Glucose homeostasis depends on insulin responsiveness in target tissues, most importantly, muscle and liver. The critical initial steps in insulin action include phosphorylation of scaffolding proteins and activation of phosphatidylinositol 3-kinase. These early events lead to activation of the serine-threonine protein kinase Akt, also known as protein kinase B. We show that mice deficient in Akt2 are impaired in the ability of insulin to lower blood glucose because of defects in the action of the hormone on liver and skeletal muscle. These data establish Akt2 as an essential gene in the maintenance of normal glucose homeostasis.

https://science.sciencemag.org/content/sci/292/5522/1728.full.pdf

Insulin Resistance and a Diabetes Mellitus-Like Syndrome in Mice Lacking the Protein Kinase Akt2 (PKBβ)

In mammals, environmental sounds stimulate the auditory receptor, the cochlea, via vibrations of the stapes, the innermost of the middle ear ossicles. These vibrations produce displacement waves that travel on the elongated and spirally wound basilar membrane (BM). As they travel, waves grow in amplitude, reaching a maximum and then dying out. The location of maximum BM motion is a function of stimulus frequency, with high-frequency waves being localized to the “base” of the cochlea (near the stapes) and low-frequency waves approaching the “apex” of the cochlea. Thus each cochlear site has a characteristic frequency (CF), to which it responds maximally. BM vibrations produce motion of hair cell stereocilia, which gates stereociliar transduction channels leading to the generation of hair cell receptor potentials and the excitation of afferent auditory nerve fibers. At the base of the cochlea, BM motion exhibits a CF-specific and level-dependent compressive nonlinearity such that responses to low-level, near-CF stimuli are sensitive and sharply frequency-tuned and responses to intense stimuli are insensitive and poorly tuned. The high sensitivity and sharp-frequency tuning, as well as compression and other nonlinearities (two-tone suppression and intermodulation distortion), are highly labile, indicating the presence in normal cochleae of a positive feedback from the organ of Corti, the “cochlear amplifier.” This mechanism involves forces generated by the outer hair cells and controlled, directly or indirectly, by their transduction currents. At the apex of the cochlea, nonlinearities appear to be less prominent than at the base, perhaps implying that the cochlear amplifier plays a lesser role in determining apical mechanical responses to sound. Whether at the base or the apex, the properties of BM vibration adequately account for most frequency-specific properties of the responses to sound of auditory nerve fibers.

/pdf/mechanics-of-the-mammalian-cochlea-368l279klj.pdf

Mechanics of the Mammalian Cochlea

Phantom auditory perception (tinnitus): mechanisms of generation and perception

The National Academy of Sciences founded The National Academies Press (NAP) with the goal of publishing reports of all four national academies. Annually, NAP publishes more than 200 books from the fields of science, engineering and medicine and offers more than 4000 titles in PDF on its website (http://www.nap.edu/) free of charge.

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The National Academies Press

The simplest cell-like structure, the lipid bilayer vesicle, can respond to mechanical deformation by elastic membrane dilation/thinning and curvature changes. When a protein is inserted in the lip...

Molecular basis of mechanotransduction in living cells

The anatomic consequences of acoustic overstimulation are explored in this presentation, and attention is directed toward issues where improvements in technology and empirical observation are needed before further advances in our understanding can be achieved. Gains have been made in the last decade in appreciating sound‐induced cochlear injury, but there is now a need to evaluate not only cochlear pathology but also the functional state of the surviving structures. There is a wealth of information about the susceptibility of inner or outer hair cells to acoustic injury; however, the etiology of this injury is not yet fully understood. In addition, current ideas concerning the effects of noise on hair‐cell stereocilia, hair‐cell synapses, the cochlear vascular supply, and the central auditory pathways are in a state of flux and are either undergoing revision or emerging. Other issues, such as the basis of temporary or permanent threshold shift at the cellular level, and the individual differences in susceptibility to injury are in need of a fresh approach. It would seem that the time is now ripe to review our knowledge, recognize its gaps, and develop testable hypotheses concerning the mechanisms of acoustic injury to the ear.

The anatomical consequences of acoustic injury: A review and tutorial.

Targeted mutagenesis in mice demonstrates that the POU-domain gene Brn4/Pou3f4 plays a crucial role in the patterning of the mesenchymal compartment of the inner ear. Brn4 is expressed extensively throughout the condensing mesenchyme of the developing inner ear. Mutant animals displayed behavioral anomalies that resulted from functional deficits in both the auditory and vestibular systems, including vertical head bobbing, changes in gait, and hearing loss. Anatomical analyses of the temporal bone, which is derived in part from the otic mesenchyme, demonstrated several dysplastic features in the mutant animals, including enlargement of the internal auditory meatus. Many phenotypic features of the mutant animals resulted from the reduction or thinning of the bony compartment of the inner ear. Histological analyses demonstrated a hypoplasia of those regions of the cochlea derived from otic mesenchyme, including the spiral limbus, the scala tympani, and strial fibrocytes. Interestingly, we observed a reduction in the coiling of the cochlea, which suggests that Brn-4 plays a role in the epithelial–mesenchymal communication necessary for the cochlear anlage to develop correctly. Finally, the stapes demonstrated several malformations, including changes in the size and morphology of its footplate. Because the stapes anlage does not express the Brn4 gene, stapes malformations suggest that the Brn4 gene also plays a role in mesenchymal–mesenchymal signaling. On the basis of these data, we suggest that Brn-4 enhances the survival of mesodermal cells during the mesenchymal remodeling that forms the mature bony labyrinth and regulates inductive signaling mechanisms in the otic mesenchyme.

https://www.jneurosci.org/content/jneuro/19/14/5980.full.pdf

Targeted mutagenesis of the POU-domain gene Brn4/Pou3f4 causes developmental defects in the inner ear.

Avoidance conditioning and the method of limits were used to measure absolute auditory thresholds, masked thresholds, and critical ratios in 4 parakeets. The same procedure was then used to study frequency difference limens in 6 additional animals. The power spectrum and "constancy of intonation" of the parakeet call were also measured and related to the absolute and differential frequency sensitivity. The mechanism of frequency analysis in the parakeet ear was considered in relation to the present results and to the anatomical and functional differences between the avian and mammalian auditory systems.

Hearing in the parakeet (Melopsittacus undulatus): absolute thresholds, critical ratios, frequency difference limens, and vocalizations.

This presentation considers important developments and new trends related to acoustic injury in the peripheral auditory system reported during the past 5 years. The discussion begins with the effect overstimulation has on the ‘‘active’’ cochlear process, and the associated loss in receptive field (tuning curve) selectivity. Exposure to intense sound also changes the structure and function of the tectorial membrane, sensory hair bundles, tip links, and intracellular organelles. All of these injuries may change the way in which energy is delivered to the transduction channels of the hair cell. Important new evidence describing the quantitative relation between hair cell loss and permanent hearing loss is reviewed, and the possibility that specific exposure conditions cause unique lesions to the inner or outer hair cells is explored. Finally, the importance of hair cell regeneration in the chick cochlea, changes in the CNS following acoustic injury, and the cochlear vascular system are considered.

James C. Saunders

Papers

The anatomical consequences of acoustic injury: A review and tutorial.

Targeted mutagenesis of the POU-domain gene Brn4/Pou3f4 causes developmental defects in the inner ear.

Hearing in the parakeet (Melopsittacus undulatus): absolute thresholds, critical ratios, frequency difference limens, and vocalizations.

The structural and functional consequences of acoustic injury in the cochlea and peripheral auditory system: a five year update.

Middle-ear development V: Development of umbo sensitivity in the gerbil