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Discovery and modelling of common molecular mechanisms disrupting hearing in genetic mutations associated with hearing loss.

Primary Supervisor: Professor Ian D Forsythe, Department of Neuroscience, Psychology & Behaviour

Second Supervisor: Dr Andrea Lecchini-Visintini, Department of Engineering

PhD project title: Discovery and modelling of common molecular mechanisms disrupting hearing in genetic mutations associated with hearing loss

University of Registration: University of Leicester 

Project outline:

Objectives: Determine the cellular and molecular changes in the auditory brainstem of mice carrying genetic mutations associated with hearing loss and language development and use modelling to evaluate common mechanisms.

Background: While you can see with one eye and hear with one ear, many cognitive functions rely on rapid integration of information from two eyes or two ears (for example, depth perception and sound localization, respectively). In addition, integration of information from eyes and ears are used for multisensory processing which underlie further mechanisms of cognition. The speed of information processing by the brain in these cognitive processes is fundamental to normal brain function and failures in rapid processing in axons and at the synapse are now thought to underlie information processing disorders, such as auditory dysynchrony, language impairment and dyslexia.

This project will suite an ambitious and talented research, interested in learning quantitative methods to decode brain activity, and with the desire to learn and apply problem solving, data analysis computational modelling and presentational skills, within a group of like-minded investigators.

My laboratory uses state-of-the-art methods, combining genetics, imaging and electrophysiology to explore and understand how neurons and synapses work in concert to process information in the brain. Our experiments are conducted in the auditory pathway, so the results are relevant to hearing and cognition and contribute to understanding auditory diseases such as hearing loss and tinnitus and broader brain dysfunction in ataxia, dementia and dyslexia.

Methods: Immunohistochemistry will be employed to show where the mutated proteins are expressed in the brain; then electrophysiology will be used to investigate the cellular mechanism in an in vitro brain slice preparation and finally computational models will be used to assess changes in synaptic parameters through collaboration with Computational Neuroscience. A dynamical model describing the biochemical mechanisms of information transfer at the synapse has been developed in support of the experimental investigation. The model will test hypotheses’ validation and reconstruct unmeasured variables. The ability to integrate data obtained from different experiments, and better characterise random processes will be a key advantage of this multidisciplinary project.

References:

  1. Lucas SJ, Michel CB, Marra V, Smalley JL, Hennig MH, Graham BP & Forsythe ID (2018). Glucose and lactate as metabolic constraints on presynaptic transmission at an excitatory synapse. J Physiol (Lond) 596, 1699–1721.
  2. Pilati N, Linley DM, Selvaskandan H, Uchitel O, Hennig MH, Kopp-Scheinpflug C & Forsythe ID (2016). Acoustic trauma slows AMPA receptor-mediated EPSCs in the auditory brainstem, reducing GluA4 subunit expression as a mechanism to rescue binaural function. J Physiol (Lond) 594, 3683–3703.
  3. Kopp-Scheinpflug C, Tozer AJB, Robinson SW, Tempel BL, Hennig MH & Forsythe ID (2011). The sound of silence: ionic mechanisms encoding sound termination. Neuron 71, 911–925.

BBSRC Strategic Research Priority: Sustainable Agriculture and Food, Understanding the Rules of Life, Renewable Resources and Clean Growth, Integrated Understanding of Health.

Techniques that will be undertaken during the project:

  • In vitro brain slice preparation
  • Calcium and ATP imaging
  • Patch clamp recording from identified neurons
  • Voltage-clamp and current clamp
  • Computational modelling of synaptic transmission

Contact: Professor Ian D Forsythe, University of Leicester