Noise trauma continues to be a major cause for hearing loss throughout the world. This exploratory grant is based on the novel finding showing a circadian variation in noise-induced hearing loss. Exactly how this circadian rhythm in the auditory system is controlled is not known. The hypothesis to be tested is that the cochlea has an intrinsic circadian clock that modulates the sensitivity of the auditory system to noise trauma. This project seeks to determine the underlying functional and molecular mechanisms underlying this new finding. The suprachiasmatic nucleus (SCN) is the master clock that synchronizes and coordinates rhythms to regulate physiological functions including metabolism, inflammatory responses, feeding, sleep-wake patterns and the hypothalamic pituitary adrenal (HPA axis). The SCN and/or the HPA axis can be regulating the auditory clock or there is an internal clock in auditory tissues (cochlea, cochlear nucleus and inferior colliculus).
Aim 1 will answer the fundamental question if circadian auditory oscillations and auditory sensitivity to trauma is controlled by central circadian pacemaker SCN, or these oscillations occur independently of the SCN. The second part of aim 1 will determine the role of the HPA axis and glucocorticoids in mediating the auditory circadian rhythm noise-induced damage. The assumption is that the SCN drives a circadian rhythm in glucocorticoid release and an intact SCN will not be effective if the output pathway is interrupted by adrenalectomy. These experiments will illustrate how and if glucocorticoids are involved in the entrainment of the auditory clock rhythmicity. The last part of aim 1 will be directly testing if the isolated auditory tissues (i.e. without influence of SCN or te HPA axis) have an intrinsic rhythm that regulates noise-induced damage.
Aim 2 will determine the physiological and molecular effects of noise trauma on PER2 knockout mice to directly demonstrate the role of PER2 in regulating sensitivity to noise trauma at different times of the day.
Aim 2 will also determine if protection and repair against noise trauma also has a circadian rhythm. Using functional and molecular techniques we will characterize the circadian effect of noise damage and protective mechanisms. These studies are of clinical importance since noise-induced hearing disorders are an important public health issue and are exponentially increasing in the human population. These novel findings will open new avenues of research and have important implications for both basic and clinical science.
The main focus of this project is to determine how the circadian clock modulates the sensitivity of the auditory system (cochlea, cochlear nucleus and inferior colliculus) to noise trauma. Using a battery of functional, morphological and molecular techniques we will localize the generator of the auditory clock and characterize its molecular and functional responses. The findings from this proposal will further our understanding of the functional and molecular mechanisms underlying noise trauma and will open new avenues of research for cochlea and central auditory structures have an intrinsic basic and clinical auditory research.
|Park, Jung-Sub; Cederroth, Christopher R; Basinou, Vasiliki et al. (2016) Identification of a Circadian Clock in the Inferior Colliculus and Its Dysregulation by Noise Exposure. J Neurosci 36:5509-19|
|Meltser, Inna; Cederroth, Christopher R; Basinou, Vasiliki et al. (2014) TrkB-mediated protection against circadian sensitivity to noise trauma in the murine cochlea. Curr Biol 24:658-63|
|Bartlang, Manuela S; Savelyev, Sergey A; Johansson, Anne-Sofie et al. (2014) Repeated psychosocial stress at night, but not day, affects the central molecular clock. Chronobiol Int 31:996-1007|