Award details

Mechanisms of cortical modulation of the auditory midbrain

Reference	BB/P003249/1
Principal Investigator / Supervisor	Professor Adrian Rees
Co-Investigators / Co-Supervisors	Dr Sasha Gartside
Institution	Newcastle University
Department	Biosciences Institute
Funding type	Research
Value (£)	468,244
Status	Completed
Type	Research Grant
Start date	20/03/2017
End date	16/09/2022
Duration	66 months

Abstract

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.

Summary

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 toachieve 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.

Impact Summary

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.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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