Outer hair cells stir cochlear fluids

Reviewer #1 (Public review):

Summary:

The authors test the "OHC-fluid-pump" hypothesis by assaying the rates of kainic acid dispersal both in quiet and in cochleae stimulated by sounds of different levels and spectral content. The main result is that sound (and thus, presumably, OHC contractions and expansions) results in faster transport along the duct. OHC involvement is corroborated using salicylate, which yielded results similar to silence. Especially interesting is the fact that some stimuli (e.g. tones) seem to provide better/faster pumping than others (e.g. noise), ostensibly due to the phase profile of the resulting cochlear traveling-wave response.

Strengths:

The experiments appear well controlled and the results are novel and interesting. Some elegant cochlear modeling that includes coupling between the organ of Corti and the surrounding fluid as well as advective flow supports the proposed mechanism.

Weaknesses:

It's not clear whether the effect size (e.g., the speed of sound-induced pumping relative to silence) is large enough to have important practical applications (e.g., for drug delivery). The authors should comment on the practical requirements and limitations.

Although helpful so far as it goes, the modeling could be taken much further to help understand some of the more interesting aspects of the data and to obtain testable predictions. In particular, the authors should systematically explore the level effects they find experimentally and determine whether the model can replicate the finding that different sounds produce different results (e.g. noise vs tone).

The model should also be used to relate the model's flow rates more quantitatively to the properties of the traveling wave (e.g., its phase profile).

Finally, the model should be used to investigate differences between active and passive OHCs (e.g., simulating the salicylate experiment by disabling the model's OHCs).

The manuscript would be stronger if the authors discussed ways to test their hypothesis that OHC motility serves a protective effect by pumping fluid. For example, do animals held in quiet after noise exposure (TTS) take longer to recover?

Reviewer #2 (Public review):

Summary:

Recent cochlear micromechanical measurements in living animals demonstrated outer hair cell-driven broadband vibration of the reticular lamina that contradicts frequency-selective cochlear amplification. The authors hypothesized that motile outer hair cells can drive cochlear fluid circulation. This hypothesis was tested by observing the effects of acoustic stimuli and salicylate, an outer hair cell motility blocker, on kainic acid-induced changes in the cochlear nucleus activities. It was found that acoustic stimuli can reduce the latency of the kainic acid effect, and a low-frequency tone is more effective than broadband noise. Salicylate reduced the effect of acoustic stimuli on kainic acid-induced changes. The authors also developed a computational model to provide the physical basis for interpreting experimental results. It was concluded that experimental data and simulations coherently indicate that broadband outer hair cell action is for cochlear fluid circulation.

Strengths:

The major strengths of this study include its high significance and the combination of electrophysiological recording of the cochlear nucleus responses with computational modeling. Cochlear outer hair cells have been believed to be responsible for the exceptional sensitivity, sharp tuning, and huge dynamic range of mammalian hearing. Recent observation of the broadband reticular lamina vibration contradicts frequency-specific cochlear amplification. Moreover, there is no effective noninvasive approach to deliver the drugs or genes to the cochlea for treating sensorineural hearing loss, one of the most common auditory disorders. These important questions were addressed in this study by observing outer hair cells' roles in the cochlear transport of kainic acid. The well-established electrophysiological method for recording cochlear nucleus responses produced valuable new data, and the purposely developed computational model significantly enhanced the interpretation of the data.

The authors successfully tested their hypothesis, and both the experimental and modeling results support the conclusion that active outer hair cells can drive cochlear fluid circulation in the living cochlea.
Findings from this study will help auditory scientists understand how the outer hair cells contribute to cochlear amplification and normal hearing.

Weaknesses:

While the statement "The present study provides new insights into the nonselective outer hair cell action (in the second paragraph of Discussion)" is well supported by the results, the authors should consider providing a prediction or speculation of how this hair cell action enhances cochlear sensitivity. Such discussion would help the readers better understand the significance of the current work.

Reviewer #3 (Public review):

Summary:

This study reveals that sound exposure enhances drug delivery to the cochlea through the non-selective action of outer hair cells. The efficiency of sound-facilitated drug delivery is reduced when outer hair cell motility is inhibited. Additionally, low-frequency tones were found to be more effective than broadband noise for targeting substances to the cochlear apex. Computational model simulations support these findings.

Strengths:

The study provides compelling evidence that the broad action of outer hair cells is crucial for cochlear fluid circulation, offering a novel perspective on their function beyond frequency-selective amplification. Furthermore, these results could offer potential strategies for targeting and optimizing drug delivery throughout the cochlear spiral.

Weaknesses:

The primary weakness of this paper lies in the surgical procedure used for drug administration through the round window. Opening the cochlea can alter intracochlear pressure and disrupt the traveling wave from sound, a key factor influencing outer hair cell activity. However, the authors do not provide sufficient details on how they managed this issue during surgery. Additionally, the introduction section needs further development to better explain the background and emphasize the significance of the work.