Corticosterone effects on the stability and vulnerability of the IHC synapse and sound processing

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Whenever the balance of physiological processes in our body is disturbed, a stress response can be triggered to restore homeostasis and to facilitate adaptation. Physiological challenge by environmental demands, positive stress and also traumatizing, damaging stress are known to influence acuity of sound perception in humans as well as acuity of cortical processing of auditory signals in animals. These influences are considered to originate in central brain regions. We recently observed beneficial and deteriorating effects of corticosterone on hearing that may result from directly affecting the inner hair cell (IHC) synapse. In the present application we address the question to the nature and function of such stress influences on auditory processing. We aim to identify the role of corticosteroid hormone receptor types, mineralocorticoid (MR) and glucocorticoid receptor (GR), at the inner hair cell level (1) through cell-specific deletion of MR and GR in conditional mouse models with deletions in either cochlea or brain, (2) through investigating the effect of MR/GR agonists/antagonists on hearing and sound processing in the mature organ, and (3) through testing presumptive acute MR/GR effects on single auditory fiber responses on cortical processing. A presumptive stress-induced effect on IHC synapse integrity or vulnerability would help to define a localized target for drug therapies and therapeutic clinical intervention.We have evidence that altered corticosterone levels in rodents directly influence the stability of IHC ribbon numbers pre- and post acoustic trauma correlated with correspondent shifts in supra-threshold ABR waves and activity-dependent gene expression in the ascending auditory pathway. As IHC ribbons define precision of spike rates and the size of supra-threshold ABR waves mirror the discharge rate and synchronicity of the summed auditory nerve, our project is expecting to provide in the best case substantial new information about stress-induced influences on temporal precise auditory information processing.Our main hypothesis of the current application suggests that differential corticosteroid receptor activities through MR or GR receptors may influence through activities on IHC synapses the integrity and vulnerability of central auditory processing and thereby can influence sound sensitivity as well as adaptive or non-adaptive plasticity changes.