Review: Neural Mechanisms of Tinnitus and Hyperacusis in Acute Drug-Induced Ototoxicity.

Purpose Tinnitus and hyperacusis are debilitating conditions often associated with age-, noise-, and drug-induced hearing loss. Because of their subjective nature, the neural mechanisms that give rise to tinnitus and hyperacusis are poorly understood. Over the past few decades, considerable progress has been made in deciphering the biological bases for these disorders using animal models. Method Important advances in understanding the biological bases of tinnitus and hyperacusis have come from studies in which tinnitus and hyperacusis are consistently induced with a high dose of salicylate, the active ingredient in aspirin. Results Salicylate induced a transient hearing loss characterized by a reduction in otoacoustic emissions, a moderate cochlear threshold shift, and a large reduction in the neural output of the cochlea. As the weak cochlear neural signals were relayed up the auditory pathway, they were progressively amplified so that the suprathreshold neural responses in the auditory cortex were much larger than normal. Excessive central gain (neural amplification), presumably resulting from diminished inhibition, is believed to contribute to hyperacusis and tinnitus. Salicylate also increased corticosterone stress hormone levels. Functional imaging studies indicated that salicylate increased spontaneous activity and enhanced functional connectivity between structures in the central auditory pathway and regions of the brain associated with arousal (reticular formation), emotion (amygdala), memory/spatial navigation (hippocampus), motor planning (cerebellum), and motor control (caudate/putamen). Conclusion These results suggest that tinnitus and hyperacusis arise from aberrant neural signaling in a complex neural network that includes both auditory and nonauditory structures.

Human chorionic gonadotropin enhances trophoblast-epithelial interaction in an in vitro model of human implantation.

Embryo implantation, which is an absolute requirement for reproduction, starts with blastocyst apposition to the uterine endometrium, followed by attachment to the endometrial surface epithelium. Recent clinical studies reported an increase in implantation and pregnancy rates among women receiving intrauterine human chorionic gonadotropin (hCG) prior to embryo transfer suggesting that, at least in some cases, female infertility is a result of inadequate secretion of hCG. In this study, we characterized the effect of hCG on trophoblast-epithelial interaction by further developing our recently described in vitro model of implantation. Here, we confirmed hCG increased attachment of trophoblast to epithelial cells, using a single-cell trophoblast-epithelial coculture system in addition to a blastocyst-like spheroid-epithelial coculture system. Furthermore, we discovered that the source and concentration was pivotal; the first preparation of hCG affected 2 molecules related to implantation, MUC16 and osteopontin, while the second preparation required additional cytokines to mimic the effects. Using this system, we can develop a comprehensive knowledge of the cellular and gene targets of hCG and other factors involved in embryo apposition and implantation and potentially increase the number of therapeutic targets for subfertile patients.