The sensory epithelium of the inner ear consists of a mosaic pattern of hair cells separated from one another by supporting cells. The Notch signalling pathway is thought to establish this pattern through a process of lateral inhibition, and has recently been shown to have an early role in inducing sensory patch formation. Several Notch ligands are expressed in the developing sensory patch, but their respective functions in relation to the two roles of Notch signalling are not clear. This thesis examines the role of two of these Notch ligands, Deltal and Jaggedl, in the development of the inner ear using conditional knockout mice. The effect of loss of these ligands upon hair cell production is strikingly different. In the absence of Jaggedl, the total number of hair cells in the cochlea is strongly reduced (although the number of inner hair cells is roughly doubled). This supports the idea that Jaggedl is required for the early inductive function of Notch in specifying the sensory patches early in development. Jaggedl conditional knockout mice also exhibit a loss of several of the vestibular sensory patches, with the cristae being most severely affected. Expression of the CDK inhibitor p27Kip1 is lost in the mutant cochlea excess proliferation may thus explain the overproduction of inner hair cells. In the absence of Deltal, auditory hair cells are produced early and in excess, in agreement with the lateral inhibition hypothesis, but, surprisingly, supporting cells are also overproduced. Deltal conditional knockout mice also exhibit defects in the vestibular patches. The cristae appear normal, while the maculae are lost or reduced. These findings confirm that Notch signalling has two distinct functions in the inner ear, for which different ligands are primarily responsible.

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The experiments described in this thesis aimed to investigate auditory learning; and examine the neural correlates of this learning In normal-hearing human participants. Furthermore; the hypothesis that the descending auditory pathway Is Involved in both localisation and auditory learning was explored, using ferrets as an experimental model.

The cochlea plays an important role in human hearing. Its basic function is to map sounds of different frequencies onto corresponding characteristic positions on the basilar membrane, BM. When sounds enter the fluid-filled cochlea, deflections of the BM occur due to pressure differences between the cochlear fluid chambers. These deflections propagate along the cochlea to a frequency-dependent characteristic position and then decay away rapidly. The mechanics of the cochlea are modelled using both analytic and numerical models. In this thesis, the passive response of the cochlea is analysed, corresponding to its behaviour at high sound levels, to study the fluid coupling and waves in the cochlea. The fluid coupling is studied in 1D and 3D, uniform and non-uniform, uncoiled and coiled geometries, all with a passive basilar membrane. A ‘uniaxial model’, which is dependent on only a single dimension, is developed to represent the three-dimensional cochlea. The finite element method is also used to provide an independent check of the results from the analytic model. Analytic methods are used to predict waves due to different mechanisms in the passive cochlea, such as 1D and 3D fluid coupling and longitudinal BM dynamics. The wave finite element, WFE, method is then used to decompose the results of a full finite element model of the coupled cochlea into wave components. Results show that apart from the conventional slow wave, other additional types of wave in the passive cochlea do not appear to play a dominant role in normal passive cochlear function.

L'audiométrie tonale liminaire est l'outil de référence pour évaluer le fonctionnement auditif, mais c'est un outil subjectif qui mesure des élévations de seuils témoignant de dégâts irréversibles sur le système auditif. La mesure des produits de distorsions acoustiques (PDAs), reflet du fonctionnement cochléaire, permet de dépister précocement des altérations de l'oreille interne causées par le bruit ou certains solvants ototoxiques. A partir d'un paradigme de mesure basé sur un enregistrement continu du PDA cubique (2f1-f2) et une stimulation controlatérale, nous avons pu expliquer, chez le rat, les effets pharmacologiques du toluène. Ce solvant aromatique agirait en particulier sur les centres nerveux impliqués dans le réflexe de protection acoustique de l'oreille moyenne. Devant les résultats obtenus chez l'animal, un prototype d'appareil adapté à l'homme a été mis au point, baptisé EchoScan. L'EchoScan a été testé sur 50 volontaires sains normo-entendant lors d'un premier protocole de recherche clinique pour vérifier la reproductibilité des mesures. Un second protocole a ensuite été conduit pour tester l'outil chez des salariés en entreprise, selon plusieurs conditions d'exposition : témoins non exposés, salariés exposés au bruit, exposés aux solvants, exposés au bruit et aux solvants. Les résultats des deux premières conditions sont présentés dans ce mémoire. Ils confirment la pertinence de la mesure du seuil du réflexe de l'oreille moyenne pour évaluer les effets de l'exposition au bruit. Les résultats des sujets exposés aux solvants évalueront la sensibilité de l'EchoScan dans la détection, voir la caractérisation des effets pharmacologiques de substances chimiques (inclusions en cours). Si l'avenir de l'EchoScan apparaît prometteur en médecine du travail, d'autres applications sont envisagées, comme l'étude des effets pharmacologiques des anesthésiques sur le réflexe de l'oreille moyenne / The pure-tone audiometry is a reference tool to assess auditory function but it is able to measure only threshold elevations showing irreversible damages. Measurement of distortion products oto-acoustic emissions (DPOAEs), reflecting the cochlear function, allows early detection of alterations in the inner ear caused by noise or some ototoxic solvents. From paradigm based on a continuous record of cubic DPOAEs (2f1-f2) and a contralateral stimulation triggering the middle-ear reflex, we could explain, in rats, the pharmacological effects of toluene. This aromatic solvent can act on the centers involved in the middle-ear acoustic protection reflex. With the results obtained in animals, a device adapted to humans has been developed, called EchoScan. The EchoScan was tested on 50 healthy volunteers with normal hearing in a first clinical research protocol to verify in particular the reproducibility of its measurements. A second research protocol was then conducted to test this tool among company employees, according to several exposure conditions: unexposed controls, workers exposed to noise, exposed to solvents, exposed to noise and solvents. The results of the first two conditions are presented in this thesis. They confirm the relevance of the measurement of the middle ear reflex threshold in assessing the effects of noise exposure. The results of subjects exposed to solvents will further evaluate the sensitivity of EchoScan in detection of the pharmacological effects, and even in the characterization of chemical substances exposure (in progress). In the future, EchoScan should be particularly promising in occupational medicine, but other applications are already considered, such as the study of pharmacological effects of anesthetics on the middle ear reflex