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Translational Auditory Neuroscience

Hearing deficits are expected to affect 900 million individuals world- wide in 2025, and has recently ranked 4th in the leading causes of years lived with disability (WHO).

One of the most prevalent and distressing condition associated with hearing loss is tinnitus, or ringing in the ears, which is defined by the perception of sounds in spite of their physical absence. This neurological disorder affects 10-15% of the population and is predicted to double in Europe by 2050. In 1 out of ten, severe tinnitus distracts sufferers from work, interferes with concentration and sleep, increases the risk of disability pension and can be so severe as to trigger suicide. Both patients and therapists are highly unsatisfied by the available therapeutic options, and ENTs most often recommend patients to “live with it”. This is in part due to the lack of fundamental knowledge on the mechanisms causing tinnitus, and those making it persistent and severe.

The goal of the laboratory is to increase the understanding of the mechanisms underlying hearing loss and the maladaptive plasticity occurring during tinnitus with hopes to develop new treatments and drugs to improve hearing function and silence tinnitus.

Our research

Our ultimate goal is the prevention and cure of hearing loss and tinnitus. For this purpose, we have established collaborations with both clinical researchers and the industry to facilitate the translation of our findings into cures. The laboratory focuses on i) the molecular mechanisms that regulate synaptic uncoupling in the ear, ii) the mechanisms that govern homeostatic plasticity in the brain during tinnitus, iii) the causative relationship between peripheral damage and phantom sound generation. We have a dual approach using animal models of hearing loss and tinnitus to decipher the signaling pathways disrupted in the ear and/or in the brain but also using genetics in multi-case families with history of tinnitus and/or hearing loss, having in aim the identification and validation of new targets for drug development.

To address this challenge, we use a battery of techniques including behavior, neuroimaging, auditory electrophysiology, molecular biology, synaptic histology, cell culture, cytometry, mouse and human genetics and epidemiology.

Group members

Christopher Cederroth - Associate Professor, group leader

Niklas Edvall - PhD student

Evangelia Tserga - PhD student

Natalia Trpchevska - PhD student

Former group members

Rocio Paublete - Postdoc

Kim Vikhe Patil (2016) - Master student

Rotation and internships

Daniele Scarcella (2019) – AMGEN summer student

Andra Lazar (2019) – visiting Medical doctor

Valeria Valieva (2019) – visiting Nurse

Petra Brüggemann (2019) – visiting Post-Doc

Alessandra Lugo (2019) – visiting Post-Doc

Eleni Genistarditi (2018) – visiting PhD student

Edis Gunan (2018) – Summer Research School student

Matilda Prada Hellberg (2018) - Summer Research School student

Lucy Yeung (2015) – visiting student

Xi Liu (2014) – trainee

Projects

Role of glutamate transporters in noise and drug-induced hearing loss and tinnitus

Using mouse genetics, we identified a role for glutamate transporters in regulating tinnitus. We are now characterizing the mechanisms by which disruption in glutamate homeostasis causes a phantom sound percept.

The main aim is to characterize the functional and molecular consequences of glutamate-mediated de-afferentation in the cochlea. Our working hypothesis is that excess glutamate release in the cochlea causes overexcitation of the auditory neurons, hyperactivate auditory relays, reorganize the auditory cortex and subsequent tinnitus.

The ultimate goal is to provide a better understanding of the ear to brain interactions. These results may have a broad clinical application, contributing to the detailed understanding of normal auditory physiology, as well as the origins of tinnitus resulting from subtle auditory dysfunctions.

Funding:

Vetenskapsrådet, KID

Publication:

GLAST Deficiency in Mice Exacerbates Gap Detection Deficits in a Model of Salicylate-Induced Tinnitus.
Yu H, Vikhe Patil K, Han C, Fabella B, Canlon B, Someya S, et al
Front Behav Neurosci 2016 ;10():158

Circadian rhythms in the auditory system

In collaboration with Prof. Barbara Canlon, we are investigating how circadian rhythms impact on auditory function.

The aim of this project is to better understand the mechanisms underlying differences in noise sensitivity throughout the day, in order to improve treatment efficacy using chronopharmacology.

Collaborations:

Frederic Gachon

Funding:

Department of Defense, NIDCD.

Publications:

Circadian Regulation of Cochlear Sensitivity to Noise by Circulating Glucocorticoids.
Cederroth CR, Park JS, Basinou V, Weger BD, Tserga E, Sarlus H, et al
Curr. Biol. 2019 Aug;29(15):2477-2487.e6

Differential Phase Arrangement of Cellular Clocks along the Tonotopic Axis of the Mouse Cochlea Ex Vivo.
Park JS, Cederroth CR, Basinou V, Sweetapple L, Buijink R, Lundkvist GB, et al
Curr. Biol. 2017 Sep;27(17):2623-2629.e2

TrkB-mediated protection against circadian sensitivity to noise trauma in the murine cochlea.
Meltser I, Cederroth CR, Basinou V, Savelyev S, Lundkvist GS, Canlon B
Curr. Biol. 2014 Mar;24(6):658-63

STOP: Swedish Tinnitus Outreach Project

Tinnitus is a very heterogeneous disorder. Distinct forms of tinnitus cannot respond as well to the same therapeutic intervention.

The goals of this study are to identify determinants of tinnitus, and use a comprehensive approach to classify tinnitus patients according to subtypes by means of questionnaires and auditory assessment in order to evaluate the prevalence of each form of tinnitus.

In a second step, we want to identify homogeneous sub-groups and perform genetic analyses to define new endophenotypes for a more accurate diagnostic of tinnitus patients at the clinic.

See the Swedish Tinnitus Outreach Project (STOP) for more information.

Collaborations:

University of Nottingham, University of Bergen, University of Granada, Institute Mario Negri (Milano), Decibel Therapeutics.

Funding:

Marie Curie ITN (ESIT), GENDER-NET Co-Plus Fund, Decibel Therapeutics.

The genetic basis of hearing loss and tinnitus

Tinnitus has always been thought to derive from environmental factors, and evidence of genetic contributions to tinnitus have been lacking. We recently evidenced in twins and adoptees the genetic transmission of tinnitus and have initiated large scale studies using GWAS, WES, and WGS to identify functional variants associated in tinnitus. In parallel, while the monogenic transmission of hearing loss is acknowledged, less is known on the complex genetic architecture that governs hearing problems. The comparison of the genetic landscape between hearing loss and tinnitus will provide insights on the pathways involved specifically in the two auditory disorders.

Collaborations:

University of Granada, Decibel Therapeutics.

Funding:

Marie Curie ITN (ESIT), GENDER-NET Co-Plus Fund, Decibel Therapeutics, Forschung für Leben, Svenska Läkaresällskapet, Lars Hiertas Minne, Tysta Skolan. 

Publications:

Association of Genetic vs Environmental Factors in Swedish Adoptees With Clinically Significant Tinnitus.
Cederroth CR, PirouziFard M, Trpchevska N, Idrizbegovic E, Canlon B, Sundquist J, et al
JAMA Otolaryngol Head Neck Surg 2019 Mar;145(3):222-229

Genetic susceptibility to bilateral tinnitus in a Swedish twin cohort.
Maas IL, Brüggemann P, Requena T, Bulla J, Edvall NK, Hjelmborg JVB, et al
Genet. Med. 2017 09;19(9):1007-1012

The epidemiology of hearing loss and tinnitus

Knowledge on the environmental contributors to tinnitus are poorly known. Our recent systematic review identifies a handful of longitudinal or case-control studies suggesting a causal relationship with the development of hearing loss and tinnitus. Here, we use cross-sectional and longitudinal data from large Swedish cohorts in order to identify exposures that contribute to the development of hearing loss and tinnitus and reversely if both auditory conditions can be used as a predictor of other disorders.

Collaborations:

Charité Tinnitus Clinic (Berlin), Institute Mario Negri (Milano), Decibel Therapeutics.

Funding:

GENDER-NET Co-Plus Fund.

Publication:

Sex-Specific Association of Tinnitus With Suicide Attempts.
Lugo A, Trpchevska N, Liu X, Biswas R, Magnusson C, Gallus S, et al
JAMA Otolaryngol Head Neck Surg 2019 Jul;145(7):685-687

TODD: Tinnitus Objective Diagnostic Device

An important gap in the care of tinnitus patients is the lack of robust objective methodologies to diagnose tinnitus. This project aims to translate to humans an objective measure of tinnitus developed in animals. Here, we use MEG to investigate cortical evoked responses to specific sequences of stimuli and assess whether the responses are altered in tinnitus subjects.

Funding:

KID.

Publication:

Differential Neural Responses Underlying the Inhibition of the Startle Response by Pre-Pulses or Gaps in Mice.
Moreno-Paublete R, Canlon B, Cederroth CR
Front Cell Neurosci 2017 ;11():19

Global Burden of Disease study

In view of the recent call for action from the WHO to better understand the impact of auditory disorders on life quality, I joined the GBD study as a collaborator with expertise in the auditory system. 

Research support

  • H2020 GENDER-NET Co Plus Fund
  • H2020 ITN (ESIT)
  • Vetenskapsrådet
  • Svenska Läkaresällskapet
  • Lars Hiertas Minne
  • Magnus Bergvalls Stiftelse
  • Loo och Hans Ostermans
  • Tysta Skolan
  • Hörselforskningsfonden
  • Karolinska Institutet

Collaborations

National collaborators

International collaborators

  • Professor Berthold Langguth, University Hospital of Regensburg, Germany
  • Professor David Baguley, University of Nottingham, UK
  • Professor Deborah Hall, University of Nottingham, UK
  • Professor Birgit Mazurek, Chartié Hospital, Germany
  • Dr. Silvano Gallus, Institute of Research Mario Negri, Italy
  • Professor Jan Bulla, University of Bergen, Norway

Additional relevant Articles/Publications

Medicine in the Fourth Dimension.
Cederroth CR, Albrecht U, Bass J, Brown SA, Dyhrfjeld-Johnsen J, Gachon F, et al
Cell Metab. 2019 Aug;30(2):238-250

Therapeutic Approaches to the Treatment of Tinnitus.
Langguth B, Elgoyhen AB, Cederroth CR
Annu. Rev. Pharmacol. Toxicol. 2019 Jan;59():291-313

Hearing loss and tinnitus--are funders and industry listening?
Cederroth CR, Canlon B, Langguth B
Nat. Biotechnol. 2013 Nov;31(11):972-4

Dissertations

2017 - Vasiliki Basinou, PhD
Title of thesis: Circadian rhythms in the auditory system
Department of Physiology and Pharmacology, Karolinska Institutet

2009 - Christopher R. Cedderroth, PhD
Title of thesis: Endocrine Disruptors and the Fetal Origin of Diseases.
Department of Genetic Medicine and Development, University of Geneva, Switzerland.

Contact

Christopher Cederroth

Senior researcher
C3 Department of Physiology and Pharmacology