Behavioral investigation of some possible effects of the central olivocochlear pathways in transgenic miceIntroductionMaterials and methodsSubjectsTesting apparatusBehavioral paradigmsThreshold calculationsAuditory brainstem responseResultsTone detection in quietTone detection in background noiseIntensity discriminationFrequency effectsThreshold stabilityThresholds for CBA/CaJ miceDiscussionHearing abnormalities in alpha9 knockout miceCentral efferent pathways for the processing of signals in noiseA re-interpretation of prior behavioral studies of OC functionAcknowledgementsReferencesBehavioral investigation of some possible e¡ects of the centralolivocochlear pathways in transgenic miceBradford J. Maya;, Cynthia A. Prosenb, Donna Weissb, Douglas VettercaDepartment of Otolaryngology-HNS, Johns Hopkins University, 505 Traylor Bldg., 720 Rutland Ave., Baltimore, MD 21205-2196, USAbDepartment of Psychology, Northern Michigan University, Marquette, MI, USAcDepartment of Neuroscience, Tufts University School of Medicine, Boston, MA, USAReceived 30 January 2002; accepted 7 May 2002AbstractThis study investigated the auditory behaviors of transgenic mice with deletions of K9 nicotinic acetylcholine receptor subunits.In the normal mammalian cochlea, the mechanical properties of outer hair cells are modified by the release of acetylcholine fromolivocochlear efferent terminals. Electrophysiological correlates of this efferent feedback have not been demonstrated in K9knockout mice, presumably because they are mediated by K9 receptors. Previous studies have associated lesions of olivocochlearpathways with hearing impairments in background noise. The prediction that K9 knockout mice would show similar deficits wastested by collecting psychophysical thresholds for tone detection and intensity discrimination from knockout mice, within-straincontrol subjects, and CBA/CaJ mice. Comparable performance was observed for the subject groups in quiet and in continuousbackground noise. The preservation of auditory function in K9 knockout mice suggests that central efferent pathways work incombination with the peripheral olivocochlear system to enhance hearing in noise, and may compensate for profoundmanipulations of peripheral feedback in highly routine testing procedures. An intriguing possibility is that these centralmechanisms include the brainstem collaterals of olivocochlear neurons since their post-synaptic targets do not express K9 receptorsand therefore are likely to maintain their effects in K9 knockout mice. 2 2002 Elsevier Science B.V. All rights reserved.Key words : Acetylcholine receptor knockout; Auditory psychophysics; Olivocochlear e¡erent feedback1. IntroductionE¡erent pathways linking the auditory brainstem tothe ear are a ubiquitous feature of mammalian anatomy(for a review, see Warr, 1992). Physiological studiessuggest that olivocochlear (OC) neurons hyperpolarizeouter hair cells by releasing acetylcholine (Blanchet etal., 1996; Evans, 1996) and thus modulate hearing sen-sitivity by altering the active mechanical properties ofthe cochlea (Housley and Ashmore, 1991; Dallos et al.,1997). The perceptual consequences of this gain controlmechanism have been explored by observing changes inbehavioral performance after OC projections are surgi-cally impaired. A common ¢nding is that lesioned ani-mals show de¢cits in their ability to process auditoryinformation in the presence of noise (Dewson, 1968;Trahoitis and Elliott, 1970; May and McQuone,1995; Heinz et al., 1998).The identi¢cation of a novel alpha 9 nicotinic acetyl-choline receptor subunit (K9 nAChR) in the mamma-lian cochlea (Elgoyhen et al., 1994) and the subsequentgenetic knockout of the subunit in a mouse model (Vet-ter et al., 1999) o¡er powerful new techniques for theevaluation of auditory e¡erent systems. These knockoutmice have intact OC pathways but are functionally ‘de-e¡erented’ because there are no K9 nAChRs to detectthe release of acetylcholine from cochlear e¡erent ter-minals.OC e¡erent neurons also send collateral projectionsto the granule cell layers of the cochlear nucleus in mice(Benson and Brown, 1990; Brown et al., 1991; Brown,0378-5955 / 02 / $ ^ see front matter 2 2002 Elsevier Science B.V. All rights reserved.PII: S0378-5955(02)00495-1* Corresponding author. Tel.: +1 (410) 955 3162;Fax: +1 (410) 955 1299.E-mail address: [email protected] (B.J. May).Abbreviations: K9 nAChR, alpha 9 nicotinic acetylcholine receptor;ABR, auditory brainstem response; CR10, critical ratio 10 dB rethreshold; vI, intensity change; OC, olivocochlearHEARES 3952 15-8-02Hearing Research 171 (2002) 142^157www.elsevier.com/locate/heares1993). These central projections are presumed to remainactive in K9 knockout mice because they involve cho-linergic receptors that do not include K9 nAChRs (El-goyhen et al., 1994). From this perspective, the K9knockout mouse is capable of providing unique insightsinto the largely unknown central in£uences of the OCpathways.This ¢rst behavioral study of K9 knockout mice eval-uated pure-tone detection and intensity discriminationthresholds. Based on a number of previous lesioningexperiments (e.g. Dewson, 1968; May and McQuone,1995), it was hypothesized that the disruption of periph-eral OC pathways would lead to performance de¢cits inthe presence of background noise. Instead, the behav-ioral thresholds of the knockout mice were comparableto those of within-strain control subjects and CBA/CaJmice. These results are interpreted as an indication thatcentral e¡erent pathways have the capacity to amelio-rate the e¡ects of background noise on auditory signalprocessing in the absence of peripheral e¡erent feed-back. The in£uence of these compensatory listeningstrategies may be augmented by the low-uncertaintycontext of highly routine psychophysical procedures.2. Materials and methodsThe behavioral procedures that were used to trainand test mice are described in detail by Prosen et al.(2000). Descriptions of the genetic manipulations thatwere used to create the K9 knockout mice can be foundin Vetter et al. (1999). Electrophysiological methods aretaken from Ngan and May (2001). All of the experi-mental procedures in this report were approved by theInstitutional Animal Care and Use Committees ofNorthern Michigan University (behavioral tests), JohnsHopkins University (physiological measures), and theSalk Institute (creation and con¢rmation of genetic ma-nipulations).2.1. SubjectsThe primary subject