Hearing loss in juvenile rats leads to excessive play fighting and hyperactivity, mild cognitive deficits and altered neuronal activity in the prefrontal cortex

  1. Jonas Jelinek
  2. Marie Johne
  3. Mesbah Alam
  4. Joachim K. Krauss
  5. Andrej Kral
  6. Kerstin Schwabe

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Abstract

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  1. Version published to 10.1016/j.crneur.2024.100124
  2. PREreview

    This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/10064133.

    This review is the result of a virtual, collaborative live review discussion organized and hosted by PREreview and the journal Current Research in Neurobiology (CRNEUR) as part of a community-based review pilot (you can read more about the pilot here). The discussion was joined by 7 people, including 2 reviewers, 3 authors, and 2 facilitators—one facilitator (DS) has subject-matter expertise and contributed to the discussion and composition of this review. We thank all participants who contributed to the discussion and made it possible for us to provide feedback to this preprint.

    Summary

    The present study aims to investigate the relationship between hearing loss and cognitive impairment at behavioral and neurobiological levels, especially early in development. There are currently competing hypotheses, including the notion that peripheral auditory processing deficits can affect higher-level cognitive function. Alternatively, cognitive deficits observed in deaf children are unlikely to result from auditory impairment per se but instead, for example, by the lack of language skill use as a consequence of early auditory sensory deprivation. The authors harnessed the power of a murine model where deafening could be evaluated in concord with behavioral and neurobiological functions at several time points during development without the language confound.

    The authors relied on a juvenile rat model to meticulously examine the differences between the socio-behavioral and locomotor performance of a deafened group of juvenile rats compared to a sham surgical control group. Furthermore, in order to understand the neurophysiological impact of deafening on the brain, the authors recorded 'resting-state' electrophysiological activity from the medial prefrontal cortex (mPFC), involved in executive function, and the sensory-motor cortex (SMCtx).

    Overall, the main findings were of a behavioral impact in the deafened animals in relation to controls, evaluated systematically for up to 24 weeks, including significantly increased play fighting and hyperactivity measures (among other social interactions that were unaffected – such as following behavior), unaffected radial maze learning but deafened animals being less reliant on subsequent arm entries indicative of an impairment in cognitive function.

    There was also a significant loss of weight in the deafened animals relative to controls, which the authors relate to the increased energy consumption to support the hyperactivity of the deafened group of rats. Finally, there was not a significant effect in the deafened animals on balancing tasks (using Rotarod).

    In terms of neurophysiological impact of deafening, the authors first confirmed the absence of auditory brainstem responses in the deafened animals and then conducted local-field potential (LFP) and single-unit (SU) recording analyses from mPFC and SMCtx under anesthesia. The relative power analyzed with canonical frequency bands of the spectral composition of LFPs recorded in the mPFC showed enhanced Theta and Alpha and decreased Beta and Gamma activity of the deafened rats compared to both controls. By comparison, the LFPs of the SMCtx showed a lower relative power on Theta but no differences were found in the rest of the frequency bands in the deafened group of rats compared to the controls. LFP coherence analyses between mPFC and SMCtx were reduced. Spiking responses were recorded largely from putatively excitatory (broad spiking) neurons, showing significantly decreased firing rates and higher firing rate variability.

    Regarding the previous electrophysiological observations, the authors concluded that the decreased activity observed in the Theta and Alpha bands of the deafened rats could be associated with a decrease in inhibitory control and cognitive function. The researchers also emphasize that a decrease in Beta activity may be related to EEG findings in children with neurodevelopmental and movement disorders.

    This study provides evidence of hearing loss affecting aspects of social behavior and cognitive function and demonstrates disrupted (enhanced or reduced) neurophysiological activity under anesthesia. The results are robustly statistically tested and statistical tests are appropriate. The study provided an animal model demonstrating behavioral and neurobiological impact of deafness, with support for the auditory deprivation hypothesis whereby hearing loss early in development is associated with social and cognitive function effects and neurobiological activity disruption. Below the reviewers list major and minor concerns, and, where appropriate, suggestions for improvements.

    Major concerns and feedback

    1. The study has been very well executed with data from deafened and control animals systematically collected at several time points throughout the 24 week monitoring period, followed by terminal neurophysiological recordings of spontaneous activity under anesthesia. Even though the behavioral results are very interesting as a function of time, some of the reported effects are present from the onset and then drop below significance, while others become significant over time. The temporal factor in the results could benefit from being more carefully discussed.

    2. The discussion could benefit from better considering whether hearing loss more likely causally or indirectly affects these behavioral and neurophysiological alterations. It is worth considering that there might be an indirect intervening factor that is not yet defined as a basis here or was not possible to measure as a mediating factor.

    3. The importance of this animal model could be more strongly and clearly stated because children's studies will always be confounded not just by the language factor but also by the fact that deaf children experience different social environments and face different degrees of disadvantages in a world predominantly built by and for hearing individuals. This rodent model study is important because it can take language skill learning out of the equation and the hearing and deafened animals experienced similar environmental conditions.

    4. The specific a-priori hypotheses are not clear at the beginning, although the reviewers recognized that some assessments (like the neurophysiological measures) are important simply because of their exploratory nature.

    5. The authors note that they relied on the 3Rs principles (in particular the Reduction of animal numbers) to determine the number of animals that they tested. However, in lieu of pre-study sample size calculations the justification could be clearer in terms of prior studies (e.g., theirs and others). Better justification for the sample sizes to non-experts would be useful, grounded in the standards for these sorts of studies in murine models.

    6. This study builds on a study previously published by some of the coauthors in which they carried out similar research on adult rats (Johne et al., 2022). The reviewers think that there is a missed opportunity to more deeply relate the current results to those in older animals or consider how the results from this study in young animals compare to the prior in older animals. For instance, the neurophysiological results in the two studies seem to go in opposite directions–most noteworthy the results related to the Theta activity in mPFC. Is it possible this is due to the age difference? What are other possible explanations of these contrasting results and why? There is substantial interest to better understand the mechanistic link between hearing loss and cognition across the lifespan (Griffiths et al., 2020, citation below), so including further arguments around this issue in the discussion would be helpful to frame the studies within the broader literature.

    Minor concerns and feedback

    1. Only male rats were used. Can the authors explain what led to that choice and consider this in their interpretations in the discussion? In the absence of any specific requirement to only focus on one sex, it is highly recommended to balance the usage of male and female animal models in cell and animal studies (McCullough et al., 2014). 

    2. The reviewers were surprised to find that there was no balance/motor impairment observed in the juvenile deafened rats. However, it was found that children with hearing loss had some locomotion impairment (Rajendran et al., 2011, Kamel et al., 2021). It would be helpful if the authors could elaborate in the discussion on why they think this was the case.

    3. The canonical frequency bands as the ones used for adult rats in this and the previous study (Johne et al., 2022) may be questioned in the future if juvenile LFP frequency bands are shown not to directly relate to adult canonical frequency bands. It would be good for the authors to share the data and code used to generate the related figures so that other researchers and readers have the option to re-analyze and visualize the results in a way that is independent of the choice of canonical frequency bands.

    4. Even though bar graphs may be preferred because of the large size of the data and for the clarity they offer in summarizing the effects, the reviewers recommend the authors consider regenerating the figures using plots that allow for a clear visualization of the data distribution (e.g., box plots, violin plots), or if they choose to stick with bar graphs to share the data used to generate the figures so that the data points that contributed to the results summary figures are available for other researchers to study.

    5. Avoid red and green of the same luminance for red-green color-blind individuals.

    We thank the authors of the preprint for posting their work as such and for agreeing to participate in this pilot. We also thank all the participants of the live review for their time and for engaging in the lively, constructive discussion that generated this review.

    Citations

    Johne, M., Helgers, S. O. A., Alam, M., Jelinek, J., Hubka, P., Krauss, J. K., Scheper, V., 723 Kral, A., & Schwabe, K. (2022). Processing of auditory information in forebrain regions 724 after hearing loss in adulthood: Behavioral and electrophysiological studies in a rat 725 model. Frontiers in Neuroscience, 16. https://doi.org/10.3389/FNINS.2022.966568 

    Griffiths, Timothy D., et al. How can hearing loss cause dementia?  Neuron 108.3 (2020): 401-412. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664986/ 

    McCullough LD, de Vries GJ, Miller VM, Becker JB, Sandberg K, McCarthy MM. NIH initiative to balance sex of animals in preclinical studies: generative questions to guide policy, implementation, and metrics. Biol Sex Differ. 2014 Oct 3;5:15. doi: 10.1186/s13293-014-0015-5. PMID: 25780556; PMCID: PMC4360141.

    Rajendran V, Roy FG. An overview of motor skill performance and balance in hearing impaired children. Ital J Pediatr. 2011 Jul 14;37:33. doi: 10.1186/1824-7288-37-33. PMID: 21756300; PMCID: PMC3143087.

    Kamel, Roshdy M. et al. 'Sensorineural Hearing Loss Imprint on Fine Motor Skills: A Pediatric and Adolescent Innovative Study'. 1 Jan. 2021 : 285 – 292.

    Competing interests

    Reviewer Daniela Saderi holds a Ph.D. in auditory neuroscience and is also the Director of PREreview, the platform that published this preprint review. Reviewer Chris Petkov is Professor of Neurosurgery at the University of Iowa and is also the Co-Editor in Chief of Current Research in Neurobiology, the journal that partnered with PREreview for a pilot series of live reviews (read more here). They took part in the review process given their expertise in auditory neuroscience and to obtain first-hand reviewer experience as part of the pilot series.

  3. Version published to 10.1101/2023.08.23.554422v1 on bioRxiv