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      Re-purposing PDE9 inhibitor as a cognitive enhancer for age-related hearing loss

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            Abstract

            Increasing evidence suggests that age-related hearing loss is the third leading cause of disability in older adults and the most relevant risk factor for cognitive decline. Older people often report difficulties in speech understanding particularly in complex listening environments which is commonly attributed to cochlear synaptopathy (loss of synapses between the hair cells and the auditory nerve fiber). This usually occurs due to accumulated damage by environmental or occupational noise to the cochlea. Nevertheless, age-related hearing loss frequently remains neglected and undiagnosed for years because of the slow progression of the disease, and clinically non-relevant audiometric screening for cochlear synaptopathy. Interestingly, when hearing loss occurs slowly over a long period, the brain may adapt to the reduced sensory input. This adaptation can take the form of auditory neural gain which compensates for a reduced auditory input in age-related cochlear synaptopathy. We previously described that middle-aged but not old animals can respond to this in two different ways: either with low or high capacity to compensate by amplifying their central neural responses. In the present study, we focused on identifying if it was possible to rescue the low compensators’ endophenotype by re-purposing a cyclic guanosine-monophosphate (cGMP) modulating drug – PDE9 inhibitor- as a cognitive enhancer for cochlear synaptopathy. We surprisingly found that the successful central auditory- and memory-dependent adjustment to cochlear synaptopathy is a cGMP- and glucocorticoid-dependent process supported by the dendritic spine remodeling.

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            Author and article information

            Conference
            RExPO24 Conference
            REPO4EU
            29 April 2024
            Affiliations
            [1 ] Department of Otolaryngology, Head and Neck Surgery, Tübingen Hearing Research Centre, Molecular Physiology of Hearing, University of Tübingen, Tübingen, Germany;
            [2 ] Department of Neuroscience, Tufts University School of Medicine, Sackler School of Biomedical Sciences, Boston, Massachusetts, USA;
            [3 ] Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany;
            Author notes
            Author information
            https://orcid.org/0009-0007-6331-0590
            Article
            10.58647/REXPO.24000041.v1
            e6d33f44-4f80-4588-ab1e-9e5ce1753bc8

            This work has been published open access under Creative Commons Attribution License CC BY 4.0 , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Conditions, terms of use and publishing policy can be found at www.scienceopen.com .

            RExPO24
            3
            Munich, Germany
            3-5 July 2024
            History
            : 29 April 2024
            Categories

            The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
            Neurosciences,Pharmacology & Pharmaceutical medicine,Life sciences
            auditory adaptation,drug re-purposing,cGMP,cochlear synaptopathy,hearing loss,Phosphodiesterase 9 inhibitor (PDE9i),dendritic spines

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