The Stress Response in the Non-sensory Cells of the Cochlea Under Pathological Conditions—Possible Role in Mediating Noise Vulnerability

Abstract

Various stressors, such as loud sounds and the effects of aging, impair the function and viability of the cochlear sensory cells, the hair cells. Stressors trigger pathophysiological changes in the cochlear non-sensory cells as well. We have here studied the stress response mounted in the lateral wall of the cochlea during acute noise stress and during age-related chronic stress. We have used the activation of JNK/c-Jun, ERK, and NF-κB pathways as a readout of the stress response, and the expression of the FoxO3 transcription factor as a possible additional player in cellular stress. In the aging cochlea, NF-κB transcriptional activity was strongly induced in the stria vascularis of the lateral wall. This induction was linked with the atrophy of the stria vascularis, suggesting a role for NF-κB signaling in mediating age-related strial degeneration. Acutely following noise exposure, the JNK/c-Jun, ERK, and NF-κB pathways were activated in the spiral ligament of the lateral wall of CBA/Ca mice. This activation was concomitant with the morphological transformation of macrophages, suggesting that the upregulation of stress signaling leads to macrophage activation. In contrast, C57BL/6J mice lacked these responses. Only the combination of noise exposure and a systemic stressor, lipopolysaccharide, exceeded the threshold for the activation of stress signaling in the lateral wall of C57BL/6J mice. In addition, we found that, at the young adult age, outer hair cells of CBA/Ca mice are much more vulnerable to loud sounds compared to these cells of C57BL/6J mice. These results suggest that the differential stress response in the lateral wall of the two mouse strains underlies, in part, the differential noise vulnerability of their outer hair cells. Together, we propose that the molecular stress response in the lateral wall modulates the outcome of the stressed cochlea.

Deficiency of the ER-stress-regulator MANF triggers progressive outer hair cell death and hearing loss

“…We dissected cochleas from heterozygote mice of the Manf KO line and perilymphatically perfused cochleas with 4% PFA, followed by immersion in the fixative at room temperature for 1.5 h. X-gal incubation was performed at +37°C for 15 h. Cochleas were thereafter postfixed, decalcified, and processed for whole mounts or paraffin sections as earlier described in Herranen et al 23 . In paraffin-embedding, deparaffination and dehydration of sections, the time in each alcohol step was kept to a minimum to avoid fading of X-gal staining.…”

RNA-seq analysis of gene expression profiles in isolated stria vascularis from wild-type and Alport mice reveals key pathways underling Alport strial pathogenesis

“…Only genes that were consistently up- or down-regulated in both independent experiments by at least two-fold are presented. We broke our analysis into four categories that the literature indicates likely reflect the underlying mechanisms of strial pathology (as described in the methods): cell morphology [[ 10 ]; Table 1 ], Injury [[ 1 ]; Table 2 ], hearing/hearing loss ( Table 3 ), and upstream regulators [[ 11 ]; Table 4 ]. It is notable that while the transcripts shown represent the significant differences identified from the 23000 mouse genes analyzed represent most of the genes modulated, they are not completely exhaustive.…”

“…For each sub-category the molecules that are significantly modulated and the degree of that modulation are listed by the software based on a two-fold cut-off for up-or down-regulation. Because this categorization has considerable redundancy, given that the program was written as for broad-spectrum analysis, we present general categories that the literature suggests reflect the underlying causes of strial pathology, which is not a category probed by the software because it is too specific [1,10,11]. This is the data presented in Tables 1-4.…”

Persistent Hearing Loss among World Trade Center Health Registry Residents, Passersby and Area Workers, 2006–2007

“…The role of exposure to traumatic events such as 9/11 and their prolonged impact on physical and mental health outcomes is the subject of increasing focus by investigators [28,29,30,31]. The literature on potential mechanisms underlying associations between stress, psychological distress and hearing problems in humans is extremely limited [32,33,34]; there is also a need for more research in animal models examining the role of acute physical and psychological trauma and chronic stress on potential adverse effects on the cochlea and auditory cortex in order to identify mechanisms potentially amendable to intervention [35,36]. Finally, studies are needed to determine if administration of proven psychological and pharmacological post-trauma interventions and other stress management strategies might also serve to reduce adverse auditory system effects following future disasters [37,38].…”