Modulation of the HPA axis alters the sensitivity of the cochlea to acoustic trauma

Abstract

The hypothalamic pituitary adrenal axis (HPA axis) regulates nearly all neuroendocrine responses of the body. An active HPA axis is crucial to maintaining homeostasis. An altered reactivity of the HPA axis can affect several physiological systems including the auditory system. The mechanism underlying the interaction between the HPA axis and the auditory system is not known. The overall objective of this thesis was to define the functional relationship between the HPA axis and the auditory system and to evaluate the underlying mechanisms.

The results presented in this thesis demonstrate how the cochlea is protected against acoustic trauma with previous activation of HPA axis. Activation of the HPA axis with either restraint stress or sound conditioning prior to acoustic trauma significantly elevates plasma corticosterone, activates GRs in the paraventricular nucleus (PVN), spiral ganglion neurons (SGN) and significantly lowers ABR threshold shifts. This protective effect was block by either adrenalectomy or combine use of glueocorticoid synthesis inhibitor (metyrapone) or receptor antagonist (RU486). Moreover, the combined use of metyrapone and RU486 prior to acoustic trauma leads to the exacerbation of hearing loss indicating that an optimal HPA axis response is crucial for the recovery from trauma.

Nuclear factor kappa B (NFκB), a GR regulated transcription factor, was also involved in this corticosterone mediated protective mechanism. Enhancement of nuclear translocation of NFκ13 in the spiral ganglion neurons coincides with lower ABR threshold shifts indicating an interaction between GR and NFκ13 in the SGNs. This can be the main factor, which contributes to the protection of cochlea against acoustic trauma. A selective NFκB inhibitor PDTC was use to confirm the role of NFκB in the cochlea. Pretreatment of PDTC caused an elevation of auditory thresholds and lowered nuclear translocation of NFκB in the SGNs. Steroid receptor co activator 1 (SRC-1), a GR co-regulatory protein also contributes to this GR mediated protective mechanism of hearing. The expression of SRC1 in the SGN was increase after sound conditioning and acoustic trauma, which could be the probable mechanism of sound conditioning triggered protection of hearing.

In conclusion, the findings from this study imply that the HPA axis modulates the sensitivity of the cochlea against acoustic trauma by the release of glucocorticoid. Glueocorticoid regulates the expression and activation of GR locally in the cochlea. Active GR interacts with transcription factor NFêB and this interaction ultimately determines the susceptibility of cochlea against acoustic trauma.