23 results found
Gianoli F, Hogan B, Dilly E, et al., 2022, Fast adaptation of cooperative channels engenders Hopf bifurcations in auditory hair cells, Biophysical Journal, Vol: 121, Pages: 897-909, ISSN: 0006-3495
Since the pioneering work of Thomas Gold, published in 1948, it has been known that we owe our sensitive sense of hearing to a process in the inner ear that can amplify incident sounds on a cycle-by-cycle basis. Called the active process, it uses energy to counteract the viscous dissipation associated with sound-evoked vibrations of the ear’s mechanotransduction apparatus. Despite its importance, the mechanism of the active process and the proximate source of energy that powers it have remained elusive, especially at the high frequencies characteristic of amniote hearing. This is partly due to our insufficient understanding of the mechanotransduction process in hair cells, the sensory receptors and amplifiers of the inner ear. It has been proposed previously that cyclical binding of Ca2+ ions to individual mechanotransduction channels could power the active process. That model, however, relied on tailored reaction rates that structurally forced the direction of the cycle. Here we ground our study on our previous model of hair-cell mechanotransduction, which relied on cooperative gating of pairs of channels, and incorporate into it the cyclical binding of Ca2+ ions. With a single binding site per channel and reaction rates drawn from thermodynamic principles, the current model shows that hair cells behave as nonlinear oscillators that exhibit Hopf bifurcations, dynamical instabilities long understood to be signatures of the active process. Using realistic parameter values, we find bifurcations at frequencies in the kilohertz range with physiological Ca2+ concentrations. The current model relies on the electrochemical gradient of Ca2+ as the only energy source for the active process and on the relative motion of cooperative channels within the stereociliary membrane as the sole mechanical driver. Equipped with these two mechanisms, a hair bundle proves capable of operating at frequencies in the kilohertz range, characteristic of amniote hearing.
Sirko P, Kozlov AS, 2022, Immunohistochemistry localises myosin-7a to cochlear efferent boutons, Wellcome Open Research, Vol: 7, Pages: 1-1
<ns4:p><ns4:bold>Background: </ns4:bold>Myosin 7a is an actin-binding motor protein involved in the formation of hair-cell stereocilia both in the cochlea and in the vestibular system. Mutations in myosin 7a are linked to congenital hearing loss and are present in 50% of Type-1 Usher syndrome patients who suffer from progressive hearing loss and vestibular system dysfunction.</ns4:p><ns4:p> <ns4:bold>Methods: </ns4:bold>Myosin 7a is often used to visualise sensory hair cells due to its well characterised and localised expression profile. We thus conducted myosin-7a immunostaining across all three turns of the adult rat organ of Corti to visualise hair cells.</ns4:p><ns4:p> <ns4:bold>Results: </ns4:bold>As expected, we observed myosin 7a staining in both inner and outer hair cells. Unexpectedly, we also observed strong myosin 7a staining in the medial olivocochlear efferent synaptic boutons contacting the outer hair cells. Efferent bouton myosin-7a staining was present across all three turns of the cochlea. We verified this localisation by co-staining with a known efferent bouton marker, the vesicular acetylcholine transporter.</ns4:p><ns4:p> <ns4:bold>Conclusions: </ns4:bold>In addition to its role in stereocilia formation and maintenance, myosin 7a or certain myosin-7a expression variants might play a role in efferent synaptic transmission in the cochlea and thus ultimately influence cochlear gain regulation. Our immunohistochemistry results should be validated with other methods to confirm these serendipitous findings.</ns4:p>
Sirko P, Kozlov AS, 2022, Immunohistochemistry localises myosin-7a to cochlear efferent boutons., Wellcome Open Res, Vol: 7, ISSN: 2398-502X
Background: Myosin 7a is an actin-binding motor protein involved in the formation of hair-cell stereocilia both in the cochlea and in the vestibular system. Mutations in myosin 7a are linked to congenital hearing loss and are present in 50% of Type-1 Usher syndrome patients who suffer from progressive hearing loss and vestibular system dysfunction. Methods: Myosin 7a is often used to visualise sensory hair cells due to its well characterised and localised expression profile. We thus conducted myosin-7a immunostaining across all three turns of the adult rat organ of Corti to visualise hair cells. Results: As expected, we observed myosin 7a staining in both inner and outer hair cells. Unexpectedly, we also observed strong myosin 7a staining in the medial olivocochlear efferent synaptic boutons contacting the outer hair cells. Efferent bouton myosin-7a staining was present across all three turns of the cochlea. We verified this localisation by co-staining with a known efferent bouton marker, the vesicular acetylcholine transporter. Conclusions: In addition to its role in stereocilia formation and maintenance, myosin 7a or certain myosin-7a expression variants might play a role in efferent synaptic transmission in the cochlea and thus ultimately influence cochlear gain regulation. Our immunohistochemistry results should be validated with other methods to confirm these serendipitous findings.
Abeytunge S, Gianoli F, Hudspeth AJ, et al., 2021, Rapid mechanical stimulation of inner-ear hair cells by photonic pressure, eLife, Vol: 10, Pages: 1-27, ISSN: 2050-084X
Hair cells, the receptors of the inner ear, detect sounds by transducing mechanical vibrations into electrical signals. From the top surface of each hair cell protrudes a mechanical antenna, the hair bundle, which the cell uses to detect and amplify auditory stimuli, thus sharpening frequency selectivity and providing a broad dynamic range. Current methods for mechanically stimulating hair bundles are too slow to encompass the frequency range of mammalian hearing and are plagued by inconsistencies. To overcome these challenges, we have developed a method to move individual hair bundles with photonic force. This technique uses an optical fiber whose tip is tapered to a diameter of a few micrometers and endowed with a ball lens to minimize divergence of the light beam. Here we describe the fabrication, characterization, and application of this optical system and demonstrate the rapid application of photonic force to vestibular and cochlear hair cells.
Gianoli F, Risler T, Kozlov AS, 2020, The Development of Cooperative Channels Explains the Maturation of Hair Cell'S Mechanotransduction, 64th Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 453A-454A, ISSN: 0006-3495
Gianoli F, Risler T, Kozlov AS, 2019, The development of cooperative channels explains the maturation of hair cell’s mechanotransduction, Biophysical Journal, Vol: 117, Pages: 1536-1548, ISSN: 0006-3495
Hearing relies on the conversion of mechanical stimuli into electrical signals. In vertebrates, this process of mechano-electrical transduction (MET) is performed by specialized receptors of the inner ear, the hair cells. Each hair cell is crowned by a hair bundle, a cluster of microvilli that pivot in response to sound vibrations, causing the opening and closing of mechanosensitive ion channels. Mechanical forces are projected onto the channels by molecular springs called tip links. Each tip link is thought to connect to a small number of MET channels that gate cooperatively and operate as a single transduction unit. Pushing the hair bundle in the excitatory direction opens the channels, after which they rapidly reclose in a process called fast adaptation. It has been experimentally observed that the hair cell’s biophysical properties mature gradually during postnatal development: the maximal transduction current increases, sensitivity sharpens, transduction occurs at smaller hair-bundle displacements, and adaptation becomes faster. Similar observations have been reported during tip-link regeneration after acoustic damage. Moreover, when measured at intermediate developmental stages, the kinetics of fast adaptation varies in a given cell depending on the magnitude of the imposed displacement. The mechanisms underlying these seemingly disparate observations have so far remained elusive. Here, we show that these phenomena can all be explained by the progressive addition of MET channels of constant properties, which populate the hair bundle first as isolated entities, then progressively as clusters of more sensitive, cooperative MET channels. As the proposed mechanism relies on the difference in biophysical properties between isolated and clustered channels, this work highlights the importance of cooperative interactions between mechanosensitive ion channels for hearing.
Gianoli F, Risler T, Kozlov AS, 2017, Lipid bilayer mediates ion-channel cooperativity in a model of hair-cell mechanotransduction, Proceedings of the National Academy of Sciences, Vol: 114, Pages: E11010-E11019, ISSN: 0027-8424
Mechanoelectrical transduction in the inner ear is a biophysical process underlying the senses of hearing and balance. The key players involved in this process are mechanosensitive ion channels. They are located in the stereocilia of hair cells and opened by the tension in specialized molecular springs, the tip links, connecting adjacent stereocilia. When channels open, the tip links relax, reducing the hair-bundle stiffness. This gating compliance makes hair cells especially sensitive to small stimuli. The classical explanation for the gating compliance is that the conformational rearrangement of a single channel directly shortens the tip link. However, to reconcile theoretical models based on this mechanism with experimental data, an unrealistically large structural change of the channel is required. Experimental evidence indicates that each tip link is a dimeric molecule, associated on average with two channels at its lower end. It also indicates that the lipid bilayer modulates channel gating, although it is not clear how. Here, we design and analyze a model of mechanotransduction where each tip link attaches to two channels, mobile within the membrane. Their states and positions are coupled by membrane-mediated elastic forces arising from the interaction between the channels' hydrophobic cores and that of the lipid bilayer. This coupling induces cooperative opening and closing of the channels. The model reproduces the main properties of hair-cell mechanotransduction using only realistic parameters constrained by experimental evidence. This work provides an insight into the fundamental role that membrane-mediated ion-channel cooperativity can play in sensory physiology.
Albert JT, Kozlov A, 2016, Comparative aspects of hearing in vertebrates and insects with antennal ears, Current Biology, Vol: 26, Pages: R1020-R1061, ISSN: 1879-0445
The evolution of hearing in terrestrial animals has resulted inremarkable adaptationsenabling exquisitelysensitive sound detection by the ear and sophisticated sound analysis by the brain. In this review, weexamineseveral such characteristics, using examples from insects and vertebrates.We focus on two strong and interdependentforces that have been shaping the auditory systems across taxa: the physical environment of auditory transducerson the small, subcellular, scale and the evolutionary environment within which hearing takes place, on a larger, sensory-ecological scale. We discuss briefly acoustical feature selectivity and invariance in the central auditory system, highlighting a major difference between insects and vertebrates, as well as a major similarity. By doing so within a sensory ecological framework,we aim to emphasize general principles underlying acute sensitivity to airborne sounds.
Kozlov A, Gentner T, 2016, Central auditory neurons have composite receptive fields, Proceedings of the National Academy of Sciences of the United States of America, Vol: 113, Pages: 1441-1446, ISSN: 0027-8424
High-level neurons processing complex, behaviorally relevant signals are sensitive to conjunctions of features. Characterizing the receptive fields of such neurons is difficult with standard statistical tools, however, and the principles governing their organization remain poorly understood. Here, we demonstrate multiple distinct receptive-field features in individual high-level auditory neurons in a songbird, European starling, in response to natural vocal signals (songs). We then show that receptive fields with similar characteristics can be reproduced by an unsupervised neural network trained to represent starling songs with a single learning rule that enforces sparseness and divisive normalization. We conclude that central auditory neurons have composite receptive fields that can arise through a combination of sparseness and normalization in neural circuits. Our results, along with descriptions of random, discontinuous receptive fields in the central olfactory neurons in mammals and insects, suggest general principles of neural computation across sensory systems and animal classes.
Kozlov AS, Gentner TQ, 2014, Central auditory neurons display flexible feature recombination functions, Journal of Neurophysiology, Vol: 111, Pages: 1183-1189, ISSN: 0022-3077
Recognition of natural stimuli requires a combination of selectivity and invariance. Classical neurobiological models achieve selectivity and invariance, respectively, by assigning to each cortical neuron either a computation equivalent to the logical “AND” or a computation equivalent to the logical “OR.” One powerful OR-like operation is the MAX function, which computes the maximum over input activities. The MAX function is frequently employed in computer vision to achieve invariance and considered a key operation in visual cortex. Here we explore the computations for selectivity and invariance in the auditory system of a songbird, using natural stimuli. We ask two related questions: does the MAX operation exist in auditory system? Is it implemented by specialized “MAX” neurons, as assumed in vision? By analyzing responses of individual neurons to combinations of stimuli we systematically sample the space of implemented feature recombination functions. Although we frequently observe the MAX function, we show that the same neurons that implement it also readily implement other operations, including the AND-like response. We then show that sensory adaptation, a ubiquitous property of neural circuits, causes transitions between these operations in individual neurons, violating the fixed neuron-to-computation mapping posited in the state-of-the-art object-recognition models. These transitions, however, accord with predictions of neural-circuit models incorporating divisive normalization and variable polynomial nonlinearities at the spike threshold. Because these biophysical properties are not tied to a particular sensory modality but are generic, the flexible neuron-to-computation mapping demonstrated in this study in the auditory system is likely a general property.
Kozlov AS, Andor-Ardo D, Hudspeth AJ, 2012, Anomalous Brownian motion discloses viscoelasticity in the ear's mechanoelectrical-transduction apparatus, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 109, Pages: 2896-2901, ISSN: 0027-8424
Kozlov AS, Risler T, Hinterwirth AJ, et al., 2012, Relative stereociliary motion in a hair bundle opposes amplification at distortion frequencies, JOURNAL OF PHYSIOLOGY-LONDON, Vol: 590, Pages: 301-308, ISSN: 0022-3751
Kozlov AS, Baumgart J, Risler T, et al., 2011, Forces between clustered stereocilia minimize friction in the ear on a subnanometre scale, NATURE, Vol: 474, Pages: 376-379, ISSN: 0028-0836
Miranda-Rottmann S, Kozlov AS, Hudspeth AJ, 2010, Highly Specific Alternative Splicing of Transcripts Encoding BK Channels in the Chicken's Cochlea Is a Minor Determinant of the Tonotopic Gradient, Molecular and Cellular Biology, Vol: 30, Pages: 3646-3660, ISSN: 0270-7306
Chiappe ME, Kozlov AS, Hudspeth AJ, 2007, The structural and functional differentiation of hair cells in a lizard's Basilar papilla suggests an operational principle of amniote cochleas, JOURNAL OF NEUROSCIENCE, Vol: 27, Pages: 11978-11985, ISSN: 0270-6474
Kozlov AS, Risler T, Hudspeth AJ, 2007, Coherent motion of stereocilia assures the concerted gating of hair-cell transduction channels, NATURE NEUROSCIENCE, Vol: 10, Pages: 87-92, ISSN: 1097-6256
Kozlov AS, Angulo MC, Audinat E, et al., 2006, Target cell-specific modulation of neuronal activity by astrocytes., Proc Natl Acad Sci U S A, Vol: 103, Pages: 10058-10063, ISSN: 0027-8424
Interaction between astrocytes and neurons enriches the behavior of brain circuits. By releasing glutamate and ATP, astrocytes can directly excite neurons and modulate synaptic transmission. In the rat olfactory bulb, we demonstrate that the release of GABA by astrocytes causes long-lasting and synchronous inhibition of mitral and granule cells. In addition, astrocytes release glutamate, leading to a selective activation of granule-cell NMDA receptors. Thus, by releasing excitatory and inhibitory neurotransmitters, astrocytes exert a complex modulatory control on the olfactory network.
Angulo MC, Kozlov AS, Charpak S, et al., 2004, Glutamate Released from Glial Cells Synchronizes Neuronal Activity in the Hippocampus, Journal of Neuroscience, Vol: 24, Pages: 6920-6927, ISSN: 0270-6474
Kozlov AS, McKenna F, Lee JH, et al., 1999, Distinct kinetics of cloned T-type Ca2 + channels lead to differential Ca2 + entry and frequency-dependence during mock action potentials., Eur J Neurosci, Vol: 11, Pages: 4149-4158, ISSN: 0953-816X
Voltage-dependent activity around the resting potential is determinant in neuronal physiology and participates in the definition of the firing pattern. Low-voltage-activated T-type Ca2 + channels directly affect the membrane potential and control a number of secondary Ca2 + -dependent permeabilities. We have studied the ability of the cloned T-type channels (alpha1G,H,I) to carry Ca2 + currents in response to mock action potentials. The relationship between the spike duration and the current amplitude is specific for each of the T-type channels, reflecting their individual kinetic properties. Typically the charge transfer increases with spike broadening, but the total Ca2 + entry saturates at different spike durations according to the channel type: 4 ms for alpha1G; 7 ms for alpha1H; and > 10 ms for alpha1I channels. During bursts, currents are inhibited and/or transiently potentiated according to the alpha1 channel type, with larger effects at higher frequency. The inhibition may be induced by voltage-independent transitions toward inactivated states and/or channel inactivation through intermediate closed states. The potentiation is explained by an acceleration in the channel activation kinetics. Relatively fast inactivation and slow recovery limit the ability of alpha1G and alpha1H channels to respond to high frequency stimulation ( > 20 Hz). In contrast, the slow inactivation of alpha1I subunits allows these channels to continue participating in high frequency bursts (100 Hz). The biophysical properties of alpha1G, H and I channels will therefore dramatically modulate the effect of neuronal activities on Ca2 + signalling.
Lu S, Steadman M, Ang GWY, et al., Composite receptive fields in the mouse auditory cortex
<jats:title>A<jats:sc>bstract</jats:sc></jats:title><jats:p>A central question in sensory neuroscience is how neurons represent complex natural stimuli. This process involves multiple steps of feature extraction to obtain a condensed, categorical representation useful for classification and behavior. It has previously been shown that central auditory neurons in the starling have composite receptive fields composed of multiple features when probed with conspecific songs. Whether this property is an idiosyncratic characteristic of songbirds, a group of highly specialized vocal learners, or a generic characteristic of central auditory systems in different animals is, however, unknown. To address this question, we have recorded responses from auditory cortical neurons in mice, and characterized their receptive fields using mouse ultrasonic vocalizations (USVs) as a natural and ethologically relevant stimulus and pitch-shifted starling songs as a natural but ethologically irrelevant control stimulus. We have found that auditory cortical neurons in the mouse display composite receptive fields with multiple excitatory and inhibitory subunits. Moreover, this was the case with either the conspecific or the heterospecific vocalizations. We then trained the sparse filtering algorithm on both classes of natural stimuli to obtain statistically optimal features, and compared the natural and artificial features using UMAP, a dimensionality-reduction algorithm previously used to analyze mouse USVs and birdsongs. We have found that the receptive-field features obtained with the mouse USVs and those obtained with the pitch-shifted starling songs clustered together, as did the sparse-filtering features. However, the natural and artificial receptive-field features clustered mostly separately. These results indicate that composite receptive fields are likely a generic property of central auditory systems in different classes of animals. They further suggest
Gianoli F, Hogan B, Dilly É, et al., Fast adaptation of cooperative channels engenders Hopf bifurcations in auditory hair cells
<jats:title>ABSTRACT</jats:title><jats:p>Since the pioneering work of Thomas Gold published in 1948, it has been known that we owe our sensitive sense of hearing to a process in the inner ear that can amplify incident sounds on a cycle-by-cycle basis. Termed the active process, it uses energy to counteract the viscous dissipation associated with sound-evoked vibrations of the ear’s mechanotransduction apparatus. Despite its importance, the mechanism of the active process and the proximate source of energy that powers it have remained elusive—especially at the high frequencies characteristic of mammalian hearing. This is partly due to our insufficient understanding of the mechanotransduction process in hair cells, the sensory receptors and amplifiers of the inner ear. It has previously been proposed that a cyclical binding of Ca<jats:sup>2+</jats:sup> ions to individual mechanotransduction channels could power the active process. That model, however, relied on tailored reaction rates that structurally forced the direction of the cycle. Here, we ground our study on our previous model of hair-cell mechanotransduction, which relied on the cooperative gating of pairs of channels, and incorporate into it the cyclical binding of Ca<jats:sup>2+</jats:sup> ions. With a single binding site per channel and reaction rates drawn from thermodynamic principles, our model shows that hair cells behave as nonlinear oscillators that exhibit Hopf bifurcations, dynamical instabilities long understood to be signatures of the active process. Using realistic parameter values, we find bifurcations at frequencies in the kilohertz range with physiological Ca<jats:sup>2+</jats:sup> concentrations. In contrast to the myosin-based mechanism, responsible for low-frequency relaxation oscillations in the vestibular hair cells of amphibians, the current model relies on the electrochemical gradient of Ca<jats:sup>2+</jats:sup&
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