title: TrkB-mediated protection against circadian sensitivity to noise trauma in the murine cochlea.
abstract: Noise-induced hearing loss (NIHL) is a debilitating sensory impairment affecting 10%-15% of the population, caused primarily through damage to the sensory hair cells or to the auditory neurons. Once lost, these never regenerate [1], and no effective drugs are available [2, 3]. Emerging evidence points toward an important contribution of synaptic ribbons in the long-term coupling of the inner hair cell and afferent neuron synapse to maintain hearing [4]. Here we show in nocturnal mice that night noise overexposure triggers permanent hearing loss, whereas mice overexposed during the day recover to normal auditory thresholds. In view of this time-dependent sensitivity, we identified a self-sustained circadian rhythm in the isolated cochlea, as evidenced by circadian expression of clock genes and ample PERIOD2::LUCIFERASE oscillations, originating mainly from the primary auditory neurons and hair cells. The transcripts of the otoprotecting brain-derived neurotrophic factor (BDNF) showed higher levels in response to day noise versus night noise, suggesting that BDNF-mediated signaling regulates noise sensitivity throughout the day. Administration of a selective BDNF receptor, tropomyosin-related kinase type B (TrkB), in the night protected the inner hair cell's synaptic ribbons and subsequent full recovery of hearing thresholds after night noise overexposure. The TrkB agonist shifted the phase and boosted the amplitude of circadian rhythms in the isolated cochlea. These findings highlight the coupling of circadian rhythmicity and the TrkB receptor for the successful prevention and treatment of NIHL.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Inna
authors.initials: I
authors.lastname: Meltser
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Cederroth
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Basinou
authors.affiliation: Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Sergey
authors.initials: S
authors.lastname: Savelyev
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden; Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Gabriella S
authors.initials: GS
authors.lastname: Lundkvist
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden. Electronic address: barbara.canlon@ki.se.
authors.forename: Barbara
authors.initials: B
authors.lastname: Canlon
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology; D002940:Circadian Rhythm / Q000502:physiology*; D003051:Cochlea / Q000187:drug effects / Q000502:physiology*; D044950:Flavanones / Q000494:pharmacology; D006198:Hair Cells, Auditory / Q000502:physiology; D006309:Hearing / Q000502:physiology; D006317:Hearing Loss, Noise-Induced / Q000503:physiopathology; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D009622:Noise / Q000009:adverse effects*; D011494:Protein Kinases / Q000502:physiology*; D020813:Receptor, trkB / Q000502:physiology
chemical_list: C478869:7,8-dihydroxyflavanone; D019208:Brain-Derived Neurotrophic Factor; D044950:Flavanones; D011494:Protein Kinases; D020813:Receptor, trkB