In the mammalian cochlea, hair bundles of the sensory outer and inner hair cells detect mechanical signals. A hair bundle comprises a set of rod-like stereocilia that pivot around their insertion points in the hair-cell’s apex. Stereocilia are linked by gating springs and connectors, also known as top or shaft connectors, side, lateral, or ankle links. Gating springs link neighboring stereocilia of differing height, while connectors link all neighboring stereocilia. Sound-induced gating-spring oscillations open and close mechanoelectrical transduction channels attached to the gating springs, causing oscillations in the hair cell’s receptor current. In contrast to gating springs, connectors are not attached to channels and their functional role is unclear. To determine how the specific properties of gating springs and connectors contribute to outer-hair-cell bundle function, we use a computational model of an outer-hair-cell bundle, which accounts for nonlinear hair-bundle splaying at rest, nonlinear fluid forces on stereocilia, and nonlinear channel gating. The model is validated by reproducing many experimental observations, including stereocilium splaying at rest and hair-bundle stiffness decreases caused by breaking gating springs or connectors. We discuss how varying the gating-spring and connector stiffnesses affects the receptor current in response to stimulation at the characteristic frequency of the hair cell.

1.
D. Ó
Maoiléidigh
and
A. J.
Ricci
, “
A bundle of mechanisms: Inner-ear hair-cell mechanotransduction
.”
Trends Neurosci
42
,
221
236
(
2019
).
2.
P.
Kazmierczak
,
H.
Sakaguchi
,
J.
Tokita
,
E. M.
Wilson-Kubalek
,
R. A.
Milligan
,
U.
Müller
, and
B.
Kachar
, “
Cadherin 23 and protocadherin 15 interact to form tip-link filaments in sensory hair cells
.”
Nature
449
,
87
91
(
2007
).
3.
A. S.
Kozlov
,
J.
Baumgart
,
T.
Risler
,
C. P. C.
Versteegh
, and
A. J.
Hudspeth
, “
Forces between clustered stereocilia minimize friction in the ear on a subnanometre scale
,”
Nature
474
,
376
379
(
2011
).
4.
A. X.
Cartagena-Rivera
,
S.
Le Gal
,
K.
Richards
,
E.
Verpy
, and
R. S.
Chadwick
, “
Cochlear outer hair cell horizontal top connectors mediate mature stereocilia bundle mechanics
.”
Sci Adv
5
,
eaat9934
(
2019
).
5.
A. W.
Peng
,
A. L.
Scharr
,
G. A.
Caprara
,
D.
Nettles
,
C. R.
Steele
, and
A. J.
Ricci
, “
Fluid jet stimulation of auditory hair bundles reveal spatial non-uniformities and two viscoelastic-like mechanisms
.”
Front Cell Dev Biol
9
,
725101
(
2021
).
6.
G. P.
Richardson
and
C.
Petit
, “
Hair-bundle links: Genetics as the gateway to function
.”
Cold Spring Harb Perspect Med
9
(
2019
), .
7.
R. J.
Goodyear
,
W.
Marcotti
,
C.
Kros
, and
G. P.
Richardson
, “
Development and properties of stereociliary link types in hair cells of the mouse cochlea
.”
J Comp Neurol
485
,
75
85
(
2005
).
8.
V.
Tsuprun
,
P. A.
Schachern
,
S.
Cureoglu
, and
M.
Paparella
, “
Structure of the stereocilia side links and morphology of auditory hair bundle in relation to noise exposure in the chinchilla
.”
J Neurocytol
32
,
1117
1128
(
2003
).
9.
E.
Verpy
,
M.
Leibovici
,
N.
Michalski
,
R. J.
Goodyear
,
C.
Houdon
,
D.
Weil
,
G. P.
Richardson
, and
C.
Petit
, “
Stereocilin connects outer hair cell stereocilia to one another and to the tectorial membrane
.”
J Comp Neurol
519
,
194
210
(
2011
).
10.
P.
Avan
,
S.
Le Gal
,
V.
Michel
,
T.
Dupont
,
J.-P.
Hardelin
,
C.
Petit
, and
E.
Verpy
, “
Otogelin, otogelin-like, and stereocilin form links connecting outer hair cell stereocilia to each other and the tectorial membrane
.”
Proc Natl Acad Sci U S A
116
,
25948
25957
(
2019
).
11.
M.
Tobin
,
A.
Chaiyasitdhi
,
V.
Michel
,
N.
Michalski
, and
P.
Martin
, “
Stiffness and tension gradients of the hair cell’s tip-link complex in the mammalian cochlea
.”
Elife
8
(
2019
), .
12.
J.-H.
Nam
,
A. W.
Peng
, and
A. J.
Ricci
, “
Underestimated sensitivity of mammalian cochlear hair cells due to splay between stereociliary columns
,”
Biophys. J.
108
,
2633
2647
(
2015
).
13.
P.
Martin
,
A. D.
Mehta
, and
A. J.
Hudspeth
, “
Negative hair bundle stiffness betrays a mechanism for mechanical amplification by the hair cell
,”
Proc. Natl. Acad. Sci. USA
97
,
12026
12031
(
2000
).
14.
D.
Strelioff
and
A.
Flock
, “
Stiffness of sensory-cell hair bundles in the isolated guinea pig cochlea
.”
Hear Res
15
,
19
28
(
1984
).
15.
D. J.
Lim
, “
Functional structure of the organ of corti: a review
.”
Hear Res
22
,
117
146
(
1986
).
16.
B.
Roth
and
V.
Bruns
, “
Postnatal development of the rat organ of corti. ii. hair cell receptors and their supporting elements
.”
Anat Embryol (Berl)
185
,
571
581
(
1992
).
17.
Y. M.
Yarin
,
A. N.
Lukashkin
,
A. A.
Poznyakovskiy
,
H.
Meissner
,
M.
Fleischer
,
J.
Baumgart
,
C.
Richter
,
E.
Kuhlisch
, and
T.
Zahnert
, “
Tono-topic morphometry of the lamina reticularis of the guinea pig cochlea with associated microstructures and related mechanical implications
.”
J Assoc Res Otolaryngol
15
,
1
11
(
2014
).
18.
J.
Howard
and
J. F.
Ashmore
, “
Stiffness of sensory hair bundles in the sacculus of the frog
.”
Hear Res
23
,
93
104
(
1986
).
19.
A. C.
Crawford
,
M. G.
Evans
, and
R.
Fettiplace
, “
Activation and adaptation of transducer currents in turtle hair cells
,”
J Physiol
419
,
405
434
(
1989
).
20.
K. D.
Karavitaki
and
D. P.
Corey
, “
Sliding adhesion confers coherent motion to hair cell stereocilia and parallel gating to transduction chan-nels
.”
J Neurosci
30
,
9051
9063
(
2010
).
21.
Y.
Wang
,
C. R.
Steele
,
S.
Puria
, and
A. J.
Ricci
, “
In situ motions of individual inner-hair-cell stereocilia from stapes stimulation in adult mice
.”
Commun Biol
4
,
958
(
2021
).
22.
D. E.
Zetes
and
C. R.
Steele
, “
Fluid-structure interaction of the stereocilia bundle in relation to mechanotransduction
.”
J Acoust Soc Am
101
,
3593
3601
(
1997
).
23.
K. K.
Miller
,
P.
Atkinson
,
K. R.
Mendoza
,
D. Ó
Maoiléidigh
, and
N.
Grillet
, “
Dimensions of a living cochlear hair bundle
.”
Front Cell Dev Biol
9
,
742529
(
2021
).
24.
V.
Bormuth
,
J.
Barral
,
J.-F.
Joanny
,
F.
Jülicher
, and
P.
Martin
, “
Transduction channels’ gating can control friction on vibrating hair-cell bundles in the ear
,”
Proc. Natl. Acad. Sci. USA
111
,
7185
7190
(
2014
).
25.
J. A.
Assad
,
G. M. G.
Shepherd
, and
D. P.
Corey
, “
Tip-link integrity and mechanical transduction in vertebrate hair cells
,”
Neuron
7
,
985
994
(
1991
).
26.
D. P.
Corey
,
D. Ó
Maoiléidigh
, and
J. F.
Ashmore
, “Mechanical transduction processes in the hair cell,” in
Understanding the Cochlea
, edited by
G. A.
Manley
,
A. W.
Gummer
,
A. N.
Popper
, and
R. R.
Fay
(
Springer International Publishing
,
Cham
,
2017
) pp.
75
111
.
27.
G. A.
Caprara
,
A. A.
Mecca
, and
A. W.
Peng
, “
Decades-old model of slow adaptation in sensory hair cells is not supported in mammals
.”
Sci Adv
6
,
eabb4922
(
2020
).
28.
D. Ó
Maoiléidigh
and
A. J.
Hudspeth
, “
Effects of cochlear loading on the motility of active outer hair cells
,”
Proc. Natl. Acad. Sci. USA
110
,
5474
5479
(
2013
).
29.
G. A.
Caprara
and
A. W.
Peng
, “
Mechanotransduction in mammalian sensory hair cells
.”
Mol Cell Neurosci
120
,
103706
(
2022
).
30.
A. J.
Ricci
,
H. J.
Kennedy
,
A. C.
Crawford
, and
R.
Fettiplace
, “
The transduction channel filter in auditory hair cells
.”
J Neurosci
25
,
7831
7839
(
2005
).
31.
H. J.
Kennedy
,
M. G.
Evans
,
A. C.
Crawford
, and
R.
Fettiplace
, “
Fast adaptation of mechanoelectrical transducer channels in mammalian cochlear hair cells
,”
Nat. Neurosci.
6
,
832
836
(
2003
).
32.
A. W.
Peng
,
T.
Effertz
, and
A. J.
Ricci
, “
Adaptation of mammalian auditory hair cell mechanotransduction is independent of calcium entry
,”
Neuron
80
,
960
972
(
2013
).
33.
J.-H.
Nam
and
R.
Fettiplace
, “
Theoretical conditions for high-frequency hair bundle oscillations in auditory hair cells
.”
Biophys J
95
,
4948
4962
(
2008
).
34.
D. M.
Freeman
and
T. F.
Weiss
, “
The role of fluid inertia in mechanical stimulation of hair cells
.”
Hear Res
35
,
201
207
(
1988
).
35.
D. N.
Furness
,
S.
Mahendrasingam
,
M.
Ohashi
,
R.
Fettiplace
, and
C. M.
Hackney
, “
The dimensions and composition of stereociliary rootlets in mammalian cochlear hair cells: comparison between high-and low-frequency cells and evidence for a connection to the lateral membrane
.”
J Neurosci
28
,
6342
6353
(
2008
).
36.
D. N.
Furness
,
Y.
Katori
,
B. Nirmal
Kumar
, and
C. M.
Hackney
, “
The dimensions and structural attachments of tip links in mammalian cochlear hair cells and the effects of exposure to different levels of extracellular calcium
.”
Neuroscience
154
,
10
21
(
2008
).
37.
M.
Beurg
,
J.-H.
Nam
, and
R.
Fettiplace
, “
The speed of the hair cell mechanotransducer channel revealed by fluctuation analysis
.”
J Gen Physiol
153
(
2021
), .
38.
A. J.
Hunt
,
F.
Gittes
, and
J.
Howard
, “
The force exerted by a single kinesin molecule against a viscous load
.”
Biophys J
67
,
766
781
(
1994
).
39.
J.
Baumgart
,
The Hair Bundle: Fluid-Structure Interaction in the Inner Ear
, Ph.D. thesis,
Technische Universität Dresden
(
2011
).
40.
J. O.
Pickles
,
M. P.
Osborne
, and
S. D.
Comis
, “
Vulnerability of tip links between stereocilia to acoustic trauma in the guinea pig
.”
Hear Res
25
,
173
183
(
1987
).
41.
J. A.
Clark
and
J. O.
Pickles
, “
The effects of moderate and low levels of acoustic overstimulation on stereocilia and their tip links in the guinea pig
.”
Hear Res
99
,
119
128
(
1996
).
42.
E. L.
Wagner
and
J.-B.
Shin
, “
Mechanisms of hair cell damage and repair
.”
Trends Neurosci
42
,
414
424
(
2019
).
43.
A. A.
Indzhykulian
,
R.
Stepanyan
,
A.
Nelina
,
K. J.
Spinelli
,
Z. M.
Ahmed
,
I. A.
Belyantseva
,
T. B.
Friedman
,
P. G.
Barr-Gillespie
, and
G. I.
Frolenkov
, “
Molecular remodeling of tip links underlies mechanosensory regeneration in auditory hair cells
,”
PLoS Biol.
11
,
e1001583
(
2013
).
44.
W.
Han
,
J.-O.
Shin
,
J.-H.
Ma
,
H.
Min
,
J.
Jung
,
J.
Lee
,
U.-K.
Kim
,
J. Y.
Choi
,
S. J.
Moon
,
D. W.
Moon
,
J.
Bok
, and
C. H.
Kim
, “
Distinct roles of stereociliary links in the nonlinear sound processing and noise resistance of cochlear outer hair cells
.”
Proc Natl Acad Sci U S A
117
,
11109
11117
(
2020
).
45.
J.
Howard
and
A. J.
Hudspeth
, “
Compliance of the hair bundle associated with gating of mechanoelectrical transduction channels in the bullfrog’s saccular hair cell
,”
Neuron
1
,
189
199
(
1988
).
46.
J.
Howard
and
A. J.
Hudspeth
, “
Mechanical relaxation of the hair bundle mediates adaptation in mechanoelectrical transduction by the bull-frog’s saccular hair cell
,”
Proc. Natl. Acad. Sci. USA
84
,
3064
3068
(
1987
).
47.
G. A.
Caprara
,
A. A.
Mecca
,
Y.
Wang
,
A. J.
Ricci
, and
A. W.
Peng
, “
Hair bundle stimulation mode modifies manifestations of mechanotrans-duction adaptation
.”
J Neurosci
39
,
9098
9106
(
2019
).
This content is only available via PDF.
You do not currently have access to this content.