Daibhid O Maoileidigh

All Publications

• A Bundle of Mechanisms: Inner-Ear Hair-Cell Mechanotransduction. Trends in neurosciences O Maoileidigh, D., Ricci, A. J. 2019

  Abstract

  In the inner ear, the deflection of hair bundles, the sensory organelles of hair cells, activates mechanically-gated channels (MGCs). Hair bundles monitor orientation of the head, its angular and linear acceleration, and detect sound. Force applied to MGCs is shaped by intrinsic hair-bundle properties, by the mechanical load on the bundle, and by the filter imparted by the environment of the hair bundle. Channel gating and adaptation, the ability of the bundle to reset its operating point, contribute to hair-bundle mechanics. Recent data from mammalian hair cells challenge longstanding hypotheses regarding adaptation mechanisms and hair-bundle coherence. Variations between hair bundles from different organs in hair-bundle mechanics, mechanical load, channel gating, and adaptation may allow a hair bundle to selectively respond to specific sensory stimuli.

  View details for DOI 10.1016/j.tins.2018.12.006

  View details for PubMedID 30661717

• Signal detection by active, noisy hair bundles 13th Mechanics of Hearing Workshop Ó Maoiléidigh, D., Salvi, J. D., Hudspeth, A. J. : 060002
• Homeostatic enhancement of active mechanotransduction 13th Mechanics of Hearing Workshop Milewski, A., Ó Maoiléidigh, D., Hudspeth, A. J. : 120007
• Multiple mechanisms for stochastic resonance are inherent to sinusoidally driven noisy Hopf oscillators. Physical Review E O Maoileidigh, D. 2018; 97: 022226

  Abstract

  To ensure their sensitivity to weak periodic signals, some physical systems likely operate near a Hopf bifurcation. Many systems operating near such a bifurcation exhibit stochastic resonance, but it is unclear which mechanisms for resonance are inherent to the bifurcation. To address this question, we study the sinusoidally forced dynamics of noisy supercritical and subcritical Hopf oscillators. We find four qualitatively different mechanisms for stochastic resonance and determine the conditions for each type of resonance.

  View details for DOI 10.1103/PhysRevE.97.022226

• Sinusoidal-signal detection by active, noisy oscillators on the brink of self-oscillation Physica D Ó Maoiléidigh, D., Hudspeth, A. J. 2018; 378-379: 33-45
• Homeostatic enhancement of sensory transduction. Proceedings of the National Academy of Sciences of the United States of America Milewski, A. R., Ó Maoiléidigh, D., Salvi, J. D., Hudspeth, A. J. 2017; 114 (33): E6794?E6803

  Abstract

  Our sense of hearing boasts exquisite sensitivity, precise frequency discrimination, and a broad dynamic range. Experiments and modeling imply, however, that the auditory system achieves this performance for only a narrow range of parameter values. Small changes in these values could compromise hair cells' ability to detect stimuli. We propose that, rather than exerting tight control over parameters, the auditory system uses a homeostatic mechanism that increases the robustness of its operation to variation in parameter values. To slowly adjust the response to sinusoidal stimulation, the homeostatic mechanism feeds back a rectified version of the hair bundle's displacement to its adaptation process. When homeostasis is enforced, the range of parameter values for which the sensitivity, tuning sharpness, and dynamic range exceed specified thresholds can increase by more than an order of magnitude. Signatures in the hair cell's behavior provide a means to determine through experiment whether such a mechanism operates in the auditory system. Robustness of function through homeostasis may be ensured in any system through mechanisms similar to those that we describe here.

  View details for DOI 10.1073/pnas.1706242114

  View details for PubMedID 28760949

• Mechanical Transduction Processes in the Hair Cell Understanding the Cochlea David, C. P., Ó Maoiléidigh, D., Ashmore, J. F. Springer International Publishing. 2017: 75?111
• Identification of Bifurcations from Observations of Noisy Biological Oscillators. Biophysical journal Salvi, J. D., Ó Maoiléidigh, D., Hudspeth, A. J. 2016; 111 (4): 798-812

  Abstract

  Hair bundles are biological oscillators that actively transduce mechanical stimuli into electrical signals in the auditory, vestibular, and lateral-line systems of vertebrates. A bundle's function can be explained in part by its operation near a particular type of bifurcation, a qualitative change in behavior. By operating near different varieties of bifurcation, the bundle responds best to disparate classes of stimuli. We show how to determine the identity of and proximity to distinct bifurcations despite the presence of substantial environmental noise. Using an improved mechanical-load clamp to coerce a hair bundle to traverse different bifurcations, we find that a bundle operates within at least two functional regimes. When coupled to a high-stiffness load, a bundle functions near a supercritical Hopf bifurcation, in which case it responds best to sinusoidal stimuli such as those detected by an auditory organ. When the load stiffness is low, a bundle instead resides close to a subcritical Hopf bifurcation and achieves a graded frequency response-a continuous change in the rate, but not the amplitude, of spiking in response to changes in the offset force-a behavior that is useful in a vestibular organ. The mechanical load in vivo might therefore control a hair bundle's responsiveness for effective operation in a particular receptor organ. Our results provide direct experimental evidence for the existence of distinct bifurcations associated with a noisy biological oscillator, and demonstrate a general strategy for bifurcation analysis based on observations of any noisy system.

  View details for DOI 10.1016/j.bpj.2016.07.027

  View details for PubMedID 27558723

  View details for PubMedCentralID PMC5002087

• Control of a hair bundle's mechanosensory function by its mechanical load. Proceedings of the National Academy of Sciences of the United States of America Salvi, J. D., Ó Maoiléidigh, D., Fabella, B. A., Tobin, M., Hudspeth, A. J. 2015; 112 (9): E1000-9

  Abstract

  Hair cells, the sensory receptors of the internal ear, subserve different functions in various receptor organs: they detect oscillatory stimuli in the auditory system, but transduce constant and step stimuli in the vestibular and lateral-line systems. We show that a hair cell's function can be controlled experimentally by adjusting its mechanical load. By making bundles from a single organ operate as any of four distinct types of signal detector, we demonstrate that altering only a few key parameters can fundamentally change a sensory cell's role. The motions of a single hair bundle can resemble those of a bundle from the amphibian vestibular system, the reptilian auditory system, or the mammalian auditory system, demonstrating an essential similarity of bundles across species and receptor organs.

  View details for DOI 10.1073/pnas.1501453112

  View details for PubMedID 25691749

  View details for PubMedCentralID PMC4352782

• Vibrational Modes and Damping in the Cochlear Partition MECHANICS OF HEARING: PROTEIN TO PERCEPTION Maoileidigh, D. O., Hudspeth, A. J. 2015; 1703

  View details for DOI 10.1063/1.4939348

  View details for Web of Science ID 000372065400035

• Middle Ear Mechanics and Progress in Cochlear Modeling: A Moderated Discussion MECHANICS OF HEARING: PROTEIN TO PERCEPTION Allen, J. B., Nakajima, H. H., Maoileidigh, D. O. 2015; 1703

  View details for DOI 10.1063/1.4939362

  View details for Web of Science ID 000372065400049

• Characterization of Active Hair-Bundle Motility by a Mechanical-Load Clamp MECHANICS OF HEARING: PROTEIN TO PERCEPTION Salvi, J. D., Maoileidigh, D. O., Fabella, B. A., Tobin, M., Hudspeth, A. J. 2015; 1703

  View details for DOI 10.1063/1.4939320

  View details for Web of Science ID 000372065400007

• Effects of cochlear loading on the motility of active outer hair cells. Proceedings of the National Academy of Sciences of the United States of America Ó Maoiléidigh, D., Hudspeth, A. J. 2013; 110 (14): 5474-5479

  Abstract

  Outer hair cells (OHCs) power the amplification of sound-induced vibrations in the mammalian inner ear through an active process that involves hair-bundle motility and somatic motility. It is unclear, though, how either mechanism can be effective at high frequencies, especially when OHCs are mechanically loaded by other structures in the cochlea. We address this issue by developing a model of an active OHC on the basis of observations from isolated cells, then we use the model to predict the response of an active OHC in the intact cochlea. We find that active hair-bundle motility amplifies the receptor potential that drives somatic motility. Inertial loading of a hair bundle by the tectorial membrane reduces the bundle's reactive load, allowing the OHC's active motility to influence the motion of the cochlear partition. The system exhibits enhanced sensitivity and tuning only when it operates near a dynamical instability, a Hopf bifurcation. This analysis clarifies the roles of cochlear structures and shows how the two mechanisms of motility function synergistically to create the cochlear amplifier. The results suggest that somatic motility evolved to enhance a preexisting amplifier based on active hair-bundle motility, thus allowing mammals to hear high-frequency sounds.

  View details for DOI 10.1073/pnas.1302911110

  View details for PubMedID 23509256

  View details for PubMedCentralID PMC3619318

• Comparison of nonlinear mammalian cochlear-partition models. journal of the Acoustical Society of America Szalai, R., Champneys, A., Homer, M., Ó Maoiléidigh, D., Kennedy, H., Cooper, N. 2013; 133 (1): 323-336

  Abstract

  Various simple mathematical models of the dynamics of the organ of Corti in the mammalian cochlea are analyzed and their dynamics compared. The specific models considered are phenomenological Hopf and cusp normal forms, a recently proposed description combining active hair-bundle motility and somatic motility, a reduction thereof, and finally a model highlighting the importance of the coupling between the nonlinear transduction current and somatic motility. It is found that for certain models precise tuning to any bifurcation is not necessary and that a compressively nonlinear response over a range similar to experimental observations and that the normal form of the Hopf bifurcation is not the only description that reproduces compression and tuning similar to experiment.

  View details for DOI 10.1121/1.4768868

  View details for PubMedID 23297905

• Frequency-Selective Exocytosis by Ribbon Synapses of Hair Cells in the Bullfrog's Amphibian Papilla JOURNAL OF NEUROSCIENCE Patel, S. H., Salvi, J. D., Maoileidigh, D. O., Hudspeth, A. J. 2012; 32 (39): 13433-13438

  Abstract

  The activity of auditory afferent fibers depends strongly on the frequency of stimulation. Although the bullfrog's amphibian papilla lacks the flexible basilar membrane that effects tuning in mammals, its afferents display comparable frequency selectivity. Seeking additional mechanisms of tuning in this organ, we monitored the synaptic output of hair cells by measuring changes in their membrane capacitance during sinusoidal electrical stimulation at various frequencies. Using perforated-patch recordings, we found that individual hair cells displayed frequency selectivity in synaptic exocytosis within the frequency range sensed by the amphibian papilla. Moreover, each cell's tuning varied in accordance with its tonotopic position. Using confocal imaging, we observed a tonotopic gradient in the concentration of proteinaceous Ca(2+) buffers. A model for synaptic release suggests that this gradient maintains the sharpness of tuning. We conclude that hair cells of the amphibian papilla use synaptic tuning as an additional mechanism for sharpening their frequency selectivity.

  View details for DOI 10.1523/JNEUROSCI.1246-12.2012

  View details for Web of Science ID 000309506300014

  View details for PubMedID 23015434

  View details for PubMedCentralID PMC3468150

• The diverse effects of mechanical loading on active hair bundles. Proceedings of the National Academy of Sciences of the United States of America Ó Maoiléidigh, D., Nicola, E. M., Hudspeth, A. J. 2012; 109 (6): 1943-1948

  Abstract

  Hair cells in the auditory, vestibular, and lateral-line systems of vertebrates receive inputs through a remarkable variety of accessory structures that impose complex mechanical loads on the mechanoreceptive hair bundles. Although the physiological and morphological properties of the hair bundles in each organ are specialized for detecting the relevant inputs, we propose that the mechanical load on the bundles also adjusts their responsiveness to external signals. We use a parsimonious description of active hair-bundle motility to show how the mechanical environment can regulate a bundle's innate behavior and response to input. We find that an unloaded hair bundle can behave very differently from one subjected to a mechanical load. Depending on how it is loaded, a hair bundle can function as a switch, active oscillator, quiescent resonator, or low-pass filter. Moreover, a bundle displays a sharply tuned, nonlinear, and sensitive response for some loading conditions and an untuned or weakly tuned, linear, and insensitive response under other circumstances. Our simple characterization of active hair-bundle motility explains qualitatively most of the observed features of bundle motion from different organs and organisms. The predictions stemming from this description provide insight into the operation of hair bundles in a variety of contexts.

  View details for DOI 10.1073/pnas.1120298109

  View details for PubMedID 22308449

  View details for PubMedCentralID PMC3277577

• Divalent counterions tether membrane-bound carbohydrates to promote the cohesion of auditory hair bundles. Biophysical journal Leboeuf, A. C., Ó Maoiléidigh, D., Hudspeth, A. J. 2011; 101 (6): 1316-1325

  Abstract

  The cell membranes in the hair bundle of an auditory hair cell confront a difficult task as the bundle oscillates in response to sound: for efficient mechanotransduction, all the component stereocilia of the hair bundle must move essentially in unison, shearing at their tips yet maintaining contact without membrane fusion. One mechanism by which this cohesion might occur is counterion-mediated attachment between glycan components of apposed stereociliary membranes. Using capillary electrophoresis, we showed that the stereociliary glycocalyx acts as a negatively charged polymer brush. We found by force-sensing photomicrometry that the stereocilia formed elastic connections with one another to various degrees depending on the surrounding ionic environment and the presence of N-linked sugars. Mg(2+) was a more potent mediator of attachment than was Ca(2+). The forces between stereocilia produced chaotic stick-slip behavior. These results indicate that counterion-mediated interactions in the glycocalyx contribute to the stereociliary coherence that is essential for hearing.

  View details for DOI 10.1016/j.bpj.2011.07.053

  View details for PubMedID 21943412

  View details for PubMedCentralID PMC3177057

• A Unified Model of Transcription Elongation: What Have We Learned from Single-Molecule Experiments? BIOPHYSICAL JOURNAL Maoileidigh, D. O., Tadigotla, V. R., Nudler, E., Ruckenstein, A. E. 2011; 100 (5): 1157-1166

  Abstract

  The transcription of the genetic information encoded in DNA into RNA is performed by RNA polymerase (RNAP), a complex molecular motor, highly conserved across species. Despite remarkable progress in single-molecule techniques revealing important mechanistic details of transcription elongation (TE) with up to base-pair resolution, some of the results and interpretations of these studies are difficult to reconcile, and have not yet led to a minimal unified picture of transcription. We propose a simple model that accounts quantitatively for many of the experimental observations. This model belongs to the class of isothermal ratchet models of TE involving the thermally driven stochastic backward and forward motion (backtracking and forward tracking) of RNAP along DNA between single-nucleotide incorporation events. We uncover two essential features for the success of the model. The first is an intermediate state separating the productive elongation pathway from nonelongating backtracked states. The rates of entering and exiting this intermediate state modulate pausing by RNAP. The second crucial ingredient of the model is the cotranscriptional folding of the RNA transcript, sterically inhibiting the extent of backtracking. This model resolves several apparent differences between single-molecule studies and provides a framework for future work on TE.

  View details for DOI 10.1016/j.bpj.2010.12.3734

  View details for Web of Science ID 000288049400003

  View details for PubMedID 21354388

  View details for PubMedCentralID PMC3043204

• High-Frequency Power Gain in the Mammalian Cochlea WHAT FIRE IS IN MINE EARS: PROGRESS IN AUDITORY BIOMECHANICS Maoileidigh, D. O., Hudspeth, A. J. 2011; 1403

  View details for DOI 10.1063/1.3658163

  View details for Web of Science ID 000301945200112

• The interplay between active hair bundle motility and electromotility in the cochlea. journal of the Acoustical Society of America O Maoiléidigh, D., Jülicher, F. 2010; 128 (3): 1175-1190

  Abstract

  The cochlear amplifier is a nonlinear active process providing the mammalian ear with its extraordinary sensitivity, large dynamic range and sharp frequency tuning. While there is much evidence that amplification results from active force generation by mechanosensory hair cells, there is debate about the cellular processes behind nonlinear amplification. Outer hair cell electromotility has been suggested to underlie the cochlear amplifier. However, it has been shown in frog and turtle that spontaneous movements of hair bundles endow them with a nonlinear response with increased sensitivity that could be the basis of amplification. The present work shows that the properties of the cochlear amplifier could be understood as resulting from the combination of both hair bundle motility and electromotility in an integrated system that couples these processes through the geometric arrangement of hair cells embedded in the cochlear partition. In this scenario, the cochlear partition can become a dynamic oscillator which in the vicinity of a Hopf bifurcation exhibits all the key properties of the cochlear amplifier. The oscillatory behavior and the nonlinearity are provided by active hair bundles. Electromotility is largely linear but produces an additional feedback that allows hair bundle movements to couple to basilar membrane vibrations.

  View details for DOI 10.1121/1.3463804

  View details for PubMedID 20815454

• THE INTERPLAY BETWEEN ACTIVE HAIR BUNDLE MECHANICS AND ELECTROMOTILITY IN THE COCHLEA CONCEPTS AND CHALLENGES IN THE BIOPHYSICS OF HEARING Maoileidigh, D., Juelicher, F. 2009: 451-456

  View details for Web of Science ID 000268443600074

• Thermodynamic and kinetic modeling of transcriptional pausing PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Tadigotla, V. R., O'Maoileidigh, D., Sengupta, A. M., Epshtein, V., Ebright, R. H., Nudler, E., Ruckenstein, A. E. 2006; 103 (12): 4439-4444

  Abstract

  We present a statistical mechanics approach for the prediction of backtracked pauses in bacterial transcription elongation derived from structural models of the transcription elongation complex (EC). Our algorithm is based on the thermodynamic stability of the EC along the DNA template calculated from the sequence-dependent free energy of DNA-DNA, DNA-RNA, and RNA-RNA base pairing associated with (i) the translocational and size fluctuations of the transcription bubble; (ii) changes in the associated DNA-RNA hybrid; and (iii) changes in the cotranscriptional RNA secondary structure upstream of the RNA exit channel. The calculations involve no adjustable parameters except for a cutoff used to discriminate paused from nonpaused complexes. When applied to 100 experimental pauses in transcription elongation by Escherichia coli RNA polymerase on 10 DNA templates, the approach produces statistically significant results. We also present a kinetic model for the rate of recovery of backtracked paused complexes. A crucial ingredient of our model is the incorporation of kinetic barriers to backtracking resulting from steric clashes of EC with the cotranscriptionally generated RNA secondary structure, an aspect not included explicitly in previous attempts at modeling the transcription elongation process.

  View details for DOI 10.1073/pnas.0600508103

  View details for Web of Science ID 000236362600023

  View details for PubMedID 16537373

  View details for PubMedCentralID PMC1450190