Cholinergic transmission is essential for survival and reproduction, as it is involved in several physiological responses. In the auditory system, both ascending and descending auditory pathways are modulated by cholinergic transmission, affecting the perception of sounds. The auditory efferent system is a neuronal network comprised of several feedback loops, including corticofugal and brainstem pathways to the cochlear receptor. The auditory efferent system's -final and mandatory synapses that connect the brain with the cochlear receptor- involve medial olivocochlear neurons and outer hair cells. A unique cholinergic transmission mediates these synapses through α9/α10 nicotinic receptors. To study this receptor, it was generated a strain of mice carrying a null mutation of the Chrna9 gene (α9-KO mice), lacking cholinergic transmission between medial olivocochlear neurons and outer hair cells, providing a unique opportunity to study the role of medial olivocochlear cholinergic transmission in auditory and cognitive functions. In this article, we review behavioral and physiological studies carried out to research auditory efferent function in the context of audition, cognition, and hearing impairments. Auditory studies have shown that hearing thresholds in the α9-KO mice are normal, while more complex auditory functions, such as frequency selectivity and sound localization, are altered. The corticofugal pathways have been studied in α9-KO mice using behavioral tasks, evidencing a reduced capacity to suppress auditory distractors during visual selective attention. Finally, we discuss the evolutionary role of the auditory efferent system detecting vocalizations in noise and its role in auditory disorders, such as the prevention of age-related hearing loss.

3rd Faculty of Medicine Charles University Prague Czechia

Centro Avanzado de Ingeniería Eléctrica y Electrónica AC3E Universidad Técnica Federico Santa María Valparaíso Chile

Department of Otolaryngology Head and Neck Surgery The Center for Hearing and Balance Johns Hopkins University School of Medicine Baltimore MD United States

Department of Otolaryngology Hospital Clínico de la Universidad de Chile Santiago Chile

Facultad de Medicina Biomedical Neuroscience Institute Universidad de Chile Santiago Chile

Facultad de Medicina Neuroscience Department Universidad de Chile Santiago Chile

Instituto de Ciencias de la Salud Universidad de O'Higgins Rancagua Chile

National Institute of Mental Health Klecany Czechia

Universidad de Valparaíso Valparaíso Chile

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Allen P. D., Luebke A. E. (2017). Reflex modification audiometry reveals dual roles for olivocochlear neurotransmission. Front. Cell. Neurosci. 11:361. 10.3389/fncel.2017.00361 PubMed DOI PMC

Boero L. E., Castagna V. C., Di Guilmi M. N., Goutman J. D., Elgoyhen A. B., Gómez- Casati M. E. (2018). Enhancement of the medial olivocochlear system prevents hidden hearing loss. J. Neurosci. 38 7440–7451. 10.1523/JNEUROSCI.0363-18.2018 PubMed DOI PMC

Boero L. E., Castagna V. C., Terreros G., Moglie M. J., Silva S., Maass J. C., et al. (2020). Preventing presbycusis in mice with enhanced medial olivocochlear feedback. Proc. Natl. Acad. Sci. U.S.A. 117 11811–11819. 10.1073/pnas.2000760117 PubMed DOI PMC

Boffi J. C., Wedemeyer C., Lipovsek M., Katz E., Calvo D. J., Elgoyhen A. B. (2013). Positive modulation of the α9α10 nicotinic cholinergic receptor by ascorbic acid. Br. J. Pharmacol. 168 954–965. 10.1111/j.1476-5381.2012.02221.x PubMed DOI PMC

Bowen M., Terreros G., Moreno-Gómez F. N., Ipinza M., Vicencio S., Robles L., et al. (2020). The olivocochlear reflex strength in awake chinchillas is relevant for behavioural performance during visual selective attention with auditory distractors. Sci. Rep. 10:14894. 10.1038/s41598-020-71399-8 PubMed DOI PMC

Chernyavsky A. I., Arredondo J., Vetter D. E., Grando S. A. (2007). Central role of α9 acetylcholine receptor in coordinating keratinocyte adhesion and motility at the initiation of epithelialization. Exp. Cell Res. 313 3542–3555. 10.1016/j.yexcr.2007.07.011 PubMed DOI PMC

Chikova A., Grando S. A. (2011). Naturally occurring variants of human α9 nicotinic receptor differentially affect bronchial cell proliferation and transformation. PLoS One 6:e27978. 10.1371/journal.pone.0027978 PubMed DOI PMC

Churchill J. A., Schuknecht H. F. (1959). The relationship of acetylcholinesterase in the cochlea to the olivocochlear bundle. Henry Ford Hosp. Med. Bull. 7 202–210. PubMed

Clause A., Kim G., Sonntag M., Weisz C. J., Vetter D. E., Rűbsamen R., et al. (2014). The precise temporal pattern of prehearing spontaneous activity is necessary for tonotopic map refinement. Neuron 82 822–835. 10.1016/j.neuron.2014.04.001 PubMed DOI PMC

Clause A., Lauer A. M., Kandler K. (2017). Mice lacking the alpha9 subunit of the nicotinic acetylcholine receptor exhibit deficits in frequency difference limens and sound localization. Front. Cell. Neurosci. 11:167. 10.3389/fncel.2017.00167 PubMed DOI PMC

Colomer C., Olivos-Oré L. A., Vincent A., McIntosh J. M., Artalejo A. R., Guérineau N. C. (2010). Functional characterization of α9-containing cholinergic nicotinic receptors in the rat adrenal medulla: implication in stress-induced functional plasticity. J. Neurosci. 30 6732–6742. 10.1523/JNEUROSCI.4997-09.2010 PubMed DOI PMC

Cox M. A., Bassi C., Saunders M. E., Nechanitzky R., Morgado-Palacin I., Zheng C., et al. (2020). Beyond neurotransmission: acetylcholine in immunity and inflammation. J. Intern. Med. 287 120–133. 10.1111/joim.13006 PubMed DOI

Delano P. H., Elgoyhen A. B. (2016). Editorial: auditory efferent system: new insights from cortex to cochlea. Front. Syst. Neurosci. 10:50. 10.3389/fnsys.2016.00050 PubMed DOI PMC

Delano P. H., Elgueda D., Hamame C. M., Robles L. (2007). Selective attention to visual stimuli reduces cochlear sensitivity in chinchillas. J. Neurosci. 27 4146–4153. 10.1523/JNEUROSCI.3702-06.2007 PubMed DOI PMC

Elgoyhen A. B., Johnson D. S., Boulter J., Vetter D. E., Heinemann S. (1994). Alpha-9: an acetylcholine receptor with novel pharmacological properties expressed in rat cochlear hair cells. Cell 79 705–715. 10.1016/0092-8674(94)90555-x PubMed DOI

Elgoyhen A. B., Katz E. (2012). The efferent medial olivocochlear-hair cell synapse. J. Physiol. 106 47–56. 10.1016/j.jphysparis.2011.06.001 PubMed DOI PMC

Elgoyhen A. B., Katz E., Fuchs P. A. (2009). The nicotinic receptor of cochlear hair cells: a possible pharmacotherapeutic target? Biochem. Pharmacol. 78 712–719. 10.1016/j.bcp.2009.05.023 PubMed DOI PMC

Elgoyhen A. B., Vetter D. E., Katz E., Rothlin C. V., Heinemann S. F., Boulter J. (2001). alpha10: a determinant of nicotinic cholinergic receptor function in mammalian vestibular and cochlear mechanosensory hair cells. Proc. Natl. Acad. Sci. U.S.A. 98 3501–3506. 10.1073/pnas.051622798 PubMed DOI PMC

Fritzsch B., Elliott K. L. (2017). Evolution and development of the inner ear efferent system: transforming a motor neuron population to connect to the most unusual motor protein via ancient nicotinic receptors. Front. Cell. Neurosci. 11:114. 10.3389/fncel.2017.00114 PubMed DOI PMC

Gould S. J. (1997). The exaptive excellence of spandrels as a term and prototype. Proc. Natl. Acad. Sci. U.S.A. 94 10750–10755. 10.1073/pnas.94.20.10750 PubMed DOI PMC

Hollenhorst M. I., Lips K. S., Weitz A., Krasteva G., Kummer W., Fronius M. (2012). Evidence for functional atypical nicotinic receptors that activate K+–dependent Cl− secretion in mouse tracheal epithelium. Am. J. Respir. Cell Mol. Biol. 46 106–114. 10.1165/rcmb.2011-0171OC PubMed DOI

Huang A., Noga B. R., Carr P. A., Fedirchuk B., Jordan L. M. (2000). Spinal cholinergic neurons activated during locomotion: localization and electrophysiological characterization. J. Neurophysiol. 83 3537–3547. 10.1152/jn.2000.83.6.3537 PubMed DOI

Hurst R., Rollema H., Bertrand D. (2013). Nicotinic acetylcholine receptors: from basic science to therapeutics. Pharmacol. Ther. 137 22–54. 10.1016/j.pharmthera.2012.08.012 PubMed DOI

Ishii M., Kurachi Y. (2006). Muscarinic acetylcholine receptors. Curr. Pharm. Des. 12 3573–3581. 10.2174/138161206778522056 PubMed DOI

Jiang W., St-Pierre S., Roy P., Morley B. J., Hao J., Simard A. R. (2016). Infiltration of CCR2+Ly6Chigh proinflammatory monocytes and neutrophils into the central nervous system is modulated by nicotinic acetylcholine receptors in a model of multiple sclerosis. J. Immunol. 196 2095–2108. 10.4049/jimmunol.1501613 PubMed DOI PMC

Jordan L. M., McVagh J. R., Noga B. R., Cabaj A. M., Majczyñski H., Sławiñska U., et al. (2014). Cholinergic mechanisms in spinal locomotion—potential target for rehabilitation approaches. Front. Neural Circ. 8:132. 10.3389/fncir.2014.00132 PubMed DOI PMC

Kang J. W., Choi H. S., Kim K., Choi J. Y. (2014). Dietary vitamin intake correlates with hearing thresholds in the older population: the Korean National Health and Nutrition Examination Survey. Am. J. Clin. Nutr. 99 1407–1413. 10.3945/ajcn.113.072793 PubMed DOI

Koval L., Lykhmus O., Zhmak M., Khruschov A., Tsetlin V., Magrini E., et al. (2011). Differential involvement of α4β2, α7 and α9α10 nicotinic acetylcholine receptors in B lymphocyte activation in vitro. Int. J. Biochem. Cell Biol. 43 516–524. 10.1016/j.biocel.2010.12.003 PubMed DOI

Kujawa S. G., Glattke T. J., Fallon M., Bobbin R. P. (1992). Intracochlear application of acetylcholine alters sound-induced mechanical events within the cochlear partition. Hear. Res. 61 106–116. 10.1016/0378-5955(92)90041-k PubMed DOI

Kujawa S. G., Glattke T. J., Fallon M., Bobbin R. P. (1994). A nicotinic-like receptor mediates suppression of distortion product otoacoustic emissions by contralateral sound. Hear. Res. 74 122–134. 10.1016/0378-5955(94)90181-3 PubMed DOI

Kujawa S. G., Liberman M. C. (2009). Adding insult to injury: cochlear nerve degeneration after “temporary” noise-induced hearing loss. J. Neurosci. 29 14077–14085. 10.1523/JNEUROSCI.2845-09.2009 PubMed DOI PMC

Lauer A. M., Jimenez S. V., Delano P. H. (2021). Olivocochlear efferent effects on perception and behavior. Hear. Res. 108207. 10.1016/j.heares.2021.108207 PubMed DOI PMC

Le T. N., Straatman L. V., Lea J., Westerberg B. (2017). Current insights in noise- induced hearing loss: a literature review of the underlying mechanism, pathophysiology, asymmetry, and management options. J. Otolaryngol. Head Neck Surg. 46:41. 10.1186/s40463-017-0219-x PubMed DOI PMC

Lee C.-H., Huang C.-S., Chen C.-S., Tu S.-H., Wang Y.-J., Chang Y.-J., et al. (2010). Overexpression and activation of the α9-nicotinic receptor during tumorigenesis in human breast epithelial cells. JNCI J. Natl. Cancer Inst. 102 1322–1335. 10.1093/jnci/djq300 PubMed DOI

Li M. D., Yang Z., Guo H., Dash B. (2016). “Evolutionary relationship of nicotinic acetylcholine receptor subunits in both vertebrate and invertebrate species,” in Nicotinic Acetylcholine Receptor Technologies Neuromethods, ed. Li M. D. (New York, NY: Springer; ), 227–254. 10.1007/978-1-4939-3768-4_12 DOI

Lips K. S., Pfeil U., Kummer W. (2002). Coexpression of α9 and α10 nicotinic acetylcholine receptors in rat dorsal root ganglion neurons. Neuroscience 115 1–5. 10.1016/S0306-4522(02)00274-9 PubMed DOI

Maison S. F., Liberman M. C. (2000). Predicting vulnerability to acoustic injury with a noninvasive assay of olivocochlear reflex strength. J. Neurosci. 20 4701–4707. 10.1523/JNEUROSCI.20-12-04701.2000 PubMed DOI PMC

Marcenaro B., Leiva A., Dragicevic C., López V., Delano P. H. (2021). The medial olivocochlear reflex strength is modulated during a visual working memory task. J. Neurophysiol. 125 2309–2321. 10.1152/jn.00032.2020 PubMed DOI

May B. J., Prosen C. A., Weiss D., Vetter D. (2002). Behavioral investigation of some possible effects of the central olivocochlear pathways in transgenic mice. Hear. Res. 171 142–157. 10.1016/s0378-5955(02)00495-1 PubMed DOI

Mikulski Z., Hartmann P., Jositsch G., Zasłona Z., Lips K. S., Pfeil U., et al. (2010). Nicotinic receptors on rat alveolar macrophages dampen ATP-induced increase in cytosolic calcium concentration. Respir. Res. 11:133. 10.1186/1465-9921-11-133 PubMed DOI PMC

Miles G. B., Hartley R., Todd A. J., Brownstone R. M. (2007). Spinal cholinergic interneurons regulate the excitability of motoneurons during locomotion. Proc. Natl. Acad. Sci. U.S.A. 104 2448–2453. PubMed PMC

Moss C. F., Schnitzler H.-U. (1995). “Behavioral studies of auditory information processing,” in Hearing by Bats Springer Handbook of Auditory Research, eds Popper A. N., Fay R. R. (New York, NY: Springer; ), 87–145. 10.1007/978-1-4612-2556-0_3 DOI

Oatman L. C., Ground A. P., May R. (1971). Role of visual attention on auditory cats evoked potentials in unanesthetized. Exp. Neurol. 356 341–356. PubMed

Panza F., Solfrizzi V., Logroscino G. (2015). Age-related hearing impairment-a risk factor and frailty marker for dementia and AD. Nat. Rev. Neurol. 11 166–175. 10.1038/nrneurol.2015.12 PubMed DOI

Parikh V., Bangasser D. A. (2020). “Cholinergic signaling dynamics and cognitive control of attention,” in Behavioral Pharmacology of the Cholinergic System Current Topics in Behavioral Neurosciences, eds Shoaib M., Wallace T. L. (Cham: Springer International Publishing; ), 71–87. PubMed PMC

Peng H., Ferris R. L., Matthews T., Hiel H., Lopez-Albaitero A., Lustig L. R. (2004). Characterization of the human nicotinic acetylcholine receptor subunit alpha (α) 9 (CHRNA9) and alpha (α) 10 (CHRNA10) in lymphocytes. Life Sci. 76 263–280. 10.1016/j.lfs.2004.05.031 PubMed DOI

Picciotto M. R., Higley M. J., Mineur Y. S. (2012). Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron 76 116–129. 10.1016/j.neuron.2012.08.036 PubMed DOI PMC

Plazas P. V., Katz E., Gomez-Casati M. E., Bouzat C., Elgoyhen A. B. (2005). Stoichiometry of the alpha9alpha10 nicotinic cholinergic receptor. J. Neurosci. 25 10905–10912. 10.1523/JNEUROSCI.3805-05.2005 PubMed DOI PMC

Prosen C. A., Bath K. G., Vetter D. E., May B. J. (2000). Behavioral assessments of auditory sensitivity in transgenic mice. J. Neurosci. Methods 97 59–67. 10.1016/S0165-0270(00)00169-2 PubMed DOI

Rothlin C. V., Katz E., Verbitsky M., Elgoyhen A. B. (1999). The alpha9 nicotinic acetylcholine receptor shares pharmacological properties with type A gamma-aminobutyric acid, glycine, and type 3 serotonin receptors. Mol. Pharmacol. 55 248–254. 10.1124/mol.55.2.248 PubMed DOI

Smith D. W., Keil A. (2015). The biological role of the medial olivocochlear efferents in hearing: separating evolved function from exaptation. Front. Syst. Neurosci. 9:12. 10.3389/fnsys.2015.00012 PubMed DOI PMC

Smith D. W., Kirk E. C., Buss E. (2005). “The function(s) of the medial olivocochlear efferent system in hearing,” in Auditory Signal Processing, eds Pressnitzer D., de Cheveigné A., McAdams S., Collet L. (New York, NY: Springer; ), 75–83. 10.1007/0-387-27045-0_10 DOI

Sourioux M., Bertrand S. S., Cazalets J.-R. (2018). Cholinergic-mediated coordination of rhythmic sympathetic and motor activities in the newborn rat spinal cord. PLoS Biol. 16:e2005460. 10.1371/journal.pbio.2005460 PubMed DOI PMC

St-Pierre S., Jiang W., Roy P., Champigny C., LeBlanc É, Morley B. J., et al. (2016). Nicotinic acetylcholine receptors modulate bone marrow-derived pro-inflammatory monocyte production and survival. PLoS One 11:e0150230. 10.1371/journal.pone.0150230 PubMed DOI PMC

Taranda J., Maison S. F., Ballestero J. A., Katz E., Savino J., Vetter D. E., et al. (2009). A point mutation in the hair cell nicotinic cholinergic receptor prolongs cochlear inhibition and enhances noise protection. PLoS Biol. 7:e1000018. 10.1371/journal.pbio.1000018 PubMed DOI PMC

Terreros G., Delano P. H. (2015). Corticofugal modulation of peripheral auditory responses. Front. Syst. Neurosci. 9:134. 10.3389/fnsys.2015.00134 PubMed DOI PMC

Terreros G., Jorratt P., Aedo C., Elgoyhen A. B., Delano P. H. (2016). Selective attention to visual stimuli using auditory distractors is altered in alpha-9 nicotinic receptor subunit knock-out mice. J. Neurosci. 36 7198–7209. 10.1523/JNEUROSCI.4031-15.2016 PubMed DOI PMC

Vetter D. E., Katz E., Maison S. F., Taranda J., Turcan S., Ballestero J., et al. (2007). The alpha10 nicotinic acetylcholine receptor subunit is required for normal synaptic function and integrity of the olivocochlear system. Proc. Natl. Acad. Sci. U.S.A. 104 20594–20599. 10.1073/pnas.0708545105 PubMed DOI PMC

Vetter D. E., Liberman M. C., Mann J., Barhanin J., Boulter J., Brown M. C., et al. (1999). Role of α9 nicotinic ACh receptor subunits in the development and function of cochlear efferent innervation. Neuron 23 93–103. 10.1016/S0896-6273(00)80756-4 PubMed DOI

Vicencio-Jimenez S., Bucci-Mansilla G., Bowen M., Terreros G., Morales-Zepeda D., Robles L., et al. (2021). The strength of the medial olivocochlear reflex in chinchillas is associated with delayed response performance in a visual discrimination task with vocalizations as distractors. Front. Neurosci. 15:759219. 10.3389/fnins.2021.759219 PubMed DOI PMC

Weisstaub N., Vetter D. E., Elgoyhen A. B., Katz E. (2002). The alpha9alpha10 nicotinic acetylcholine receptor is permeable to and is modulated by divalent cations. Hear. Res. 167 122–135. 10.1016/s0378-5955(02)00380-5 PubMed DOI

Zablotni A., Dakischew O., Trinkaus K., Hartmann S., Szalay G., Heiss C., et al. (2015). Regulation of acetylcholine receptors during differentiation of bone mesenchymal stem cells harvested from human reaming debris. Int. Immunopharmacol. 29 119–126. 10.1016/j.intimp.2015.07.021 PubMed DOI

Zagoraiou L., Akay T., Martin J. F., Brownstone R. M., Jessell T. M., Miles G. B. (2009). A cluster of cholinergic premotor interneurons modulates mouse locomotor activity. Neuron 64 645–662. 10.1016/j.neuron.2009.10.017 PubMed DOI PMC

Zorrilla De San Martín J., Ballestero J., Katz E., Elgoyhen A. B., Fuchs P. A. (2007). Ryanodine is a positive modulator of acetylcholine receptor gating in cochlear hair cells. JARO. J. Assoc. Res. Otolaryngol. 8 474–483. 10.1007/s10162-007-0090-y PubMed DOI PMC

Maintained Spatial Learning and Memory Functions in Middle-Aged α9 Nicotinic Receptor Subunit Knock-Out Mice