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Genetic and molecular mechanisms of brain structural plasticity and neurodegeneration

Principal Supervisor: Dr Alicia Hidalgo, School of Biosciences

Co-supervisor: To be confirmed

PhD project title: Genetic and molecular mechanisms of brain structural plasticity and neurodegeneration

University of Registration: University of Birmingham

Project outline:

The project will test the potential of a molecular mechanism that we recently discovered, in modulating brain structural plasticity versus neurodegeneration. The brain changes throughout life: neurons, neurites and synapses are formed enabling us to adapt and learn; and they are also eliminated, to maintain homeostasis, and these destructive forces take over in ageing and brain disease (from depression to neurodegeneration). The cost of brain diseases to society doubles that of cancer and cardiovascular diseases put together, so it is urgent to discover novel molecular mechanisms that can promote plasticity, reduce degeneration, and could be targeted with drugs or stem cells, to treat brain disease. We have recently discovered a novel mechanism that regulates these constructive and destructive cellular events. Now we aim to test the power of this mechanism in promoting neuroprotection and plasticity. We use the fruit-fly Drosophila, as a model organism, as this is the most powerful genetic model organism to discover molecular mechanisms and investigate gene function in vivo, in time-lapse, with single cell and neural circuit resolution. Ultimately, our findings will have important implications to understand how to regulate brain plasticity and neurodegeneration also in humans. The project will use technical approaches of Drosophila genetics, molecular biology, cell culture, microscopy and imaging, optogenetics, computational modelling and behaviour.

References:

  • Ulian- Benitez S, Bishop S, Foldi I, Wentzell J, Okenwa C, Forero M, Zhu B, Moreira M, Phizacklea M, McIlroy G, Gay NJ, Hidalgo A (2017) Kek-6: a truncated Trk-like receptor for Drosophila Neurotrophin 2 regulates structural synaptic plasticity. PLoS Genetics, 13(8): e1006968
  • Foldi I, Anthoney N, Harrison N, Gangloff M, Verstak B, Ponnadai Nallasivan M, AlAhmed S, Phizacklea M, Losada-Perez M, Moreira M, Gay NJ and Hidalgo A (2017) Three-tier regulation of cell number plasticity by neurotrophins and Tolls in Drosophila. J Cell Biol 216(5):1421
  • McIlroy G, Foldi I, Aurikko J, Wentzell JS, Lim MA, Fenton JC, Gay NJ and Hidalgo A (2013) Toll-6 and Toll-7 function as neurotorphin receptors in the Drosophila melanogaster CNS. Nature Neuroscience 16, 1248-1256. doi: 10.1038/nn.3474.
  • Zhu, Pennack, McQuilton, Forero, Mizuguchi, Sutcliffe, Gu, Fenton and Hidalgo (2008) Drosophila Neurotrophins reveal a common mechanism for nervous system formation. PLoS Biology 6, e284

See also a review on our findings:

  • Keeler * Deppmann (2017) The evolutionary origins of antagonistic neurotrophin signaling” Journal of Cell Biology doi: 10.1083/jcb.201702115

BBSRC Strategic Research Priority: Molecules, Cells and Systems

Techniques that will be undertaken during the project:

  • Drosophila genetics
  • Molecular biology and cell culture
  • Microscopy and imaging
  • Optogenetics manipulation
  • Recording of neuronal activity, computational modelling and behaviour.

Contact: Dr Alicia Hidalgo, School of Biosciences