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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. 

The Department of Biological Sciences at Minnesota State University, Mankato, a primarily undergraduate institution, is developing and implementing the “Research Immersive Scholastic Experience in Biology” (RISEbio) program. RISEbio is a National Science Foundation-funded scholarship and support program that is targeting incoming Biological Sciences freshmen with demonstrated financial need and academic potential. The overall goal of RISEbio is to increase student academic success through: (1) Increasing student social integration and support, (2) developing student technical and professional skills, and (3) implementing a freshman immersive research program. To form a social support network, scholars will be part of a RISEbio learning community. A unique, core component of RISEbio is to provide scholars with an authentic real-world research experience by modifying freshman research initiatives utilized by research-intensive universities to fit within the available infrastructure at Minnesota State University, Mankato. During a scholar’s first year, they exchange their Introductory Biology 1 lab for an applied course, Foundational Methods in Biology. In their second semester, scholars join a research stream in exchange for their Introductory Biology 2 lab. The stream research continues on to their third semester. One of two initial research streams is focused on neuroscience and is titled “Brain and Behavior.” Students in this stream examine the neural control of reproductive behavior by examining gene expression in the brain of the seasonally breeding green anole lizard (Anolis carolinensis). Students will extract RNA from the hypothalamus of breeding and non-breeding lizard brains, then design primers and use quantitative PCR in conjunction with bioinformatic analysis to identify genes that are differentially expressed in the brain between seasons. If differentially expressed genes are found, students will learn how to design and perform in situ hybridizations to examine the localization of these genes within the brain. Following the third semester, scholars enter the “next steps” stage which offers support to identify additional opportunities on and off campus, including mentoring the next group of RISEbio Scholars or joining research labs to continue conducting undergraduate research. RISEbio will also provide a platform to test how this program translates to student persistence and academic success. To our knowledge, this is the first freshman research initiative developed at a regional comprehensive university.