Mechanisms of cortical modulation of the auditory midbrain

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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.