What is the quietest sound the ear can detect? All sounds begin as vibrating air molecules, which enter the ear and cause the eardrum to vibrate. We can detect vibrations that move the eardrum by a distance of less than one picometer. That’s one thousandth of a nanometer, or about 100 times smaller than a hydrogen atom. But how does the ear achieve this level of sensitivity?

Vibrations of the eardrum cause three small bones within the middle ear to vibrate. The vibrations then spread to the cochlea, a fluid-filled spiral structure in the inner ear. Tiny hair cells lining the cochlea move as a result of the vibrations. There are two types of hair cells: inner and outer. Outer hair cells amplify the vibrations. It is this amplification that enables us to detect such small movements of the eardrum. Inner hair cells then convert the amplified vibrations into electrical signals, which travel via the auditory nerve to the brain.

The bases of outer hair cells are connected to a structure called the basilar membrane, while their tops are anchored to a structure called the reticular lamina. It was generally assumed that outer hair cells amplify vibrations of the basilar membrane via a local positive feedback mechanism that requires the hair cells to vibrate first. But by comparing the timing of reticular lamina and basilar membrane vibrations in gerbils, He et al. show that this is not the case. Outer hair cells vibrate after the basilar membrane, not before. This indicates that outer hair cells use a mechanism other than commonly assumed local feedback to amplify sounds.

The results presented by He et al. change our understanding of how the cochlea works, and may help bioengineers to design better hearing aids and cochlea implants. Millions of patients worldwide who suffer from hearing loss may ultimately stand to benefit.

The exceptional sensitivity of mammalian hearing has been attributed to a micromechanical feedback system inside the cochlea, also called ‘the cochlear amplifier’ or ‘cochlear active process’ (Dallos et al., 2008; Davis, 1983; Fettiplace and Hackney, 2006; Hudspeth, 2014; Robles and Ruggero, 2001; Russell et al., 2007). When sound-induced basilar membrane vibrations deflect hair bundles of the outer hair cells, mechanoelectrical transduction of these cells generates the receptor potential (Dallos et al., 1982; Russell and Sellick, 1983). In response to the membrane potential change, mammalian outer hair cells change their length and generate force primarily through the somatic motility driven by the motor protein, prestin (Ashmore, 2008; Brownell et al., 1985; Liberman et al., 2002; Mammano and Ashmore, 1993; Mellado Lagarde et al., 2008; Ren et al., 2016a; Santos-Sacchi, 1989; Zheng et al., 2000). This cellular force is thought to be directly applied to the basilar membrane at its generation location on a cycle-by-cycle basis, consequently amplifying the sound-induced basilar membrane vibration and boosting hearing sensitivity (Dallos et al., 2008; de Boer, 1995b; Dong and Olson, 2013; Hudspeth, 2014; Liu and Neely, 2009; Reichenbach and Hudspeth, 2014).

For optimal amplification, the cellular force must act on the basilar membrane at an appropriate time at every vibration cycle (Dallos et al., 2008; Nilsen and Russell, 1999). Therefore, timing of the cochlear feedback has been a central research topic in the field of auditory neuroscience since the cochlear amplifier was proposed (Ashmore, 2008; Davis, 1983; Gold, 1948; Gummer et al., 1996). Because cochlear amplification depends on normal cochlear metabolism and the integrity of cochlear mechanical properties (Cooper and Rhode, 1992; Fisher et al., 2012; Lee et al., 2015; Lee et al., 2016; Nuttall et al., 1991; Ren and Nuttall, 2001; Rhode, 1971; Robles and Ruggero, 2001; Ruggero and Rich, 1991; van der Heijden and Versteegh, 2015), the cochlear feedback has to be investigated ultimately in living cochleae. Timing of cochlear feedback was studied in vivo by measuring basilar membrane vibrations at different locations across the width of the basilar membrane in guinea pig (Nilsen and Russell, 1999). Based on their observation, the authors suggest that forces generated by the outer hair cells directly drive the region of the basilar membrane beneath the Deiters' cells. The temporal relationship between the reticular lamina and basilar membrane vibration was previously observed in guinea pigs using a time-domain optical coherence tomography system as a homodyne interferometer (Chen et al., 2011). It was reported that the phase of the reticular lamina vibration led the phase of the basilar membrane vibration at the best frequency (Figure 5, Chen et al., 2011). This phase lead has been thought to ensure the right timing of the outer hair cell force for cochlear amplification. However, the mouse micromechanical data measured using a heterodyne low-coherence interferometer showed no significant phase difference between the reticular lamina and basilar membrane vibration at the best frequency (Ren et al., 2016b). This discrepancy may have been caused by the animal species and technical differences, that is mouse versus guinea pig and homodyne interferometry versus heterodyne interferometry. Although a number of studies have been conducted recently to measure micromechanical responses in living cochleae (Gao et al., 2014; Lee et al., 2016; Ramamoorthy et al., 2016; Recio-Spinoso and Oghalai, 2017; Cooper et al., 2018) the timing of the cochlear feedback remains unclear. Since the apical end of outer hair cells is directly connected to the reticular lamina, the reticular lamina vibration can reflect the movement of the outer hair cell under physiological conditions. Therefore, the timing of the cochlear feedback was determined in this study by measuring the latency difference between the reticular lamina and basilar membrane vibration using a custom-built heterodyne low-coherence interferometer (Hong and Freeman, 2006; Ren et al., 2016a; Ren et al., 2016b). The present data collected from the gerbil, one of the most commonly used animals for auditory research, demonstrate for the first time that the reticular lamina vibrates after, not before, the basilar membrane vibration.

This paper reports the first in vivo measurement of the latency difference between the outer hair cell-driven reticular lamina vibration and the basilar membrane vibration. The present data demonstrate that the latency of the reticular lamina vibration is greater than that of the basilar membrane vibration, and there is no significant phase difference between the two structures near the best frequencies. This result is consistent with the mouse data measured using heterodyne interferometry (Ren et al., 2016b) but inconsistent with the guinea pig data, which showed that the phase of the reticular lamina vibration leads the phase of the basilar membrane vibration by ~90° at the best frequency and the phase lead decreases with sound pressure level (Chen et al., 2011). The current result also confirms recent studies in the mouse (Ren et al., 2016b) and in the guinea pig (Recio-Spinoso and Oghalai, 2017) that the physiologically vulnerable reticular lamina vibration is significantly greater than the basilar membrane vibration not only at the best frequency but also at low frequencies. Since an ~90° phase lead of the reticular lamina vibration is thought to be required for cochlear feedback to amplify basilar membrane vibration (Chen et al., 2011; Gummer et al., 1996; Nilsen and Russell, 1999; Robles and Ruggero, 2001; Russell and Nilsen, 1997), and since cochlear amplification has been predicted to work only near the best frequency location (de Boer, 1995a; Dong and Olson, 2013; Liu et al., 2017; Liu and Neely, 2009; Meaud and Grosh, 2012; Motallebzadeh et al., 2018; Ni et al., 2016132016; Ramamoorthy et al., 2007; Wang et al., 2016), the current result is inconsistent with the local cochlear feedback hypothesis. Instead, the latency difference between the reticular lamina and basilar membrane vibration found in this study supports the global hydromechanical mechanism for cochlear amplification (Ren et al., 2016b), which is discussed below.

The longitudinal patterns of the reticular lamina and basilar membrane vibrations at the best-frequency (26 kHz) are presented by plotting displacements and phases (Figure 1A,B,E,F) as a function of the location along the cochlear length (blue and red lines in Figure 5A–D), which was derived from the stimulus frequency according to the cochlear frequency-location function (Müller, 1996). While a 30 dB SPL tone-induced response occurred at a < 0.2 mm region at the best-frequency location (Figure 5A,C), a 70 dB SPL tone-induced vibration extended from the best-frequency location to the base (Figure 5B,D). The overlapping phase curves near the 2.05 mm location (blue and red lines in Figure 5C,D) indicate that the reticular lamina and basilar membrane vibrated approximately in the same direction at the best-frequency location. The ~180 degree separation between the blue and red lines near the cochlear base (Figure 5D) indicates opposite vibrations of the reticular lamina and basilar membrane.

Figure 5

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The outer hair cell-driven active movement was estimated by vector subtraction of the basilar membrane vibration from the measured reticular lamina vibration and is presented by green lines in Figure 5A–D. The overlapping blue and green lines in Figure 5A and C indicate that, at low sound levels, reticular lamina vibration is dominated by outer hair cell-driven movement. At 70 dB SPL, the outer hair cell-driven responses saturated near the best-frequency location, indicated by the diverged blue and green lines near the response peak (Figure 5B).

Time waveforms of the outer hair cell-driven reticular lamina vibrations (green) and the basilar membrane vibrations (red) in Figure 5E,F were derived from magnitude and phase in Figure 5A–D at two sequential times. The time difference between solid and dotted green curves is ~6 µs, equivalent to ~57 degree phase difference at 26 kHz. For clearer comparison, basilar membrane time waveforms (red curves) were shifted down by 4 nm in Figure 5E and by 50 nm in Figure 5F respectively. When the basilar membrane moves upward to the scala vestibuli near the cochlear base (red arrow at 0.8 mm in Figure 5F), depolarized outer hair cells shorten and induce a large downward reticular lamina displacement (green arrow at 0.8 mm in Figure 5F). While this movement creates a positive fluid pressure between the reticular lamina and basilar membrane at the cochlear base (0.7–1.2 mm in Figure 5F,G), the reticular lamina at locations ~ 1.2–1.8 mm, however, moves upward (green arrows near 1.6 mm in Figure 5F), resulting in a negative fluid pressure inside the cochlear partition. This pressure gradient from the base to an apical location likely results in fluid movement in the apical direction inside the cochlear partition (blue arrows in Figure 5F,G) as demonstrated in vitro by electrically stimulating the organ of Corti (Karavitaki and Mountain, 2007; Zagadou and Mountain, 2012). Since the organ of Corti sits on the basilar membrane, the longitudinal fluid movement can travel forward to the best-frequency location as a result of the basilar membrane traveling wave. Thus, a large population of outer hair cells from a broad cochlear area can change the fluid space between the reticular lamina and basilar membrane at the best frequency location on a cycle-by-cycle basis, consequently enhancing the reticular lamina vibration. In addition, in-phase vibrations of the reticular lamina and basilar membrane result in constructive interference near the best-frequency location (Figure 5E,F,G), which further enhances reticular lamina vibration at the apical end of outer hair cells. The magnitude of the resulting constructive interference decreases as phase differences move into destructive interference regimes at frequencies below and above the best frequency. While this frequency dependent interference may consequently enhance the tuning of the reticular lamina vibration, its effects probably is relatively small due to the large magnitude difference between the reticular lamina and basilar membrane vibration. The interaction between the reticular lamina and basilar membrane at low frequencies may also be involved in two-tone suppression of the auditory nerve or basilar membrane response (Delgutte, 1990; Ruggero et al., 1992). It has been shown that the proposed global hydromechanical mechansm is consistent with the observation that auditory nerve activities can be suppressed by stimulating medial olivocochlear efferents or by a low-frequency bias tone not only at the best frequency but also at tail (low) frequencies (Nam and Guinan, 2017; Stankovic and Guinan, 1999).

Since the stereocilia bundles of both the inner and outer hair cells are anchored in the hair cell cuticular plates which make up a portion of the reticular lamina, the outer hair cell-driven reticular lamina vibration likely results in fluid movement in the subtectorial space and consequently stimulates inner hair cells. It has been shown in vitro that electrical stimulation of outer hair cells of guinea pig cochleae resulted in a counterphasic motion of the tectorial membrane and inner hair cells at frequencies below 3 kHz (Nowotny and Gummer, 2006). This result was believed to indicate direct fluid coupling between outer hair cells and inner hair cells through a pulsatile fluid motion. It has also been demonstrated in vitro that outer hair cell stereocilia not only move sideways but also change length in response to sound stimulation (Hakizimana et al., 2012). The large bundle deflection was observed when the length change was small, indicating that hair cells are maximally stimulated when the stereocilia length change is minimal. Considering the firm connection of the tallest stereocilia to the tectorial membrane, the stereocilia length change also suggests the interaction between the reticular lamina vibration and the tectorial membrane vibration. Thus, outer hair cells may also play a role in the traveling wave on the tectorial membrane, which has been demonstrated in vitro (Ghaffari et al., 2007; Ghaffari et al., 2010) and in vivo (Dong and Cooper, 2006; Lee et al., 2015; Lee et al., 2016; Recio-Spinoso and Oghalai, 2017; Rhode and Cooper, 1996). The interaction between the reticular lamina and tectorial membrane vibration may enhance the stimulus to the inner hair cells and boost hearing sensitivity. Specific mechanisms on how the outer hair cell-driven reticular lamina vibration stimulates inner hair cells, however, remain to be determined experimentally until in vivo micromechanical measurements with cellular spatial resolution become available.

The observed additional delay of the reticular lamina vibration was likely caused by mechanoelectrical (Corey and Hudspeth, 1979) and electromechanical (Brownell et al., 1985) transduction of outer hair cells and mechanical coupling inside the cochlear partition. Although delays for prestin-associated currents in vitro (Santos-Sacchi and Tan, 2018) are longer than the latency difference between the reticular lamina and basilar membrane vibration in vivo, they vary with the membrane voltage of outer hair cells. Voltage excitation away from the resting membrane potential has been shown to have a faster response. Moreover, the depolarized resting potential can minimize the outer hair cell time constant and expanding the bandwidth of the membrane filter by activating voltage-dependent K + conductance (Johnson et al., 2011). Mechanical loads on the outer hair cells, such as in vivo condition, could further improve the cell's frequency response (Iwasa, 2017). Since Deiters' cells are located between the outer hair cells and the basilar membrane, the acoustical and cellular forces to and from the outer hair cells have to be transmitted through Deiters' cells. The soft Deiter's cell soma likely induces delays, which can contribute to the delay difference between the reticular lamina and basilar membrane vibration. This apparently is supported by the postmortem magnitude and phase difference between the reticular lamina and basilar membrane vibration (Figure 2). When the outer hair cell-generated force is absent under postmortem conditions, the reticular lamina should move passively following the basilar membrane travelling wave with equal magnitude and phase, if the connection between the two structures is rigid. The larger postmortem magnitude and phase difference in gerbils (Figure 2) than those in mice (Figure 2G and H, Ren et al., 2016b) indicate that the mechanical coupling between the reticular lamina and basilar membrane in the gerbil may not be as tight as that in the mouse.

Compared to a large time period (T) at a low frequency (f) (T = 1/f) (such as T = 2,000 µs, where f = 500 Hz), a 17.9-µs latency difference (Figure 3J) is negligible and results in an insignificant phase difference. Thus, the ~180 degree phase difference between the reticular lamina and basilar membrane vibration at a low frequency mainly reflects the opposite movements of both ends of outer hair cells (Brownell et al., 1985). The same latency difference, however, can result in ~180 degree phase difference at the best frequency, due to the small period (such as T = 38 µs, where f = 26 kHz). This latency-induced phase lag of the reticular lamina vibration, compensating for the ~180 degree phase difference observed at low frequencies, accounts for in-phase vibrations of the reticular lamina and basilar membrane at the best frequency. Therefore, the present in vivo results do not conflict with the in vitro observation that both ends of the cylindrical outer hair cells move in opposite directions at low frequencies (Brownell et al., 1985; Santos-Sacchi, 1989).

In summary, heterodyne low-coherence interferometry demonstrates in vivo that the outer hair cell-driven reticular lamina vibration occurs after, not before, the basilar membrane vibration. The reticular lamina and basilar membrane move in opposite directions at low frequencies and in phase near the best frequency. This experimental finding conflicts with commonly accepted cochlear local feedback theory and suggests that outer hair cells enhance hearing sensitivity through a global hydromechanical mechanism.

Twenty-three young healthy Mongolian gerbils of both sexes at age of 4 to 8 weeks (40–80 g) were used in this study.

Measurement of reticular lamina and basilar membrane vibrations

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Animal anesthesia and surgical procedures were the same as described previously (Ren, 2002; Ren et al., 2011; Ren and Nuttall, 2001). Briefly, after about one third of the round window membrane was removed and the opened round window was partially covered with a glass coverslip, the object light from the interferometer was focused on the center of the outer hair cell region of the cochlear partition at the basal turn (Figure 6A). The transverse locations of the basilar membrane and reticular lamina were determined by measuring the backscattered light (carrier) level as a function of the transverse location. The locations of the basilar membrane and reticular lamina were indicated by the two peaks of the backscattered light level (Figure 6B) and confirmed by the distinct magnitude and phase of the cochlear partition vibrations at the two locations (Figure 6C,D). Cochlear partition vibrations were measured as a function of the transverse location at the best frequency (30 kHz) and at different sound levels (0–80 dB SPL).

Figure 6

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When the object beam of the interferometer was focused on the basilar membrane or the reticular lamina, acoustical tones at different frequencies and levels were delivered to the ear canal. The tone frequency was changed from 1.8 to 40.0 kHz by ~0.2 kHz per step. The magnitude and phase of the cochlear partition vibration were measured using a lock-in amplifier (SR830, Stanford Research System, Inc. Sunnyvale, CA) and recorded on a computer. The best frequency was determined by the peak of the basilar membrane displacement as a function of frequency at 30 dB SPL. For recording time waveforms of the reticular lamina and basilar membrane vibration, a 10-µs electrical pulse was generated by a dynamic signal analyzer (PXI-4461, National Instruments, Austin, TX) and used to drive an electrostatic speaker (EC1, Tucker-Davis Technologies, Alachua, FL). Displacements of the reticular lamina and basilar membrane vibrations were digitized at the rate of 200,000 samples per second and averaged synchronously with stimuli for 100 times. Time waveforms from the same time window were plotted to show the temporal relationship between the reticular lamina and basilar membrane vibration (Figure 4). The reticular lamina and basilar membrane vibration were measured in a random order.

Cochlear sensitivity was monitored by continuously recording distortion product otoacoustic emission (DPOAE). The DPOAE at 16 kHz was evoked by two 60 dB SPL tones at 20 and 24 kHz. A cochlea with <5 dB DPOAE decrease was considered sensitive. Postmortem data were collected 10 to 30 min after the animal's death from anesthetic overdose. Stapes vibration was recorded under the same conditions as for the cochlear mechanical measurement.

All data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

1. Wenxuan He

   Oregon Hearing Research Center, Department of Otolaryngology, Oregon Health & Science University, Portland, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

2. David Kemp

   University College London Ear Institute, University College London, London, United Kingdom

   Contribution

   Formal analysis, Validation, Writing—review and editing

   Competing interests

   No competing interests declared

3. Tianying Ren

   Oregon Hearing Research Center, Department of Otolaryngology, Oregon Health & Science University, Portland, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing—original draft, Project administration, Writing—review and editing

   For correspondence

   rent@ohsu.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-2533-7203

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