Christina D. Tulbert

Enhanced Endothelin Activity Prevents Vasodilation to Insulin in Insulin Resistance

Although insulin-mediated vasodilation is impaired in insulin resistance, the mechanisms of this are unknown. We investigated factors mediating vasoactive responses to insulin in control and insulin-resistant rats. Responses to insulin in small mesenteric arteries from control and insulin-resistant rats were investigated after blocking endothelin-A receptors, cyclooxygenase, nitric oxide synthase, and potassium channels. In addition, insulin’s effect on prostacyclin production in small mesenteric blood vessels was assessed by enzyme immunoassay. Insulin induced a concentration-dependent vasodilation in control arteries that was absent in arteries from insulin-resistant rats. However, in the presence of BQ610, an endothelin-A receptor antagonist, the response to insulin was normalized in insulin-resistant arteries. In control arteries, insulin-induced vasodilation was completely inhibited by indomethacin, meclofenamate, glibenclamide, or potassium chloride. In contrast, neither n-nitro-l-arginine nor the combination of charybdotoxin and apamin altered vasodilation to insulin. In insulin-resistant arteries in the presence of BQ610, vasodilation was also inhibited by indomethacin, glibenclamide, and potassium chloride. Insulin increased prostacyclin production in small mesenteric blood vessels from both groups of rats to a similar degree. Insulin-induced vasodilation in small rat mesenteric arteries is mediated through prostacyclin- and ATP-dependent potassium channels. However, insulin-resistant arteries do not vasodilate to insulin unless endothelin-A receptors are blocked. Thus, impaired relaxation to insulin in insulin-resistant rats is due to enhanced vasoconstriction by endothelin, which offsets a normal vasodilatory response to insulin.

Longitudinal 1H MRS of rat forebrain from infancy to adulthood reveals adolescence as a distinctive phase of neurometabolite development

This study represents the first longitudinal, within‐subject 1H MRS investigation of the developing rat brain spanning infancy, adolescence and early adulthood. We obtained neurometabolite profiles from a voxel located in a central location of the forebrain, centered on the striatum, with smaller contributions for the cortex, thalamus and hypothalamus, on postnatal days 7, 35 and 60. Water‐scaled metabolite signals were corrected for T1 effects and quantified using the automated processing software LCModel, yielding molal concentrations. Our findings indicate age‐related concentration changes in N‐acetylaspartate + N‐acetylaspartylglutamate, myo‐inositol, glutamate + glutamine, taurine, creatine + phosphocreatine and glycerophosphocholine + phosphocholine. Using a repeated measures design and analysis, we identified significant neurodevelopment changes across all three developmental ages and identified adolescence as a distinctive phase in normative neurometabolic brain development. Between postnatal days 35 and 60, changes were observed in the concentrations of N‐acetylaspartate + N‐acetylaspartylglutamate, glutamate + glutamine and glycerophosphocholine + phosphocholine. Our data replicate past studies of early neurometabolite development and, for the first time, link maturational profiles in the same subjects across infancy, adolescence and adulthood. Copyright

Intrauterine exposure to maternal stress alters Bdnf IV DNA methylation and telomere length in the brain of adult rat offspring

DNA methylation (addition of methyl groups to cytosines) and changes in telomere length (TTAGGG repeats on the ends of chromosomes) are two molecular modifications that result from stress and could contribute to the long‐term effects of intrauterine exposure to maternal stress on offspring behavior. Here, we measured methylation of DNA associated with the Brain‐derived neurotrophic factor (Bdnf) gene, a gene important in development and plasticity, and telomere length in the brains of adult rat male and female offspring whose mothers were exposed to unpredictable and variable stressors throughout gestation. Males exposed to prenatal stress had greater methylation (Bdnf IV) in the medial prefrontal cortex (mPFC) compared to non‐stressed male controls and stressed females. Further, prenatally‐stressed animals had shorter telomeres than controls in the mPFC. Together findings indicate a long‐term impact of prenatal stress on brain DNA methylation and telomere biology with relevance for behavioral and health outcomes, and contribute to a growing literature linking stress to intergenerational molecular changes.