The functional role of the lateral olivocochlear system and mechanisms underlying sound condtioning

Sammanfattning: Sound conditioning is a process induced by a low-level, non-damaging acoustic stimulus that provides protection against subsequent detrimental forms of acoustic trauma. Many hypotheses have been advanced to explain the effect of sound conditioning, but the mechanisms underlying this phenomenon are still not yet known. There is increasing evidence for endogenous protective systems, which, if enhanced, can provide protection against subsequent damage. The overall objective of this thesis was to study the functional role of the lateral olivocochlear (LOC) system and the mechanisms underlying the phenomenon of sound conditioning. Sound conditioning is effective in protecting against hair cell loss and thereby preserving hearing sensitivity. In this thesis, it was found that acoustic trauma caused the release of cytochrome c from the mitochondria into the cytoplasm and induced the programmed cell death in the outer hair cells. Sound conditioning was found to trigger a protection against these detrimental changes by upregulating the bcl-2 level in the outer hair cells. A role of bcl-2 as an inducible gene underlying protection against acoustic trauma by sound conditioning is demonstrated. Sound conditioning is also effective in protecting against a temporary hearing loss induced by acoustic trauma. The protection by a short-term sound conditioning was found when delivered either before, or after a traumatic exposure. Trauma-induced threshold shifts between 20-25 dB were prevented by a forward or backward sound conditioning paradigm at 1 kHz. Since pretreatment with 6hydroxydopamine blocked the protective effect of sound conditioning by destroying tyrosine hydroxylase (TH) in the cochlea, a role of the lateral efferent system was suggested. TH positive nerve fibers were found only under the inner hair cells and originated from the neurons located in the LOC system. An increase of the TH immunoreactivity both in the fibers and neurons of the LOC system was found after sound conditioning. The elevation of TH is one protective mechanism offered by sound conditioning. Dopamine, a neurotransmitter released from lateral efferents is involved in the modulation of the auditory nerve activity. The D1 receptor and its signal transduction pathway in the cochlea were characterized. The D1 receptor was found in the spiral ganglia neurons and their afferent dendrites under the inner hair cells. A D1 agonist enhanced the amplitude of cochlear compound action potential (CAP) and increased the level of GluR1 phosphorylation at the PKA site (Ser845). These effects were abolished by a protein kinase A (PKA) inhibitor. Conversely, a D1 antagonist inhibited the CAP amplitude and decreased the level of GluR1 phosphorylation, while a PKA activator prevented theses effects. These findings demonstrated a positive effect of the D1 receptor on the auditory nerve activity through the PKA-dependent the GluR1 phosphorylation. In conclusion, the LOC system, via the TH, contributes as an endogenous protective mechanism underlying sound conditioning.Sound conditioning is a process induced by a low-level, non-damaging acoustic stimulus that provides protection against subsequent detrimental forms of acoustic trauma. Many hypotheses have been advanced to explain the effect of sound conditioning, but the mechanisms underlying this phenomenon are still not yet known. There is increasing evidence for endogenous protective systems, which, if enhanced, can provide protection against subsequent damage. The overall objective of this thesis was to study the functional role of the lateral olivocochlear (LOC) system and the mechanisms underlying the phenomenon of sound conditioning. Sound conditioning is effective in protecting against hair cell loss and thereby preserving hearing sensitivity. In this thesis, it was found that acoustic trauma caused the release of cytochrome c from the mitochondria into the cytoplasm and induced the programmed cell death in the outer hair cells. Sound conditioning was found to trigger a protection against these detrimental changes by upregulating the bcl-2 level in the outer hair cells. A role of bcl-2 as an inducible gene underlying protection against acoustic trauma by sound conditioning is demonstrated. Sound conditioning is also effective in protecting against a temporary hearing loss induced by acoustic trauma. The protection by a short-term sound conditioning was found when delivered either before, or after a traumatic exposure. Trauma-induced threshold shifts between 20-25 dB were prevented by a forward or backward sound conditioning paradigm at 1 kHz. Since pretreatment with 6hydroxydopamine blocked the protective effect of sound conditioning by destroying tyrosine hydroxylase (TH) in the cochlea, a role of the lateral efferent system was suggested. TH positive nerve fibers were found only under the inner hair cells and originated from the neurons located in the LOC system. An increase of the TH immunoreactivity both in the fibers and neurons of the LOC system was found after sound conditioning. The elevation of TH is one protective mechanism offered by sound conditioning. Dopamine, a neurotransmitter released from lateral efferents is involved in the modulation of the auditory nerve activity. The D1 receptor and its signal transduction pathway in the cochlea were characterized. The D1 receptor was found in the spiral ganglia neurons and their afferent dendrites under the inner hair cells. A D1 agonist enhanced the amplitude of cochlear compound action potential (CAP) and increased the level of GluR1 phosphorylation at the PKA site (Ser845). These effects were abolished by a protein kinase A (PKA) inhibitor. Conversely, a D1 antagonist inhibited the CAP amplitude and decreased the level of GluR1 phosphorylation, while a PKA activator prevented theses effects. These findings demonstrated a positive effect of the D1 receptor on the auditory nerve activity through the PKA-dependent the GluR1 phosphorylation. In conclusion, the LOC system, via the TH, contributes as an endogenous protective mechanism underlying sound conditioning.