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Gestational hypothyroidism can impair development, cognition, and mood. Here, we tested whether multisensory stimulation (MS) improves the phenotype of rats born to surgically thyroidectomized (Tx) dams suboptimally treated with LT4. 8-week-old female Tx Wistar rats were kept on daily LT4 (0.7 µg/100 g body weight) dosed by gavage (serum TSH and T4 levels indicated moderate hypothyroidism) and 3 weeks later placed for breeding. MS of the litter started at age 60 days and lasted for 8 weeks. It consisted of twice per week of physical, cognitive, sensorial, and food stimuli. The offspring were assessed before and after MS for standardized tests of locomotor activity, cognition, and mood. Gestational hypothyroidism resulted in reduced litter size and increased offspring mortality. The pups exhibited delayed physical development, impairment of short- and long-term memory, and anxiety- and depressive-like behaviors. Nonetheless, ambulatory activity, social memory, and social preference were not affected by gestational hypothyroidism. MS restored short-term memory and anxiety while improving depressive like-behaviors. MS did not improve long-term memory. MS also did not modify the performance of control litter born to intact dams. We conclude that cognition and mood impairments caused by moderate gestational hypothyroidism were reversed or minimized in rats through MS. Further studies should define the molecular mechanisms involved.

Status epilepticus (SE) is an abnormally prolonged seizure that results from either a failure of mechanisms that terminate seizures or from initiating mechanisms that inherently lead to prolonged seizures. Here we report that mice experiencing a 3 hours of SE caused by pilocarpine exhibit a rapid increase in expression of type 2 iodothyronine deiodinase gene (Dio2) and a decrease in the expression of type 3 iodothyronine deiodinase gene in hippocampus, amygdala and prefrontal cortex. Type 3 iodothyronine deiodinase in hippocampal sections was seen concentrated in the neuronal nuclei, typical of ischemic injury of the brain. An unbiased analysis of the hippocampal transcriptome of mice undergoing 3 hours of SE revealed a number of genes, including those involved with response to oxidative stress, cellular homeostasis, cell signaling, and mitochondrial structure. In contrast, in mice with targeted disruption of Dio2 in astrocytes (Astro D2KO mouse), the highly induced genes in the hippocampus were related to inflammation, apoptosis, and cell death. We propose that Dio2 induction caused by SE accelerates production of T3 in different areas of the central nervous system and modifies the hippocampal gene expression profile, affecting the balance between adaptive and maladaptive mechanisms.

Thyroid hormone acts in virtually every biological system in vertebrates by controlling the expression of different sets of genes. To achieve this, thyroid hormone interacts with two receptors (TR), TR and TR , located in the nucleus of its target cells, which turn gene transcription on or offand thusmediate thebiological effectsassociatedwith the thyroid secretion (1, 2). The distribution of TR and TR among different target tissues is not homogeneous: TR pathways are implicated in the brain, skeletal muscle, heart, and bone, whereas the TR pathways play a metabolic role in liver and adipose tissue (3). Together both TR isoforms control avastnetworkofbiologicalprocesses that includescritical roles in development, growth, and metabolic homeostasis (4). The determination of the TR structure made it clear that differences in the ligand binding pocket of the receptors would allow for the development of small molecules with a reasonable degree of binding selectivity (5). This was achieved in the late 1990s and GC-1, the first of such molecules to exhibit TR selectivity, was tested in cell systems and in animals (6). Today an array of TR -selective ligands exists, expanding not only our understanding of thyroid hormone action but also the exciting possibility of pharmacological intervention in disease states (7). The latter is based on the fact that beneficial metabolic effects can be obtained by activating TR pathways in liver and adipose tissue and avoiding the undesirable side effects of the TR pathway activation in the brain, heart, and bone (8). In the current issue of Endocrinology, GrijotaMartinez et al. (9) report the analysis of TR-dependent pathways in developing hypothyroid rats using GC-24, a highly TR -selective molecule, and CO23, a thyromimetic with reportedly TR -specific effects in vitro and in tadpoles (10). Whereas GC-24 exhibited the expected selectivity for TR pathways, equimolar amounts of CO23 failed to activate either TR-dependent pathway. Only at much higher doses did CO23 exhibit thyromimetic activity, without the expected selectivity for TR pathways. Such a failure is hard to explain but could be the result of unfavorable pharmacokinetics in mammals unforeseen from the GC series experience. Any of several small problems could be killing the effects of CO23, including impaired absorption, distribution, and/or transport into target cells and accelerated metabolism or excretion, resulting in death by a thousand cuts. That different TR isoforms control separate biological processes became clear from a series of studies in mice with inactivation or mutation of different TR isoforms as well as studies in patients with the syndrome of resistance to thyroid hormone (3). However, a landmark in this field was established with the demonstration that treatment of hypothyroid rats with GC-1 normalizes serum cholesterol and triglycerides through TR activation in the liver without increasing heart rate or expression of typical T3 target genes in the heart, all TR -dependent processes (11). Later an additional key observation was made: that chronic treatment with GC-1 in euthyroid female rats lowered serum cholesterol by approximately 20% and spared bone mass as assessed by histomorphometry and dual-x-ray bone absorptiometry (12). Further studies illustrated that a substantial degree of TR selectivity could be achieved with GC-1, even in tissues with active TR and TR pathways, such as the brown adipose tissue (BAT). In hypothyroid mice, treatment with GC-1 normalized BAT uncoupling protein-1 expression (a highly T3 responsive