Dau, Torsten

Encina-Llamas, Gerard

Epp, Bastian

Harte, James Michael

Several non-human animal studies have demonstrated a permanent loss of auditory nerve (AN) fiber synapses after noise over-exposure, termed cochlear synaptopathy, without causing hair cell loss nor altering normal auditory thresholds (e.g., Kujawa and Liberman, 2009). Studies in human listeners are generally inconclusive, mainly because assessing the status of the AN in humans represents a major challenge. In a previous study, we proposed the use of envelope following responses (EFR) as a tool to investigate synaptopathy both in mice and humans (Encina-Llamas et al., under review; Parthasarathy et al., 2017). Similar patterns in synaptopathic mice and humans were found. The use of a "humanized" version of the AN model by Zilany et al. (2009, 2014) could qualitatively account for the patterns obtained in the human listeners. Nevertheless, the use of the original animal version of the AN model (based on the cat) failed to simulate EFRs in mice. It was argued that a species-specific AN model could improve the non-human animal simulations. Given that the mouse is the most used and best characterized species in connection with cochlear synaptopathy, the present study proposes a modification of the original AN model by Zilany et al. (2009, 2014) based on cat data adapted to the mous

Online Research Database In Technology

                       General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.  • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal   If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.     Downloaded from orbit.dtu.dk on: Aug 03, 2018A mouse model of the auditory nerve to study cochlear synaptopathyEncina-Llamas, Gerard; Dau, Torsten; Harte, James Michael; Epp, BastianPublication date:2018Document VersionPublisher's PDF, also known as Version of recordLink back to DTU OrbitCitation (APA):Encina-Llamas, G., Dau, T., Harte, J. M., & Epp, B. (2018). A mouse model of the auditory nerve to studycochlear synaptopathy. Poster session presented at 41st MidWinter Meeting of the Association for Research inOtolaryngology, San Diego, United States.A Mouse Model of the Auditory Nerve to Study Cochlear SynaptopathyGerard Encina-Llamas1, Torsten Dau1, James M. Harte2 and Bastian Epp11 Hearing Systems, Technical University of Denmark (DTU) - 2 Interacoustics Research Unit (IRU)IntroductionSeveral non-human animal studies have demonstrated a per-manent loss of auditory nerve (AN) fiber synapses after noiseover-exposure, termed cochlear synaptopathy, without caus-ing hair cell loss nor altering normal auditory thresholds (e.g.,Kujawa and Liberman, 2009). Studies in human listeners aregenerally inconclusive, mainly because assessing the statusof the AN in humans represents a major challenge. In aprevious study, we proposed the use of envelope followingresponses (EFR) as a tool to investigate synaptopathy bothin mice and humans (Encina-Llamas et al., under review;Parthasarathy et al., 2017). Similar patterns in synaptopathicmice and humans were found. The use of a "humanized" ver-sion of the AN model by Zilany et al. (2009, 2014) couldqualitatively account for the patterns obtained in the humanlisteners. Nevertheless, the use of the original animal ver-sion of the AN model (based on the cat) failed to simulateEFRs in mice. It was argued that a species-specific AN modelcould improve the non-human animal simulations. Given thatthe mouse is the most used and best characterized speciesin connection with cochlear synaptopathy, the present studyproposes a modification of the original AN model by Zilany etal. (2009, 2014) based on cat data adapted to the mouse.Aim of the project• Modify the AN model by Zilany et al. (2009, 2014) basedon the cat to adapt it to the mouse.• Due to the complexity of the AN model, it was intentionallydecided to modify as few parameters as possible.• Three main blocks were modified: the middle-ear filter, thecochlear tuning (Q10 dB values), and the range of sensitivecharacteristic frequencies (CF).• The ultimate goal was to use the model to simulate EFRsin non-synaptopathic and synaptopathic mice.MethodsModel:- "Mousified" version based on the ANmodel by Zilany et al. (2009, 2014).- 200 characteristic frequencies (CF),ranging from 4.5 to 75 kHz.- Synapses per IHC are simulated byseveral independent computationsof each AN CF (30-60 fibers per CFwith a total of 10000 fibers).- Synaptopathy is simulated by computinga given CF less times..5.6 11.3 22 32 45 64Characteristic frequency [kHz]05101520AN fibers per IHCAN loss: -2.4% 0.4% 50.7% 52.9% 61.3% 43.0%Data (control)Fit (control)Data (exposed)Fit (exposed)Fig. 1 Synaptic counts in the control (black)and exposed (gray) 32 weeks-old mice.315.0 315.6 316.2 316.8 317.3 317.9Time [ms]4.56.28.512.116.522.230.341.455.075.0Frequency [kHz]AN-gram @ 80 dB SPL0510OFF-frequency (50 kHz)0510OFF-frequency (40 kHz)0510ON-frequency (30.5 kHz)315.0 315.6 316.2 316.8 317.3 317.9Time [s]01020Sum across all CFsSynaptic response [# of spikes]Fig. 2 Example of a simulated AN output at the synaptopathic frequency and level of 80 dB SPL.Stimuli:- Non-synaptopathic frequency: ƒc = 12.1 kHz @ ƒm = 1024 Hz- Synaptopathic frequency: ƒc = 30.5 kHz @ ƒm = 1024 HzLevels:- EFRs in mice: 20 to 80 dB SPL, 10 dB steps.- Simulated EFRs: 10 to 100 dB SPL, 5 dB steps.Modulations:- Strong m = 85%; shallow m = 25%."Mousification" of the AN modelMiddle-ear filter:0.1e3 1e3 10e3Frequency [Hz]2002040Gain [dB]A)CAT middle-ear filter - MagnitudeME Cat filter - Bruce et al.  (2003)ME Cat filter - Zilany & Bruce (2006)0.1e3 1e3 10e3Frequency [Hz]202Phase [rad.]B)CAT middle-ear filter - PhaseME Cat filter - Bruce et al.  (2003)ME Cat filter - Zilany & Bruce (2006)2e3 10e3 50e3Frequency [Hz]6040200Gain [dB]C)MOUSE middle-ear filter - MagnitudeME Mouse TF - Dong et al.  (2013)ME Mouse filter2e3 10e3 50e3Frequency [Hz]202Phase [rad.]D)MOUSE middle-ear filter - PhaseME Mouse TF - Dong et al.  (2013)ME Mouse filterFig. 3 Magnitude and phase responses ofthe middle-ear (ME) filters.Panels A & B show the ME filters in thecat model. The solid lines correspond tothe original 11th -order IIR filter in Bruce etal. (2003). The dashed lines correspond tothe simplified 5th -order in a second-ordersection structure filter in Zilany & Bruce(2006).Panels C & D show the ME filter in themouse model. The solid lines correspondto the measurement of the stapes veloc-ity relative to the sound pressure at theeardrum of C57BL mice (Dong et al., 2013).The dashed lines represent the ME filterdesigned based on the stapes measure-ment and adjusted to the 5th -order ina asecond-order section structure.AN tuning:0.1 1.0 10.0 100.0Characteristic frequency [kHz]100101102Q10dB valuesAN tuning  -  CAT vs MOUSECAT Q10 dB - Miller et al.  (1997)MOUSE Q10 dB - Taberner & Liberman (2005)CAT fitting - Zhang et al.  (2001) - Q10 dB | Cat = 10(0.4708 log10(CF/1e3) + 0.4664)MOUSE fitting - Q10 dB | Mouse = 10(0.2977 log10(CF/1e3) + 0.3855)Fig. 4 AN tuning (Q10 dB values). Cat AN data (plus signs, Miller et al., 1997) and fittedline (Zhang et al., 2001) are represented in brown. Mouse (CBA/CaJ) AN data (crosses,Taberner & Liberman, 2005) and fitted line are represented in green.AN threshold:2 10 100Characteristic frequency [kHz]20020406080Stimulus level [dB SPL]AN thresholds  -  CBA/CaJ mouseAN threshold - Taberner & Liberman (2005)CAP threshold - Yoshida et al.  (2000)Simulated AN thresholdsFig. 5 Gray dots show AN threshold in CBA/CaJ mice (Taberner & Liberman, 2005). Lightgreen squares compound action potential (CAP) thresholds in CBA/CaJ mice (Yoshida etal., 2000). Dark green line shows simulated AN thresholds using the mouse model.Results IEFRs recorded in mice:10 20 30 40 50 60 70 80 90 100Stimulus level [dB SPL]55504540353025201510EFR magnitude  [dB re 1V]A)(fc | mouse = 12.1 kHz)Non-synaptopathic frequency10 20 30 40 50 60 70 80 90 100Stimulus level [dB SPL]55504540353025201510 EFR magnitude  [dB re 1V]B)(fc | mouse = 30.5 kHz)Synaptopathic frequencyEFR (control), m=85% EFR (control), m=25% EFR (exposed), m=85% EFR (exposed), m=25%Fig. 6 EFR level-growth function recordedat the non-synaptopathic (Panel A, ƒc =12.1 kHz) and synaptopathic (Panel B, ƒc =30.5 kHz) frequencies for exposed (circles,solid lines) and non-exposed (squares,dashed lines) mice using strongly (blue)and shallowly (red) modulated tones. (Formore information, attend to the podium PD112 by Parthasarathy et al., 2018).Simulated EFRs using the CAT model:10 20 30 40 50 60 70 80 90 100Stimulus level [dB SPL]55504540353025201510EFR magnitude  [a.u. in dB](fc | cat = 2.28 kHz  fc | mouse = 12.1 kHz)Non-synaptopathic frequencyA)10 20 30 40 50 60 70 80 90 100Stimulus level [dB SPL]55504540353025201510 EFR magnitude  [a.u. in dB](fc | cat = 12.93 kHz  fc | mouse = 30.5 kHz)Synaptopathic frequencyB)EFR (control), m=85% EFR (control), m=25% EFR (exposed), m=85% EFR (exposed), m=25%Fig. 7 Simulated AN EFR level-growthfunction using the CAT model at the non-synaptopathic (Panel A, ƒc = 2.28 kHz)and synaptopathic (Panel B, ƒc = 12.93kHz) frequencies in the healthy (circles,solid lines) and the model with synap-tic loss (squares, dashed lines) usingstrongly (blue) and shallowly (red) modu-lated tones.Simulated EFRs using the MOUSE model:10 20 30 40 50 60 70 80 90 100Stimulus level [dB SPL]55504540353025201510EFR magnitude  [a.u. in dB](fc | mouse = 12.1 kHz)Non-synaptopathic frequencyA)10 20 30 40 50 60 70 80 90 100Stimulus level [dB SPL]55504540353025201510 EFR magnitude  [a.u. in dB](fc | mouse = 30.5 kHz)Synaptopathic frequencyB)EFR (control), m=85% EFR (control), m=25% EFR (exposed), m=85% EFR (exposed), m=25%Fig. 8 Simulated AN EFR level-growthfunction using the MOUSE model at thenon-synaptopathic (Panel A, ƒc = 12.1kHz) and synaptopathic (Panel B, ƒc =30.5 kHz) frequencies in the healthy (cir-cles, solid lines) and the model withsynaptic loss (squares, dashed lines) usingstrongly (blue) and shallowly (red) modu-lated tones.Results IIAnalysis at on- and off-frequencies and different fiber types:-60-50-40-30-20EFR Magnitude[a.u. in dB] across frequencyHigh-SR fibersON frequency(CF at 30.49 kHz)OFF frequency(CF at 40 kHz)-70-60-50-40-30 EFR Magnitude[a.u. in dB]OFF frequency(CF at 50 kHz)-60-50-40-30-20EFR Magnitude[a.u. in dB]Medium-SR fibers-75-65-55-45-35 EFR Magnitude[a.u. in dB]-75-65-55-45-35EFR Magnitude[a.u. in dB]Low-SR fibers-85-75-65-55-45 EFR Magnitude[a.u. in dB]0 10 20 30 40 50 60 70 80 90 100Stimulus level [dB SPL]-55-45-35-25-15EFR Magnitude[a.u. in dB] SR fibers0 10 20 30 40 50 60 70 80 90 100Stimulus level [dB SPL]0 10 20 30 40 50 60 70 80 90 100Stimulus level [dB SPL]0 10 20 30 40 50 60 70 80 90 100Stimulus level [dB SPL]-65-55-45-35-25 EFR Magnitude[a.u. in dB]Fig. 9 Simulated EFR level-growth functions in the MOUSE model using strongly (blue) and shallowly (red) amplitude modulated tones. Columns show simulated EFR level-growthfunctions at on- and off-frequencies. Rows show simulated EFRs for different types of AN fibers.Conclusion• The modifications applied to "mousify" the AN model (MEfilter, AN tuning and range of sensitive CFs) were sufficientto generally account for the mouse AN thresholds.• The mouse model improved significantly the simulation ofEFR level-growth functions in mice with respect to the useof the cat model.• Although the model simulations capture the general trendof the EFR level-growth functions, there are still discrepan-cies in particular at the lower and higher stimulus levels atthe synaptopathic frequency.• Simulated EFRs using the mouse model at supra-thresholdlevels are dominated by the activity of high-SR fibers atoff-frequency contributions, similarly to the humanized ANmodel (Encina-Llamas et al., under review).ReferencesREFERENCESBruce et al. (2003). JASA, 113(1), 369-388. DOI: 10.1121/1.1519544.Dong et al. (2013). Hear Res, 301:27-34. DOI: 10.1016/j.heares.2012.11.015.Encina-Llamas et al. (under review). JARO.Kujawa and Liberman (2009). J. Neurosci. 29(45), 14077-85. DOI:10.1523/JNEUROSCI.2845-09.2009.Miller et al. (1997). JASA, 101(6), 3602-3616. DOI: 10.1121/1.418321Parthasarathy et al. (2017). ARO MidWinter meeting, 2017.Parthasarathy et al. (2018). ARO MidWinter meeting, 2018. PD 113.Taberner & Liberman (2005). J. Neurophysiol. 93(1), 557-69. DOI:10.1152/jn.00574.2004.Yoshida et al. (2000). Hearing Res. 141(1-2), 97-106. DOI:10.1016/S0378-5955(99)00210-5.Zhang et al. (2001). JASA, 109(2), 648-670. DOI: 10.1121/1.1336503.Zilany & Bruce (2006). JASA, 120(3), 1446-1466. DOI: 10.1121/1.2225512.Zilany et al. (2009, 2014). JASA, 126(5), 2390-412. DOI: 10.1121/1.3238250.ACKNOWLEDGMENTThis research was supported by the Oticon Center of Excellence for Hearing andSpeech Sciences (CHeSS) at the Technical University of Denmark (DTU).

A mouse model of the auditory nerve to study cochlear synaptopathy

http://orbit.dtu.dk/ws/files/151021628/encina_llamas_ARO_2018_poster.pdf

A mouse model of the auditory nerve to study cochlear synaptopathy

Abstract

Similar works

Full text

Available Versions

Online Research Database In Technology