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Regenerative and adult neurogenesis in Drosophila

Primary Supervisor: Professor Alicia Hidalgo, School of Biosciences

Secondary supervisors: Dr Yun Fan

PhD project title: Regenerative and adult neurogenesis in Drosophila

University of Registration: University of Birmingham

Project outline:

It is very intriguing that during normal growth and development, cells ‘know’ how to build an organism with appropriate structure leading to normal behaviour. Some animals can regenerate limbs or organs after injury or loss, revealing that cells also ‘know’ how to rebuild a complete body and restore normal behaviour. How on earth do cells know this? We want to find out.

Animals that can regenerate their CNS do so by inducing neurogenesis, forming new neurons which presumably integrate into neural circuits to restore not only structure but also behaviour. Intriguingly, these neurons are not always generated from standard, developmental neural stem cells, but instead, other cell types.

But wait a minute – if some cells can become naturally reprogrammed to generate neurons, this could mean that neurogenesis may occur in the normal brain. It is in fact known that new neurons are generated daily in the human brain, and perhaps this is necessary to encode time into memories. If new neurons are generated, how do they integrate into neural circuits, and how does this modify neural connectivity patterns and behaviour? Could signals produced in injury enhance a natural, underlying ability of adult neurogenesis, which could facilitate regeneration?

The human spinal cord and brain do not regenerate upon injury or disease. However, if we could understand whether and how cells respond to environmental challenges, we might be able to promote regeneration in the central nervous system (CNS).

Here, we will tackle this fundamental problem to ask whether we can induce neurons in the adult fly by in vivo reprogramming of cells.

We will use the fruit-fly Drosophila as a model organism, as it is the most powerful genetic model organism. Drosophila genetics has for nearly a century provided ground-breaking discoveries of immense relevance for human health. Drosophila research so far has resulted in six Nobel Prizes, ranging from the discovery of the chromosomal basis of inheritance, to the genetic basis of the body pattern, the universal mechanism of innate immunity and biological clocks. The Drosophila genome was the first complex genome to be sequenced. All the fruit-fly neural circuits are currently being mapped, way ahead of the mapping of human circuits. There are cutting edge genetic and molecular (e.g. CRISPR/Cas9 gene editing) tools to visualise and manipulate neurons and glia, neural circuits, genes, neuronal activity, in vivo, not in a dish, and visualise how this changes behaviour. Investigating CNS injury and repair in fruit-flies does not raise ethical issues.

We aim to discover genetic, molecular mechanisms of cellular reprogramming into neurons, adult neurogenesis and regeneration, and investigate the interaction between gene networks, cell biology, neuronal activity, neural circuits and behaviour – after CNS injury. With these methods, we aim to understand how to direct CNS regeneration upon injury.

Our findings will have a tremendous impact to understand, not only the fruit-fly, but also fundamental principles of how brains work and how to promote regeneration and repair.

Objective:

To investigate genetic mechanisms of regenerative and adult neurogenesis in the fruit-fly Drosophila.

Methods:

We will use a combination of injury and regeneration experiments with genetics, molecular cell biology including CRISPR/Cas9 gene editing technology and transgenesis, microscopy, including laser scanning confocal microscopy and calcium imaging in time-lapse, computational imaging approaches for analysis of images and movies, stimulating neuronal function with opto- and thermos-genetics in vivo, and recording and analysing fruit-fly behaviour. We will collaborate with: Professor Ilan Davis (University of Oxford) for live imaging and visualisation of integration of neurons into neural circuits; Dr Manuel G. Forero (Colombia) for automatic solution of imaging and analysis; Dr Carolina Rezaval (University of Birmingham) to analyse the recovery of behaviour.

References:

See our lab websites, link found in: https://www.birmingham.ac.uk/staff/profiles/biosciences/hidalgo-alicia.aspx

  1. Harrison N, Connolly E, Gascón Gubieda A, Yang Z, Altenhein B, Losada-Perez M, Moreira M, Hidalgo A (2021) Regenerative neurogenesis is induced from glia by Ia-2 driven neuron-glia communication. eLife10:e58756 DOI: 10.7554/eLife.58756
  2. Li G and Hidalgo A (2020) Adult neurogenesis in the Drosophila brain: the evidence and the void. International Journal of Molecular Sciences 21(18), 6653
  3. Li G, Forero MG, Wentzell JS, Durmus I, Wolf R, Anthoney NC, Parker M, Jiang R, Hasenauer J, Strausfeld NJ,Heisenberg M, Hidalgo A (2020) A Toll-receptor map underlies structural brain plasticity eLife, 9: e52743DOI: 7554/eLife.52743
  4. eLife Digest article 17 March 2020 dedicated to our paper: “How experience shapes the brain” https://elifesciences.org/digests/52743/how-experience-shapes-the-brain
  5. Losada-Perez M, Harrison N, Hidalgo A. (2016) Molecular mechanism of central nervous system repair by the Drosophila NG2 homologue kon-tiki. Journal of Cell Biology 214, 587
  6. Kato, Forero and Hidalgo (2011) The glial regenerative response to CNS injury is enabled by Pros-Notch ad Pros-NFkB feed-back. PLoS Biology 9, e1001133

BBSRC Strategic Research Priority: Understanding the Rules of Life: Immunology & Neuroscience and behaviour & Stem Cells & Integrated Understanding of Health: Ageing & Regenerative Biology

Techniques that will be undertaken during the project:

  • Molecular biology: cloning, PCR, CRISPR/Cas9 gene editing

  • Genetics: transgenesis, generation of mutants, knock-outs and knock-ins, reporter lines to visualise cells eg with GFP, etc.

  • Cell biology: to test for protein-protein interactions, eg co-immunoprecipitations

  • Microscopy: laser scanning confocal microscopy, epi-fluorescence microscopy, time-lapse including calcium imaging using GcAMP reporters

  • Opto and thermogenetics to manipulate neuronal activity: increase or inhibit neuronal activity and see the consequences with cell biology, GcAMP and behaviour

  • Behaviour: locomotion, optomotor response, learning and memory, etc.

Contact: Professor Alicia Hidalgo, University of Birmingham