Pathological ensembles in the auditory thalamocortical circuit following acoustic trauma

Lead Research Organisation: University of Strathclyde
Department Name: Inst of Pharmacy and Biomedical Sci

Abstract

The brain is like a social network, where billions of neurons are connecting and chemically talking each other. In brain sciences, one of the biggest mysteries is how the brain can create sensations. While our sensations result from processing of sensory stimuli by the brain circuit, the brain circuit also creates abnormal sensations, such as a phantom limb, tinnitus and hallucinations, from which millions of people around the world is suffering.

Tinnitus, for instance, is the perception of sound or noise in the absence of auditory stimuli. Many of us have some experience a buzzing or ringing in the ears, especially after exposure to loud noise, such as music or sports events. Although this is a temporary problem for most people, this phantom auditory perception is persistent in 5-15% of the general population. In around 2%, tinnitus causes severe impairment of the quality of lives, such as sleep disturbance, depression, anxiety, and even suicide. Moreover, tinnitus is strongly associated with ageing. Given the fact that human longevity is increasing, the impact of tinnitus on society will get worse. Therefore tinnitus is a major public health issue. But unfortunately treatment options remain limited.

What is known about tinnitus?

Over the past decades, scientists have identified several mechanisms of tinnitus in the brain. Although tinnitus is initiated by focal damage to the peripheral auditory pathway, so-called the cochlea, the central auditory pathway also struggles to adapt to it. For example, neurons in the central auditory pathway become hyperactive without auditory inputs. Tonal frequency maps in the brain, so-called tonotopic maps, are also altered. These abnormalities are thought as possible mechanisms of tinnitus. But we have not fully understood exactly how tinnitus is generated.

There is an important brain circuit for sensory perception. This circuit consists of the thalamus and cortex. In the auditory system, they are called the auditory thalamus and auditory cortex, respectively. In general, the sensory thalamus is directly transferring sensory signals from periphery to the sensory cortex while the cortex is also returning signals back to the thalamus. This thalamocortical loop has long been implicated in sensory perceptions. Therefore we suspect that abnormal activity in the auditory thalamocortical circuit is a possible mechanism of phantom auditory perception, tinnitus. Although there is indirect evidence for this prediction, no one has directly measured neural activity from both the auditory thalamus and cortex in this context.

In this proposed research, by using behavioural and state-of-the-art electrophysiological approaches, we aim to determine relationships between tinnitus and pathological activities in the auditory thalamus and cortex.

The results of our research will provide further insights into the mechanisms of tinnitus at the level of neuronal circuits. Our long-term perspective envisions the development of better strategies to treat tinnitus. Therefore, this proposal will contribute to both sensory neuroscience and human health.

Technical Summary

We aim to identify neural correlates of phantom auditory perception (tinnitus) at the level of neuronal circuits. By using a massively parallel extracellular recording technique and a behavioural approach in awake rats, we will determine relationships between tinnitus and abnormal neural population activity in the auditory thalamocortical circuit.

Tinnitus is the perception of sound in the absence of auditory stimuli. Tinnitus is persistent in ~10% of the general population. In ~2%, it causes severe impairment of the quality of lives. Given the strong association between tinnitus and ageing, the impact of tinnitus on society will likely get worse. However, treatment options remain limited and it is still elusive how tinnitus is generated.

At least two mechanisms in the central nervous system have been proposed to underlie tinnitus: abnormalities in spontaneous neural activity and reorganization of tonotopic maps. The pathological activity has been identified across the auditory pathway and even in limbic areas, suggesting abnormal interactions between distributed circuits.

Here we will address two issues: first, previous animal neurophysiological studies have been done under anaesthesia where tinnitus is unlikely present. Second, little is known about how tinnitus is associated with functional interactions in the auditory thalamocortical circuit, which has long been implicated in auditory perception.

Specifically, we will test the hypothesis that tinnitus is associated with pathological neural population activity in the auditory thalamocortical circuit. We will assess behavioural correlates of tinnitus in rats following acoustic trauma. Then we will monitor neural population activity in the auditory thalamocortical circuit of head-restrained, awake rats.

The results of our proposal will provide insights into the mechanisms of tinnitus at the neural circuit level. This proposal contributes to both sensory neuroscience and human health.

Planned Impact

The general public and charities will benefit from our hearing research. Tinnitus is persistent in 5-15% of the general population. In around 2%, tinnitus causes severe impairment of the quality of lives. Moreover, tinnitus is strongly associated with ageing. Given the fact that human longevity is increasing, the economic and social impact of tinnitus will get worse particularly in developed countries. Although this proposal is not likely to generate commercially exploitable results, our research will contribute to raising public awareness of tinnitus, hearing loss, and other hearing problems in the short-term. To this end, we will keep our web sites updated, and will participate in fundraising events of charities, such as Deafness Research UK.

Because this research aims to identify neural mechanisms of tinnitus, this research will also contribute to the development of better strategies for treatment by expanding our research programmes in the long-term.


Neurotechnology industry is a potential beneficiary because our in vivo electrophysiological technique is related to some markets of the neurotech industry, in particular neuroprosthetic devices.

In general, the neurotech industry includes companies researching, developing and marketing pharmaceuticals, biologics, cell-based therapeutics and medical devices, as well as diagnostic and surgical equipment for the treatment of neurological diseases, nervous system ailments and psychiatric illnesses. According to the Neurotechnology Industry Organization in the US, over 850 companies were involved in the neurotech industry in 2008 with $144.5 billion revenues and 9.0% growth. One of three sectors in the industry is called "Neurodevices" and generated revenues of $6.1 billion with 18.6% annual growth. This sector further consists of four markets, one of which is related to neuroprosthetic devices where our in vivo electrophysiological technique is a promising means to develop neural prosthetics. Thus, our proposal will potentially contribute to the development of auditory prosthetics and brain-machine interfaces in the long-term. By making connections with related industrial companies primarily through activity of CeNsUS (Centre for Neuroscience, University of Strathclyde), we will maximise the impact of our research in the short-term.


The other potential beneficiary is academic community working on large-scale computer simulations of the brain circuit. Recently, systems and computational neuroscientists are trying to develop large-scale computer simulations of the brain circuits (such as the Blue Brain Project). This approach will not just contribute to biomedical researches, but will also provide alternatives to animal researches, that is, brain researches in silico ultimately. Sharing our experimental data with such computational neuroscientists, our proposal will contribute to this field. We will maximise the impact of our research by sharing our experimental data with researchers and enhancing multidisciplinary collaborations.

Publications

10 25 50
 
Description BBSRC
Amount £310,058 (GBP)
Funding ID BB/K016830/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 08/2013 
End 08/2016
 
Title Data for: "State-dependent and cell type-specific temporal processing in auditory thalamocortical circuit" 
Description Dataset for manuscript "State-dependent and cell type-specific temporal processing in auditory thalamocortical circuit." Data files contains all processed (spike sorted) data and all original figures. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
 
Title State-dependent and cell type-specific temporal processing in auditory thalamocortical circuit 
Description Not Available 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact Not Applicable 
 
Description Information Theory 
Organisation University of Glasgow
Country United Kingdom 
Sector Academic/University 
PI Contribution Sharing experimental data
Collaborator Contribution Analysing experimental data
Impact No output yet
Start Year 2013
 
Description Optogenetics and pharmacogenetics 
Organisation Nagoya University
Department Department of Neuroscience
Country Japan 
Sector Academic/University 
PI Contribution applying new molecular tools to control brain activities
Collaborator Contribution developing new molecular tools
Impact A postdoctoral researcher of my partner was awarded by the travel grant and fellowship to join my research team in 2014
Start Year 2013
 
Description Tinnitus 
Organisation RIKEN
Department RIKEN Brain Science Institute
Country Japan 
Sector Public 
PI Contribution sharing experimental data
Collaborator Contribution analysing experimental data
Impact Poser presentations at the Computational Neuroscience Society and the Society for Neuroscience
Start Year 2011
 
Description microLED probe 
Organisation University of Strathclyde
Department Institute of Photonics
Country United Kingdom 
Sector Academic/University 
PI Contribution Testing new devices for in vivo optogenetics
Collaborator Contribution Fabricating new devices for in vivo optogenetics
Impact Opt Lett. 2013 Mar 15;38(6):992-4. doi: 10.1364/OL.38.000992. Thermal and optical characterization of micro-LED probes for in vivo optogenetic neural stimulation. McAlinden N, Massoubre D, Richardson E, Gu E, Sakata S, Dawson MD, Mathieson K.
Start Year 2012