse model. LepR-positive cells were identified using a ‘floxed’ viral cell-filling approach and co-labeling immunohistochemically for cell-type-specific markers, i.e., NeuN, VGlut2, GAD67, parvalbumin, somatostatin, 5-HT3R, WFA, S100β, and GFAP. In the cortex, LepR-positive cells were localized to lower layers (primarily layer 6) and exhibited non-pyramidal cellular morphologies. The majority of cortical LepR-positive cells were neurons, while the remainder were identified primarily as astrocytes or other glial cells. The majority of cortical LepR-positive neurons co-expressed parvalbumin, while none expressed somatostatin or 5-HT3R. In contrast, all hippocampal LepR-positive cells were neuronal, with none co-expressing GFAP. These data suggest that leptin can potentially influence neural processing in forebrain regions associated with sensation and limbic-related functions.
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Ectopic brain-derived insulin-like growth factor-1 partially rescues neuroanatomical defects associated with developmental hypothyroidism
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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- Award ID(s):
- 1726859
- PAR ID:
- 10112187
- Date Published:
- Journal Name:
- Abstracts - Society for Neuroscience
- ISSN:
- 0190-5295
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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