The Cochlear CRF Signaling Systems and their Mechanisms of Action in Modulating Cochlear Sensitivity and Protection Against Trauma

Graham, Christine; Basappa, Johnvesly; Turcan, Şevin; Vetter, Douglas E.

doi:10.1007/s12035-011-8203-3

Cited by 19 publications

(10 citation statements)

References 165 publications

(208 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Knockout of CRF‐R1 causes increased auditory thresholds and abnormal development of synaptic morphology in hair cells of naïve mice (Graham et al . ). The importance of CRF‐R1 for normal auditory development is corroborated by a strong transient expression of the CRF‐R1 ligand UCN1 just around hearing onset (Kaiser et al .…”

Section: Discussionmentioning

confidence: 97%

See 1 more Smart Citation

Urocortin 3 signalling in the auditory brainstem aids recovery of hearing after reversible noise‐induced threshold shift

Fischl

Ueberfuhr

Drexl³

et al. 2019

The Journal of Physiology

View full text Add to dashboard Cite

Key points Ongoing, moderate noise exposure does not instantly damage the auditory system but may cause lasting deficits, such as elevated thresholds and accelerated ageing of the auditory system.The neuromodulatory peptide urocortin‐3 (UCN3) is involved in the body's recovery from a stress response, and is also expressed in the cochlea and the auditory brainstem.Lack of UCN3 facilitates age‐induced hearing loss and causes permanently elevated auditory thresholds following a single 2 h noise exposure at moderate intensities.Outer hair cell function in mice lacking UCN3 is unaffected, so that the observed auditory deficits are most likely due to inner hair cell function or central mechanisms.Highly specific, rather than ubiquitous, expression of UCN3 in the brain renders it a promising candidate for designing drugs to ameliorate stress‐related auditory deficits, including recovery from acoustic trauma. AbstractEnvironmental acoustic noise is omnipresent in our modern society, with sound levels that are considered non‐damaging still causing long‐lasting or permanent changes in the auditory system. The small neuromodulatory peptide urocortin‐3 (UCN3) is the endogenous ligand for corticotropin‐releasing factor receptor type 2 and together they are known to play an important role in stress recovery. UCN3 expression has been observed in the auditory brainstem, but its role remains unclear. Here we describe the detailed distribution of UCN3 expression in the murine auditory brainstem and provide evidence that UCN3 is expressed in the synaptic region of inner hair cells in the cochlea. We also show that mice with deficient UCN3 signalling experience premature ageing of the auditory system starting at an age of 4.7 months with significantly elevated thresholds of auditory brainstem responses (ABRs) compared to age‐matched wild‐type mice. Following a single, 2 h exposure to moderate (84 or 94 dB SPL) noise, UCN3‐deficient mice exhibited significantly larger shifts in ABR thresholds combined with maladaptive recovery. In wild‐type mice, the same noise exposure did not cause lasting changes to auditory thresholds. The presence of UCN3‐expressing neurons throughout the auditory brainstem and the predisposition to hearing loss caused by preventing its normal expression suggests UCN3 as an important neuromodulatory peptide in the auditory system's response to loud sounds.

show abstract

Section: Discussionmentioning

confidence: 97%

“…Graham et al . () demonstrated that naïve CRF‐R2 knockout mice were more sensitive to sound, but paid for this gain in function with a higher susceptibility to acoustic trauma. However, to date it is unknown if the neuromodulatory peptide UCN3 is present in the cochlea.…”

Section: Introductionmentioning

confidence: 99%

Urocortin 3 signalling in the auditory brainstem aids recovery of hearing after reversible noise‐induced threshold shift

Fischl

Ueberfuhr

Drexl³

et al. 2019

The Journal of Physiology

View full text Add to dashboard Cite

show abstract

“…Classic HPA signaling involves CRF release from the hypothalamus. As previously described at greater length (Graham et al, 2011), CRF binds to CRFR1 expressed by pituitary corticotropes and stimulates cleavage of POMC to produce ACTH, which then travels via blood circulation to the adrenal cortex where it binds melanocortin 2 receptor (MC2R, also known as the ACTH receptor), inducing production and release of glucocorticoids. Therefore, immunofluorescence was used to ascertain whether and where POMC, ACTH, and MC2R expression occurs in the cochlea (Graham and Vetter, 2011).…”

Section: The Cochlea Expresses An Hpa-equivalent Signaling Systemmentioning

confidence: 92%

“…Mississippi Medical Center (to DEV). The reader is advised that some figures and portions of text have appeared in previous publications of the authors (Basappa et al, 2010; Graham et al, 2010; Graham et al, 2011; Graham and Vetter, 2011), and are reproduced in this invited review with permission.…”

Section: Acknowledgementsmentioning

confidence: 99%

The cochlea as an independent neuroendocrine organ: Expression and possible roles of a local hypothalamic–pituitary–adrenal axis-equivalent signaling system

et al. 2012

Self Cite

View full text Add to dashboard Cite

A key property possessed by the mammalian cochlea is its ability to dynamically alter its own sensitivity. Because hair cells and ganglion cells are prone to damage following exposure to loud sound, extant mechanisms limiting cochlear damage include modulation involving both the mechanical (via outer hair cell motility) and neural signaling (via inner hair cell-ganglion cell synapses) steps of peripheral auditory processing. Feedback systems such as that embodied by the olivocochlear system can alter sensitivity, but respond only after stimulus encoding, allowing potentially damaging sounds to impact the inner ear before sensitivity is adjusted. Less well characterized are potential cellular signaling systems involved in protection against metabolic stress and resultant damage. Although pharmacological manipulation of the olivocochlear system may hold some promise for attenuating cochlear damage, targeting this system may still allow damage to occur that does not depend on a fully functional feedback loop for its mitigation. Thus, understanding endogenous cell signaling systems involved in cochlear protection may lead to new strategies and therapies for prevention of cochlear damage and consequent hearing loss. We have recently discovered a novel cochlear signaling system that is molecularly equivalent to the classic hypothalamic-pituitary-adrenal (HPA) axis. This cochlear HPA-equivalent system functions to balance auditory sensitivity and susceptibility to noise-induced hearing loss, and also protects against cellular metabolic insults resulting from exposures to ototoxic drugs. This system may represent a local cellular response system designed to mitigate damage arising from various types of insult.

show abstract

“…This system (Fig. 1) includes local expression of all the major stress-response signaling molecules (POMC, ACTH, MC2R (the ACTH receptor), CRFR1, and CRFR2) commonly associated with HPA axis-mediated systemic signaling [96, 97]. Most cells within the organ of Corti, the region directly around the hair cells, express CRF, the primary endogenous ligand for the CRF receptors.…”

Section: A Novel Theory Concerning Protective Mechanisms Against Nihlmentioning

confidence: 99%

Cellular signaling protective against noise-induced hearing loss – A role for novel intrinsic cochlear signaling involving corticotropin-releasing factor?

Vetter

2015

Biochemical Pharmacology

Self Cite

View full text Add to dashboard Cite

Hearing loss afflicts approximately 15% of the world's population, and crosses all socioeconomic boundaries. While great strides have been made in understanding the genetic components of syndromic and non-syndromic hearing loss, understanding of the mechanisms underlying noise-induced hearing loss (NIHL) have come much more slowly. NIHL is not simply a mechanism by which older individuals loose their hearing. Significantly, the incidence of NIHL is increasing, and is now involving ever younger populations. This may predict future increased occurrences of hearing loss. Current research has shown that even short-term exposures to loud sounds generating what was previously considered temporary hearing loss, actually produces an almost immediate and permanent loss of specific populations of auditory nerve fibers. Additionally, recurrent exposures to intense sound may hasten age-related hearing loss. While NIHL is a significant medical concern, to date, few compounds have delivered significant protection, arguing that new targets need to be identified. In this commentary, we will explore cellular signaling processes taking place in the cochlea believed to be involved in protection against hearing loss, and highlight new data suggestive of novel signaling not previously recognized as occurring in the cochlea, that is perhaps protective of hearing. This includes a recently described local hypothalamic-pituitary-adrenal axis (HPA)-like signaling system fully contained in the cochlea. This system may represent a local cellular stress-response system based on stress hormone release similar to the systemic HPA axis. Its discovery may hold hope for new drug therapies that can be delivered directly to the cochlea, circumventing systemic side effects.

show abstract

The Cochlear CRF Signaling Systems and their Mechanisms of Action in Modulating Cochlear Sensitivity and Protection Against Trauma

Cited by 19 publications

References 165 publications

Urocortin 3 signalling in the auditory brainstem aids recovery of hearing after reversible noise‐induced threshold shift

Urocortin 3 signalling in the auditory brainstem aids recovery of hearing after reversible noise‐induced threshold shift

The cochlea as an independent neuroendocrine organ: Expression and possible roles of a local hypothalamic–pituitary–adrenal axis-equivalent signaling system

Cellular signaling protective against noise-induced hearing loss – A role for novel intrinsic cochlear signaling involving corticotropin-releasing factor?

Contact Info

Product

Resources

About