Thyroid hormones regulate many aspects of brain development and function, and alterations in the levels of thyroid hormone action lead to abnormal anxiety-and depression-like behaviors. A complement of factors in the brain function independently of circulating levels of hormone to strictly controlled local thyroid hormone signaling. A critical factor is the type 3 deiodinase (DIO3), which is located in neurons and protects the brain from excessive thyroid hormone. Here, we examined whether a local increase in brain thyroid hormone action secondary to DIO3 deficiency is of consequence for social behaviors. Although we did not observe alterations in sociability, Dio3−/− mice of both sexes exhibited a significant increase in aggression-related behaviors and mild deficits in olfactory function. In addition, 85% of Dio3−/− dams manifested no pup-retrieval behavior and increased aggression toward the newborns. The abnormal social behaviors of Dio3−/− mice were associated with sexually dimorphic alterations in the physiology of oxytocin (OXT) and arginine vasopressin (AVP), 2 neuropeptides with important roles in determining social interactions. These alterations included low adult serum levels of OXT and AVP, and an abnormal expression of Oxt, Avp and their receptors in the neonatal and adult hypothalamus. Our results demonstrate that DIO3 is essential for normal aggression and maternal behaviors, and indicate that abnormal local regulation of thyroid hormone action in the brain may contribute to the social deficits associated with neurodevelopmental disorders.
As the only effective energy substrate in the absence of O2, glucose (Glc) is central to all cellular strategies for hypoxic adaptation. Obligatory reliance on Glc also explains associated induction of glycolytic enzymes such as hexokinases which catalyze the first committed step of Glc metabolism. HIF1α contributes to HK2 expression in cancer cells, but the specific cis‐acting sequences are undefined and corresponding effects in nontransformed cells are unexplored. We therefore used chimeric reporter genes to delineate hypoxia‐responsive cis‐acting HK2 promoter regions in nontransformed NRK‐52E cells.Major hypoxic control of HK2 expression mapped to a phylogenetically conserved tandem pair of canonical HIF‐binding motifs just 5' to the 157 bp basal promoter region. Targeted mutagenesis of either motif abrogated hypoxia‐responsiveness, as did their spatial separation by a half (+5 bp) ‐ but not a full (+10 bp) ‐ helical turn. Similar results with hypoxia‐mimetics (e.g. CoCl2) and stabilized mutants of HIF1α ‐ but not HIF2α ‐ suggest HIF1α selectivity. Independent hypoxic enhancer activity responsive to both HIF1α and HIF2α ‐ but not other known HK2 transcriptional regulators ‐ was also observed within 90 bp of the transcription start site. These results suggest complex hypoxic gene regulation involving both combinatorial interactions and cis‐acting elements with differing HIFα isoform specificities.
In rat pups a reduction in serotonin (5HT) input to respiratory networks impairs anoxic auto‐resuscitation and impairs arousal during hypoxia. In contrast, blockade of adenosine receptors enhances auto‐resuscitation and attenuates the VE decline during the biphasic hypoxic ventilatory response. Caffeine (Caf), an adenosine receptor antagonist, used to treat apnea of prematurity in human infants, has well known effects on sleep and vigilance in adults and in some reports increases the levels of brain 5HT. We therefore examined the pharmacodynamics and the physiological effects of single IP injections of Caf (base) at 5 to 40 mg/kg in P9–P11 pups. Plasma Caf levels reached 10.9 and 76.3 mg/l for 5 and 40 mg/kg, respectively, at 60 min, and were stable until at least 90 min. Caf increased the % time awake at 10 and 40 mg/kg and at 40 mg/kg decreased the % time in active sleep. Caf did not change baseline heart or respiratory rate but the effect of Caf on VT and VE was dependent on state and dose. At 40 mg/kg, VT was increased during wake and quiet sleep whereas VE was increased only during wake. No increases in brainstem 5HT were found at either 10 or 40 mg/kg. In rat pups, a low dose of Caf alters sleep and at higher doses stimulates respiration. The effects of Caf on auto‐resuscitation and ventilation during hypoxia do not appear to be related to an increase in brainstem 5HT levels. NICHD 5‐PO1 HD036379 15
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