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Loss of central mineralocorticoid or glucocorticoid receptors impacts auditory nerve processing in the cochlea.

ABSTRACT: The key auditory signature that may associate peripheral hearing with central auditory cognitive defects remains elusive. Suggesting the involvement of stress receptors, we here deleted the mineralocorticoid and glucocorticoid receptors (MR and GR) using a CaMKIIα-based tamoxifen-inducible Cre^ERT2/loxP approach to generate mice with single or double deletion of central but not cochlear MR and GR. Hearing thresholds of MRGR^{CaMKIIαCreERT2} conditional knockouts (cKO) were unchanged, whereas auditory nerve fiber (ANF) responses were larger and faster and auditory steady state responses were improved. Subsequent analysis of single MR or GR cKO revealed discrete roles for both, central MR and GR on cochlear functions. Limbic MR deletion reduced inner hair cell (IHC) ribbon numbers and ANF responses. In contrast, GR deletion shortened the latency and improved the synchronization to amplitude-modulated tones without affecting IHC ribbon numbers. These findings imply that stress hormone-dependent functions of central MR/GR contribute to "precognitive" sound processing in the cochlea.

SUBMITTER: Marchetta P

PROVIDER: S-EPMC8914323 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Loss of central mineralocorticoid or glucocorticoid receptors impacts auditory nerve processing in the cochlea.

Marchetta Philine P Eckert Philipp P Lukowski Robert R Ruth Peter P Singer Wibke W Rüttiger Lukas L Knipper Marlies M

iScience 20220226 3

The key auditory signature that may associate peripheral hearing with central auditory cognitive defects remains elusive. Suggesting the involvement of stress receptors, we here deleted the mineralocorticoid and glucocorticoid receptors (MR and GR) using a CaMKIIα-based tamoxifen-inducible CreERT2/loxP approach to generate mice with single or double deletion of central but not cochlear MR and GR. Hearing thresholds of MRGRCaMKIIαCreERT2 conditional knoc ...[more]

PMID: 35281733

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Project description:Key pointsSound information is transmitted by different subtypes of spiral ganglion neurons (SGN) from the ear to the brain. Selective damage of SGN peripheral synapses (cochlear synaptopathy) is widely recognized as one of the primary mechanisms of hearing loss, whereas the mechanisms at the SGN central synapses remain unclear. We report that different subtypes of SGN central synapses converge at different ratios onto individual target cochlear nucleus neurons with distinct physiological properties, and show biased morphological and physiological changes during age-related hearing loss (ARHL). The results reveal a new dimension in cochlear nucleus neural circuitry that systematically reassembles and processes auditory information from different SGN subtypes, which is altered during ageing and probably contributes to the development of ARHL. In addition to known cochlear synaptopathy, the present study shows that SGN central synapses are also pathologically changed during ageing, which collectively helps us better understand the structure and function of SGNs during ARHL.AbstractSound information is transmitted from the cochlea to the brain by different subtypes of spiral ganglion neurons (SGN), which show varying degrees of vulnerability under pathological conditions. Selective cochlear synaptopathy, the preferential damage of certain subtypes of SGN peripheral synapses, has been recognized as one of the main mechanisms of hearing loss. The organization and function of the auditory nerve (AN) central synapses from different subtypes of SGNs remain unclear, including how different AN synapses reassemble onto individual neurons in the cochlear nucleus, as well as how they differentially change during hearing loss. Combining immunohistochemistry with electrophysiology, we investigated the convergence pattern and subtype-specific synaptopathy of AN synapses at the endbulb of Held, as well as the response properties of their postsynaptic bushy neurons in CBA/CaJ mice of either sex under normal hearing and age-related hearing loss (ARHL). We found that calretinin-expressing (type Ia ) and non-calretinin-expressing (type Ib /Ic ) endbulbs converged along a continuum of different ratios onto individual bushy neurons with varying physiological properties. Endbulbs degenerated during ageing in parallel with ARHL. Furthermore, the degeneration was more severe in non-calretinin-expressing synapses, which correlated with a gradual decrease in bushy neuron subpopulation predominantly innervated by these inputs. These synaptic and cellular changes were profound in middle-aged mice when their hearing thresholds were still relatively normal and prior to severe ARHL. Our findings suggest that biased AN central synaptopathy and the correlated shift in cochlear nucleus neuronal composition play significant roles in weakened auditory input and altered central auditory processing during ARHL.

Dataset Information

Loss of central mineralocorticoid or glucocorticoid receptors impacts auditory nerve processing in the cochlea.

Publications

Loss of central mineralocorticoid or glucocorticoid receptors impacts auditory nerve processing in the cochlea.

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