By Maša Švent, University of Leicester, Leicester, UK
What is tinnitus?
Have you ever heard a buzzing or ringing noise in your ears that came “out of nowhere”? Were you relieved that it disappeared as suddenly as it arrived? For as many as 1 in 8 adults in the UK, such phantom noise called tinnitus is persistent and forms a disruptive background to their lives. Despite its prevalence, there is currently no available cure.
Where does ringing in the ears come from?
We know that tinnitus is generated by the neurons in the central nervous system rather than in the ear itself. Tinnitus often accompanies hearing loss, suggesting that the perception of a phantom sound occurs when neurons in the central nervous system compensate for the decreased auditory information by increasing their activity levels. It is likely that this compensatory increase in neuronal activity creates the perception of a phantom sound.
But where exactly in the brain does tinnitus occur? Neuronal hyperactivity can be observed at various brain regions involved in the processing of a sound.
One particularly interesting region is the dorsal cochlear nucleus (DCN). The DCN receives both the auditory signals as well as multisensory information such as positioning of the head. Neurons in the DCN combine both types of information in a process called multisensory integration to determine the location of a sound.
We recently showed that reducing neuronal activity in the DCN restores impaired auditory perception in an animal model of tinnitus (1). Understanding how tinnitus is generated in the DCN is therefore important for identifying therapeutic targets for this debilitating condition.
How can we silence tinnitus?
Our lab, led by Martine Hamann, investigates the processes which regulate multisensory integration in the DCN. We are particularly interested in identifying the signalling pathways responsible for the increase in neuronal activity that compensates for hearing loss.
In the DCN, multisensory integration is mediated by the principal neurons, which form synapses with both the auditory nerve and the multisensory inputs. When either of these inputs are activated (e.g. when you hear a sound or move your head), glutamate is released into the synapse where it binds to the glutamate receptors and activates the principal neurons.
We recently showed that noise exposure, a common cause of hearing loss and tinnitus, oppositely affects glutamate release at the auditory and multisensory synapses in animal models of tinnitus. We showed that while noise exposure decreases glutamate release at the auditory nerve synapses (2), it increases glutamate release at the multisensory synapses (1), suggesting the presence of a compensatory mechanism in the DCN.
I am interested in understanding what types of receptors glutamate activates at the multisensory synapses, as blocking these could decrease the perception of tinnitus.
In my PhD, I used a sensitive technique to record electrical activity from individual DCN principal neurons. I showed that activation of one type glutamate receptors (called NMDA receptors) promotes glutamate release and increases principal neuron activity, indicating that a compensatory increase in neuronal activity occurs at the level of single principal cells.
As glutamate release is closely linked to a rise in presynaptic calcium, I complemented my electrophysiological studies with presynaptic calcium imaging. I used transgenic mice expressing a genetically-encoded calcium indicator which reports fluorescence levels linked to presynaptic calcium (3). This calcium indicator was recently developed by Nicholas Hartell at the University of Leicester and allowed me to show that inhibition of NMDA receptors decreases the presynaptic calcium at the multisensory synapses. This result suggests that NMDA receptor inhibitors could decrease the glutamate release at multisensory synapses and in this way reduce the neuronal hyperactivity observed in tinnitus.
Finally, I showed that the effects of NMDA receptors on presynaptic calcium were mediated by a particular subtype of NMDA receptors (i.e. those containing the NR2B subunit). As NMDA receptors are widely expressed across the brain, identifying the NMDA receptor subtypes which increase the neuronal activity in tinnitus is an important step towards identifying specific targets for pharmacological interventions.
I am grateful that I had the opportunity to present my research at the Future Physiology 2020 conference and am honoured to be awarded the Michael J Rennie Oral Communication Prize, an award for the best oral communication by an Early Career Researcher..
References:
- Tagoe T, Deeping D, Hamann M. Saturation of long-term potentiation in the dorsal cochlear nucleus and its pharmacological reversal in an experimental model of tinnitus. Exp Neurol. 2017;292:1-10.
- Tagoe T, Barker M, Jones A, Allcock N, Hamann M. Auditory nerve perinodal dysmyelination in noise-induced hearing loss. J Neurosci. 2014;34(7):2684-2688.
- Al-Osta I, Mucha M, Pereda D, et al. Imaging calcium in hippocampal presynaptic terminals with a ratiometric calcium sensor in a novel transgenic mouse. Front Cell Neurosci. 2018;12:1-16.