Research

Our current research examines the molecular mechanisms that maintain the survival and function of hair cells and neurons of the cochlea. We study how these homeostatic mechanisms operate under normal conditions and how they respond to environmental stressors, particularly to loud sounds. Based on this knowledge, we study if cellular stress could be manipulated for therapeutic purposes to protect against hearing loss.
In our second project, we characterize the molecular mechanisms in auditory brainstem neurons that are activated upon noise exposure and reduced auditory input. We link this knowledge to changes in neuronal activity and connectivity. We believe that this knowledge contributes to the understanding of neurobiology of tinnitus, opening avenues for the treatment of this disorder.
Our experimental approach involves in vivo functional measurements of hearing, use of various transgenic mouse models, analysis of gene and protein expression, versatile microscopic imaging, organotypic cultures, and viral-mediated gene transfer and drug delivery to the cochlea.

Stress signaling

We have recently shown the mode of action of JNK/c-Jun stress signaling in the lesioned cochlea. We have provided genetic and pharmacological evidence that inhibition of JNK/c-Jun signaling acutely following noise exposure attenuates hair cell loss (Anttonen, Herranen et al., eNeuro 2016). Most recently, we have studied the role of JNK/c-Jun, ERK and NF-kB stress pathways in the lateral wall of the cochlea. We have implicated the lateral wall stress response in inflammation, in the sensitivity of hair cells to loud sounds, and in aging (Herranen et al., JARO 2018).

Illustration of the effect of noise-exposure on c-Jun cellular stress signalling in the cochlea.

Suggested mechanism how c-Jun activation regulates hair cell death.

 

Mouse strain differences in hair cell loss following noise exposure shown in immunofluorescence picture.

Differences in noise vulnerability between mouse strains is demonstrated here by hair cell loss.

 

NF-kB transcriptional activity in the mouse cochlea prior and after noise-exposure.

Transcriptional activity of NF-kB in the mouse cochlea.

 

Repair

We have recently described the modes of hair cell death and the events of actin cytoskeleton-based wound healing in the lesioned organ of Corti of the cochlea, using serial block-face scanning electron microscopy (SBEM). This method is very suitable for 3D subcellular modelling of the organ of Corti (Anttonen et al., JARO 2014, eNeuro 2017).

Cytoskeletal impaitment upon RhoA inactivation in the cochlea.

RhoA inactivation impairs hair cell development.

 

Regeneration

We have recently studied regeneration capacity of the inner ear supporting cells. These cells serve as a potential platform for new hair cell formation. We have shown that DNA damage coupled with limited DNA repair capacity forms a critical barrier for the attempts to stimulate supporting cell proliferation in the adult cochlea. These studies were done using viral-mediated gene transfer in organotypic cultures and the analysis of transgenic mouse models in vitro and in vivo (Mdm2, p53) (Laos et al., Aging 2014, Sci Rep 2017).

Example image of immunohistochemistry in the organ of Corti.

Stimulation of proliferation is challenging in the post-natal cochlea, as shown in the organotypic culture model.

 

Development

We have recently shown that the GTPases Cdc42 and RhoA are required for planar cell polarity and normal cytoskeletal development of hair cells and supporting cells of the cochlea. These studies were done using transgenic mouse models in vivo (Anttonen et al., Sci Rep 2012, eNeuro 2017; Kirjavainen et al., Biol Open 2015).

Planar cell polarity immunofluoresence image sheet.

Cdc42 inactivation impairs planar cell polarity in the developing cochlea.

 

Tinnitus neurobiology

Brainstem neuron stained with green fluorescent, with additional purple colouring for dendrites.

Neurons of the ascending central auditory pathway are finely tuned and very active - but might also be vulnerable.

We study the molecular mechanisms underlying cellular and neuroplastic changes in brainstem auditory neurons following sensory deprivation. Such deprivation can happen e.g. following noise-exposure that has caused damage to the cochlea. We aim to find a connection between the peripheral trauma and the cell-level changes in central brainstem neurons; such new knowledge helps us understand disorders in the auditory system, such as tinnitus, on a neurobiological level.