A point mutation in the hair cell nicotinic cholinergic receptor prolongs cochlear inhibition and enhances noise protection

The transduction of sound in the auditory periphery, the cochlea, is inhibited by efferent cholinergic neurons projecting from the brainstem and synapsing directly on mechanosensory hair cells. One fundamental question in auditory neuroscience is what role(s) this feedback plays in our ability to hear. In the present study, we have engineered a genetically modified mouse model in which the magnitude and duration of efferent cholinergic effects are increased, and we assess the consequences of this manipulation on cochlear function. We generated the Chrna9L9′T of knockin mice with a threonine for leucine change (L9′T) at position 9′ of the second transmembrane domain of the α9 nicotinic cholinergic subunit, rendering α9-containing receptors that were hypersensitive to acetylcholine and had slower desensitization kinetics. The Chrna9L9′T allele produced a 3-fold prolongation of efferent synaptic currents in vitro. In vivo, Chrna9L9′T mice had baseline elevation of cochlear thresholds and efferent-mediated inhibition of cochlear responses was dramatically enhanced and lengthened: both effects were reversed by strychnine blockade of the α9α10 hair cell nicotinic receptor. Importantly, relative to their wild-type littermates, Chrna9L9′T/L9′T mice showed less permanent hearing loss following exposure to intense noise. Thus, a point mutation designed to alter α9α10 receptor gating has provided an animal model in which not only is efferent inhibition more powerful, but also one in which sound-induced hearing loss can be restrained, indicating the ability of efferent feedback to ameliorate sound trauma.Fil: Taranda, Julian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Tufts University School of Medicine; Estados UnidosFil: Maison, Stéphane F.. Massachusetts Eye and Ear Infirmary; Estados UnidosFil: Ballestero, Jimena Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Katz, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Savino, Jessica. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Vetter, Douglas E.. Tufts University School of Medicine; Estados UnidosFil: Boulter, Jim. University of California at Los Angeles; Estados UnidosFil: Liberman, M. Charles. Massachusetts Eye and Ear Infirmary; Estados UnidosFil: Fuchs, Paul A.. The Johns Hopkins University School of Medicine; Estados UnidosFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentin

Elder Orphans Hiding in Plain Sight: A Growing Vulnerable Population

Adults are increasingly aging alone with multiple chronic diseases and are geographically distant from family or friends. It is challenging for clinicians to identify these individuals, often struggling with managing the growing difficulties and the complexities involved in delivering care to this population. Clinicians often may not recognize or know how to address the needs that these patients have in managing their own health. While many such patients function well at baseline, the slightest insult can initiate a cascade of avoidable negative events. We have resurrected the term elder orphan to describe individuals living alone with little to no support system. Using public data sets, including the US Census and University of Michigan’s Health and Retirement Study, we estimated the prevalence of adults 65 years and older to be around 22%. Thus, in this paper, we strive to describe and quantify this growing vulnerable population and offer practical approaches to identify and develop care plans that are consistent with each person’s goals of care. The complex medical and psychosocial issues for elder orphans significantly impact the individual person, communities, and health-care expenditures. We hope to encourage professionals across disciplines to work cooperatively to screen elders and implement policies to prevent elder orphans from hiding in plain sight