Hypoxia and dehydroepiandrosterone in old age: a mouse survival study

BACKGROUND: Survival remains an issue in pulmonary hypertension, a chronic disorder that often affects aged human adults. In young adult mice and rats, chronic 50% hypoxia (11% FIO2 or 0.5 atm) induces pulmonary hypertension without threatening life. In this framework, oral dehydroepiandrosterone was recently shown to prevent and reverse pulmonary hypertension in rats within a few weeks. To evaluate dehydroepiandrosterone therapy more globally, in the long term and in old age, we investigated whether hypoxia decreases lifespan and whether dehydroepiandrosterone improves survival under hypoxia. METHODS: 240 C57BL/6 mice were treated, from the age of 21 months until death, by normobaric hypoxia (11% FIO2) or normoxia, both with and without dehydroepiandrosterone sulfate (25 mg/kg in drinking water) (4 groups, N = 60). Survival, pulmonary artery and heart remodeling, weight and blood patterns were assessed. RESULTS: In normoxia, control mice reached the median age of 27 months (median survival: 184 days). Hypoxia not only induced cardiopulmonary remodeling and polycythemia in old animals but also induced severe weight loss, trembling behavior and high mortality (p < 0.001, median survival: 38 days). Under hypoxia however, dehydroepiandrosterone not only significantly reduced cardiopulmonary remodeling but also remarkably extended survival (p < 0.01, median survival: 126 days). Weight loss and trembling behavior at least partially remained, and polycythemia completely, the latter possibly favorably participating in blood oxygenation. Interestingly, at the dose used, dehydroepiandrosterone sulfate was detrimental to long-term survival in normoxia (p < 0.05, median survival: 147 days). CONCLUSION: Dehydroepiandrosterone globally reduced what may be called an age-related frailty induced by hypoxic pulmonary hypertension. This interestingly recalls an inverse correlation found in the prospective PAQUID epidemiological study, between dehydroepiandrosterone blood levels and mortality in aged human smokers and former smokers

Evidence of Key Tinnitus-Related Brain Regions Documented by a Unique Combination of Manganese-Enhanced MRI and Acoustic Startle Reflex Testing

Animal models continue to improve our understanding of tinnitus pathogenesis and aid in development of new treatments. However, there are no diagnostic biomarkers for tinnitus-related pathophysiology for use in awake, freely moving animals. To address this disparity, two complementary methods were combined to examine reliable tinnitus models (rats repeatedly administered salicylate or exposed to a single noise event): inhibition of acoustic startle and manganese-enhanced MRI. Salicylate-induced tinnitus resulted in wide spread supernormal manganese uptake compared to noise-induced tinnitus. Neither model demonstrated significant differences in the auditory cortex. Only in the dorsal cortex of the inferior colliculus (DCIC) did both models exhibit supernormal uptake. Therefore, abnormal membrane depolarization in the DCIC appears to be important in tinnitus-mediated activity. Our results provide the foundation for future studies correlating the severity and longevity of tinnitus with hearing loss and neuronal activity in specific brain regions and tools for evaluating treatment efficacy across paradigms

Deafness in TR Mutants Is Caused by Malformation of the Tectorial Membrane

Thyroid hormone receptor beta(TR beta) dysfunction leads to deafness in humans and mice. Deafness in TR beta(-/-) mutant mice has been attributed to TR beta-mediated control of voltage- and Ca(2+)-activated K(+) (BK) channel expression in inner hair cells (IHCs). However, normal hearing in young constitutive BK alpha(-/-) mutants contradicts this hypothesis. Here, we show that mice with hair cell-specific deletion of TR beta after postnatal day 11 (P11) have a delay in BK alpha expression but normal hearing, indicating that the origin of hearing loss in TR beta(-/-) mutant mice manifested before P11. Analyzing the phenotype of IHCs in constitutive TR beta(-/-) mice, we found normal Ca2(+) current amplitudes, exocytosis, and shape of compound action potential waveforms. In contrast, reduced distortion product otoacoustic emissions and cochlear microphonics associated with an abnormal structure of the tectorial membrane and enhanced tectorin levels suggest that disturbed mechanical performance is the primary cause of deafness resulting from TR beta deficiency

Parallel detection of violations of color constancy

The perceived colors of reflecting surfaces generally remain stable despite changes in the spectrum of the illuminating light. This color constancy can be measured operationally by asking observers to distinguish illuminant changes on a scene from changes in the reflecting properties of the surfaces comprising it. It is shown here that during fast illuminant changes, simultaneous changes in spectral reflectance of one or more surfaces in an array of other surfaces can be readily detected almost independent of the numbers of surfaces, suggesting a preattentive, spatially parallel process. This process, which is perfect over a spatial window delimited by the anatomical fovea, may form an early input to a multistage analysis of surface color, providing the visual system with information about a rapidly changing world in advance of the generation of a more elaborate and stable perceptual representation