Mechanisms of cortical modulation of the auditory midbrain
Lead Research Organisation:
Newcastle University
Department Name: Biosciences Institute
Abstract
Hearing is immensely important to us for communication, navigating our environment and appreciating music. What we hear is not simply determined by the sound waves that strike our ears. Rather our perception of incoming sounds depends on several additional factors including recently heard sounds that govern our expectations, signals from vision and other senses, and where our attention is directed. These mechanisms can aid our ability to understand sounds by providing contextual information or by 'tuning' our hearing. A decline in such systems with ageing may contribute to hearing difficulties (such as understanding speech in noisy environments) that often occur independently of any overall loss of sensitivity to sound.
The auditory pathway consists of a series of brain centres which process sound-related information and feed it to the auditory cortex. The mechanisms by which recent sound experience and information from visual and other senses affect hearing are not clear. However, we know that the cortical regions where this information is represented send nerve fibre connections back to lower levels in the auditory pathway. The auditory centre that receives the most inputs from cortical regions is called the inferior colliculus. The inferior colliculus also receives converging inputs from lower parts of the auditory pathway, so it is a prime site at which to expect cortical modification to occur.
Our overarching goal is to discover how the higher levels of the auditory system control lower centres in the auditory pathway. Specifically in this project using the rat as a model, we aim to discover how information from cortical regions influences the responses of inferior colliculus neurons to sounds. Although we know the inferior colliculus receives inputs from the cortex, we don't know the precise origin of these connections, what sorts of cells they contact in the inferior colliculus, or what neural signalling mechanisms they activate. We have three strategies to achieve this goal:
First, we will discover the organisation of the connections between cortical regions and the inferior colliculus using tracer molecules that are picked up and transported by neurons as well as viruses which produce fluorescent proteins in the neurons. These methods allow us to see the neurons connecting different areas under the microscope. Importantly, we will do this along with mapping the auditory cortex with sounds to see how the projections relate to the different maps of sound frequency found there. We will also discover if there are inputs to the inferior colliculus from cortical regions concerned with vision or other senses.
Second, we will use a method called 'optogenetics' to switch on and off the cortical neurons that project to the inferior colliculus using different colours of light delivered by a fine optical fibre. We will study how changing the activity of the cortical neurons affects the firing of nerve cells in the inferior colliculus in response to sounds played to the ears of an anaesthetised rat.
Third, we aim to discover the mechanisms by which cortical neurons influence the inferior colliculus. Our pilot experiments show that the part of the inferior colliculus that receives most connections from the cortex has many neurons that produce a chemical neurotransmitter called nitric oxide. In other parts of the brain, nitric oxide interacts with a type of receptor for the neurotransmitter glutamate called the NMDA receptor. We think that an interaction of nitric oxide and NMDA receptors might be involved in the effects that cortical neurons have on the inferior colliculus. We will combine our recording and optogenetic methods with a technique that allows us to apply drugs to the inferior colliculus that block NMDA receptors and interfere with nitric oxide.
These experiments will help us understand the important question of how the higher cortical centres influence processing earlier in the auditory pathway.
The auditory pathway consists of a series of brain centres which process sound-related information and feed it to the auditory cortex. The mechanisms by which recent sound experience and information from visual and other senses affect hearing are not clear. However, we know that the cortical regions where this information is represented send nerve fibre connections back to lower levels in the auditory pathway. The auditory centre that receives the most inputs from cortical regions is called the inferior colliculus. The inferior colliculus also receives converging inputs from lower parts of the auditory pathway, so it is a prime site at which to expect cortical modification to occur.
Our overarching goal is to discover how the higher levels of the auditory system control lower centres in the auditory pathway. Specifically in this project using the rat as a model, we aim to discover how information from cortical regions influences the responses of inferior colliculus neurons to sounds. Although we know the inferior colliculus receives inputs from the cortex, we don't know the precise origin of these connections, what sorts of cells they contact in the inferior colliculus, or what neural signalling mechanisms they activate. We have three strategies to achieve this goal:
First, we will discover the organisation of the connections between cortical regions and the inferior colliculus using tracer molecules that are picked up and transported by neurons as well as viruses which produce fluorescent proteins in the neurons. These methods allow us to see the neurons connecting different areas under the microscope. Importantly, we will do this along with mapping the auditory cortex with sounds to see how the projections relate to the different maps of sound frequency found there. We will also discover if there are inputs to the inferior colliculus from cortical regions concerned with vision or other senses.
Second, we will use a method called 'optogenetics' to switch on and off the cortical neurons that project to the inferior colliculus using different colours of light delivered by a fine optical fibre. We will study how changing the activity of the cortical neurons affects the firing of nerve cells in the inferior colliculus in response to sounds played to the ears of an anaesthetised rat.
Third, we aim to discover the mechanisms by which cortical neurons influence the inferior colliculus. Our pilot experiments show that the part of the inferior colliculus that receives most connections from the cortex has many neurons that produce a chemical neurotransmitter called nitric oxide. In other parts of the brain, nitric oxide interacts with a type of receptor for the neurotransmitter glutamate called the NMDA receptor. We think that an interaction of nitric oxide and NMDA receptors might be involved in the effects that cortical neurons have on the inferior colliculus. We will combine our recording and optogenetic methods with a technique that allows us to apply drugs to the inferior colliculus that block NMDA receptors and interfere with nitric oxide.
These experiments will help us understand the important question of how the higher cortical centres influence processing earlier in the auditory pathway.
Technical Summary
Hearing begins with the transduction of sound waves to electrical signals that are processed along the auditory pathway leading to the auditory cortex. Sound perception, however, depends not only on ascending information, but also on top-down influences, including predictive information derived from stimulus history, input from other senses, such as vision, and cognitive mechanisms such as attention. Where and how these influences impact on the processing of in-coming sounds is not clear, but one putative pathway is through the extensive descending projections from the cortex back to lower levels of the auditory pathway. The auditory structure which receives the largest number of cortical fibres is the inferior colliculus (IC). This centre processes input from several brainstem circuits and sends information, via the thalamus, to the auditory cortex.
Using the rat as a model, and employing neuroanatomical, electrophysiological and optogenetic methods, we propose to test hypotheses about the organisation of the cortical inputs to the IC and the synaptic mechanisms through which they exert their effects. We will use tract tracing to define the input the IC receives from physiologically defined regions of the auditory cortex and determine whether it also receives projections from visual or other non-auditory cortices. Using optogenetics in vivo to stimulate and inactivate cortical projections to the IC, we will determine their influence on the responses of IC neurons to sounds, examining both acute modulation of activity and plasticity of responses. Finally, we will combine these methods with local application of drugs into the IC to test the hypothesis that cortico-collicular effects are mediated by glutamate, NMDA-receptor and nitric oxide signalling.
The experiments will further our understanding of a potentially important, but poorly understood, aspect of sensory processing, and provide insights into how age-related cortical changes could impact on hearing.
Using the rat as a model, and employing neuroanatomical, electrophysiological and optogenetic methods, we propose to test hypotheses about the organisation of the cortical inputs to the IC and the synaptic mechanisms through which they exert their effects. We will use tract tracing to define the input the IC receives from physiologically defined regions of the auditory cortex and determine whether it also receives projections from visual or other non-auditory cortices. Using optogenetics in vivo to stimulate and inactivate cortical projections to the IC, we will determine their influence on the responses of IC neurons to sounds, examining both acute modulation of activity and plasticity of responses. Finally, we will combine these methods with local application of drugs into the IC to test the hypothesis that cortico-collicular effects are mediated by glutamate, NMDA-receptor and nitric oxide signalling.
The experiments will further our understanding of a potentially important, but poorly understood, aspect of sensory processing, and provide insights into how age-related cortical changes could impact on hearing.
Planned Impact
Impact beyond academia includes:
The BBSRC. In addressing the fundamental mechanisms of hearing at the systems level, and how connections from the cerebral cortex impact on earlier stages in the hearing pathway the work is relevant to the BBRC's Strategic priorities Bioscience for Health, and responsive mode priorities 1) healthy ageing across the life course, and 2) systems approaches to the biosciences.
Hearing Charities such as Action on Hearing Loss who provided a pump-priming Flexigrant to gather pilot data for this proposal. Charities benefit from being able to communicate recent scientific discoveries to the public which offer hope to patients. This supports fundraising, which in turn supports further research and services for people with hearing problems.
The general public. The work will contribute to public engagement activities organised by the Institute of Neuroscience, including lectures, open days and science festivals. The public benefit from a greater understanding of the neuroscience of hearing, and how it impacts on the alleviation of deafness. Such events are also stimulate an interest in fundamental science in school children and young scientists. The role of nitric oxide - a gas that works as a neurotransmitter - is an exciting topic for public engagement in neuroscience.
Private sector companies developing sound recognition systems
A better understanding of the brain mechanisms of hearing will benefit the development of improved machine-based automatic speech recognition. The unachieved gold standard is for systems that can understand a speaker in the presence of multiple voices. Human hearing far exceeds the capability of any machine based system in this regard, and understanding the auditory pathway will be relevant for devising speech recognition systems inspired by biological mechanisms.
Private sector companies developing brain implants and prosthetic hearing devices;
Knowledge about the function of the auditory pathways will benefit companies developing of auditory brain implants to restore hearing in patients who have lost auditory nerve input.
Currently these devices are implanted in the brainstem at the level of the cochlear nuclei, (currently around ~1200 implantations world-wide). They offer limited restoration of function and work is underway to develop a midbrain implant targeted at the inferior colliculus (IC). Progress depends on understanding the circuitry of the IC for the configuration of stimulating electrodes, and the development of the stimulation paradigms. A general understanding of brain mechanisms underlying auditory perception is also important in the development of hearing aid and cochlear implant technology. Such developments will lead to life enhancing technologies for those who suffer from hearing loss and economic benefits for the companies concerned.
Candidates for auditory brain implants and the clinicians treating them
The work will benefit the development of prosthetic devices (see above) to improve the quality of life for patients who have lost auditory nerve function by trauma, or disease such as neurofibromatosis type II. Surgery for this condition severs the cochlear nerve leaving the patient totally deaf. Brain implants restore some degree of hearing in these patients, and the inferior colliculus is a target structure for such a device.
Training of postdoctoral research assistants and students to maintain skills in in vivo neuroscience
The work uses sophisticated in vivo techniques in systems neuroscience, a speciality that has declined in the UK over the past twenty five years. Such approaches are vital for progress in neuroscience and retention of these skills is important to maintain capacity in the commercial sector and academia. The project will offer training in this area to the postdoctoral researcher and to students. Such experience and training will help expand the pool of skilled in vivo researchers.
The BBSRC. In addressing the fundamental mechanisms of hearing at the systems level, and how connections from the cerebral cortex impact on earlier stages in the hearing pathway the work is relevant to the BBRC's Strategic priorities Bioscience for Health, and responsive mode priorities 1) healthy ageing across the life course, and 2) systems approaches to the biosciences.
Hearing Charities such as Action on Hearing Loss who provided a pump-priming Flexigrant to gather pilot data for this proposal. Charities benefit from being able to communicate recent scientific discoveries to the public which offer hope to patients. This supports fundraising, which in turn supports further research and services for people with hearing problems.
The general public. The work will contribute to public engagement activities organised by the Institute of Neuroscience, including lectures, open days and science festivals. The public benefit from a greater understanding of the neuroscience of hearing, and how it impacts on the alleviation of deafness. Such events are also stimulate an interest in fundamental science in school children and young scientists. The role of nitric oxide - a gas that works as a neurotransmitter - is an exciting topic for public engagement in neuroscience.
Private sector companies developing sound recognition systems
A better understanding of the brain mechanisms of hearing will benefit the development of improved machine-based automatic speech recognition. The unachieved gold standard is for systems that can understand a speaker in the presence of multiple voices. Human hearing far exceeds the capability of any machine based system in this regard, and understanding the auditory pathway will be relevant for devising speech recognition systems inspired by biological mechanisms.
Private sector companies developing brain implants and prosthetic hearing devices;
Knowledge about the function of the auditory pathways will benefit companies developing of auditory brain implants to restore hearing in patients who have lost auditory nerve input.
Currently these devices are implanted in the brainstem at the level of the cochlear nuclei, (currently around ~1200 implantations world-wide). They offer limited restoration of function and work is underway to develop a midbrain implant targeted at the inferior colliculus (IC). Progress depends on understanding the circuitry of the IC for the configuration of stimulating electrodes, and the development of the stimulation paradigms. A general understanding of brain mechanisms underlying auditory perception is also important in the development of hearing aid and cochlear implant technology. Such developments will lead to life enhancing technologies for those who suffer from hearing loss and economic benefits for the companies concerned.
Candidates for auditory brain implants and the clinicians treating them
The work will benefit the development of prosthetic devices (see above) to improve the quality of life for patients who have lost auditory nerve function by trauma, or disease such as neurofibromatosis type II. Surgery for this condition severs the cochlear nerve leaving the patient totally deaf. Brain implants restore some degree of hearing in these patients, and the inferior colliculus is a target structure for such a device.
Training of postdoctoral research assistants and students to maintain skills in in vivo neuroscience
The work uses sophisticated in vivo techniques in systems neuroscience, a speciality that has declined in the UK over the past twenty five years. Such approaches are vital for progress in neuroscience and retention of these skills is important to maintain capacity in the commercial sector and academia. The project will offer training in this area to the postdoctoral researcher and to students. Such experience and training will help expand the pool of skilled in vivo researchers.
Organisations
People |
ORCID iD |
| Adrian Rees (Principal Investigator) | |
| Sasha Gartside (Co-Investigator) |
Publications
Olthof B
(2019)
Multiple Nonauditory Cortical Regions Innervate the Auditory Midbrain
in The Journal of Neuroscience
Olthof BM
(2022)
Nitric oxide signalling underlies salicylate-induced increases in neuronal firing in the inferior colliculus: A central mechanism of tinnitus?
in Hearing research
Olthof BMJ
(2019)
Puncta of Neuronal Nitric Oxide Synthase (nNOS) Mediate NMDA Receptor Signaling in the Auditory Midbrain.
in The Journal of neuroscience : the official journal of the Society for Neuroscience
Olthof BMJ
(2018)
Non-auditory projections to the inferior colliculus; a tracing study.
Olthof BMJ
(2019)
Non-auditory projections to the inferior colliculus
| Description | Our research addresses how sounds are processed in the brain, and it focusses on the inferior colliculus, an important centre in the auditory pathway located in the midbrain. Under this award we are investigating how higher centres in the auditory pathway send feedback to the inferior colliculus. We hypothesise that these connections are important for predictive coding. This is a process whereby the brain guesses the identification of the incoming sound based on prior experience and attempts to narrow the difference between this guess and the information about the sound detected by the ear. This speeds up information processing and helps to overcome the difficulty of hearing out individual conversations in noisy environments. In our research, we seek to determine what connections occur between the cerebral cortex and the inferior colliculus and how these connections influence the responses of nerve cells in the inferior colliculus. Thus far we have made two important discoveries from the research funded by this award. 1. It is well established that the inferior colliculus receives connections from the auditory part of the cerebral cortex, but we have now discovered that there are also extensive connections to the inferior colliculus from several other regions of the cerebral cortex. These include regions serving the senses of vision, skin sensation, control of movement, and executive function. Such extensive connections suggest that, far from being a centre concerned only with processing sound, it also integrates signals related to other senses and functions too. Other senses are known to enhance our hearing, for example the additional information gained from being able to see the moving lips of a speaker, but this was always considered to be a process that involved interactions solely within the cerebral cortex. Our findings suggest the process of multisensory interaction begins at a much earlier stage in the auditory pathway than previously understood. Such inputs from cortical regions sub-serving vision and other senses may help to identify and locate sounds by influencing sound processing. Similarly, input from the movement region of the cortex may be helpful for separating the self-generated sounds that an animal or person makes when moving around in the environment, from those emanating from sources external to it. We have identified these connections by using injections of fluorescent beads and other tracer molecules into the brain. These are carried by nerve fibres from the injection site back to the cells that give rise to those connections and so allow us to identify their sites of origin. We have presented this work at a recent international meeting (ARO Midwinter Meeting 2019 Baltimore, USA) where it was received with great interest, and it is now published Olthof et al 2019 (J Neuroscience DOI: https://doi.org/10.1523/JNEUROSCI.1436-19.2019) and has been cited 10 times and was also highlighted in the journal's what's new section. We currently analysing data that addresses the function of these connections in the brain by studying the effects of stimulating the cortical sites where they originate and recording the responses this stimulation evokes in the inferior colliculus. A second discovery relates to the organisation of neural circuits in the inferior colliculus. We have demonstrated that neurons in the inferior colliculus express an enzyme called neuronal nitric oxide synthase (nNOS). In the central subdivision of the colliculus this enzyme appears in the form of tiny puncta scattered over the surface of the nerve cells. These puncta are associated with neurotransmitter receptors called NMDA receptors at synapses (the regions of the cell where contacts are made by other neurons). We have established the mechanism whereby NMDA receptors operate in this region of the brain and demonstrated that the function of these receptors depends on the release of nitric oxide through the action of nNOS. We hypothesised that the NMDA receptors associated with the nNOS puncta would receive connections from the cerebral cortex that were discussed earlier. To our surprise, however, we have discovered that they are activated by inputs from an earlier stage of the pathway. This is a fascinating and unexpected finding that requires us to revise our thinking about the role of nitric oxide in the inferior colliculus. We now need to determine the precise origin of these inputs to neurons in the IC and discover their function. This part of the study has recently been published in Journal of Neuroscience (Olthof et al 2019 J Neuroscience DOI: https://doi.org/10.1523/JNEUROSCI.1918-18.2018). Since publication it is in the top 25% of all research outputs scored by Altmetric and it has received 13 citations. We were also delighted to have one of our images on the cover of the journal. Most recently we have discovered novel connections from the hippocampus to the IC. This provides further evidence for a role for the IC in the cognitive aspects of hearing, an aspect of auditory processing that has previously been viewed as a preserve of the cerebral cortex. This work is currently in preparation for a leading journal in the field. |
| Exploitation Route | Our understanding of the contribution of the inferior colliculus to hearing is radically changed by our findings that reveal connections from areas of the cerebral cortex not specifically related to hearing, but rather related to other senses (e.g. vision, skin sensation), movement and cognitive mechanisms. In addition to furthering fundamental science in this field, our findings will benefit the development of more sophisticated hearing prostheses and computer based approaches to separating speech in noise. Further experiments based on our findings on the expression of neuronal nitric oxide synthase in the auditory pathway has shown that nitric oxide synthase expression is modulated in animals with tinnitus, and we reported in a bioRxiv preprint that blockade of nitric oxide synthase in the midbrain blocks the changes in firing rate that occur in the salicylate model of tinnitus. This is an exciting finding which may suggest a distinct brain pathway that mediates tinnitus. As we discover more about this association there may be opportunities to explore possible pharmacological treatment or tinnitus involving this pathway. |
| Sectors | Digital/Communication/Information Technologies (including Software),Healthcare,Pharmaceuticals and Medical Biotechnology |
| URL | https://www.jneurosci.org/content/39/5.cover-expansion |
| Description | LBC Radio Interview |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Public/other audiences |
| Results and Impact | Radio interview with James O'Brien of radio station LBC about the 'Laural Yanny' effect that had become a social media phenomena during that week. |
| Year(s) Of Engagement Activity | 2018 |
| URL | https://www.lbc.co.uk/radio/presenters/james-obrien/yanny-or-laurel-we-asked-a-science-professor/ |
| Description | Pint of Science Presentation Thanks for Listening, Tuning in down the pub |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | This event was an engagement event for the general public under the auspices of Pint of Science in which scientist present their work to an audience in a local pub. My presentation was centred on the problem of listening to individual conversations in a noisy environment (hence the title Tuning In... Down the Pub). It discussed how the brain is much more effective at doing this compared with artificial voice recognition systems, and considered the possible brain mechanisms, including the feedback connections we are investigating in our project, that help us achieve this feat. |
| Year(s) Of Engagement Activity | 2017 |
| URL | https://pintofscience.co.uk/event/thanks-for-listening |