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Molecular and genetic mechanisms of brain structural plasticity and neurodegeneration in the fruit-fly Drosophila.

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Awaiting Funding Decision/Possible External Funding
    Awaiting Funding Decision/Possible External Funding

Project Description

The brain changes throughout life: brain plasticity enables the brain to adjust in response to experience, whereas during aging natural neurodegeneration takes over. Homeostasis ensures the brain is constrained to maintain stability. These events are manifested in structural changes to neurons and synapses. The healthy brain is kept in balance between the opposite forces of structural plasticity, homeostasis and neurodegeneration, to deliver normal behaviour. Exercise and learning increase plasticity, whilst aging is accompanied by a decrease in plasticity, and brain diseases are linked to loss of this balance, e.g. brain tumours (e.g. gliomas), psychiatric diseases, neurodegeneration (eg Alzheimer’s and Parkinson’s disease). We want to understand how these forces operate in the brain. Ultimately, this will reveal fundamental principles of how the brain works. Importantly, it will reveal how to help treat brain disease.

We tackle this big question by aiming to discover underlying genetic mechanisms, and investigate the interaction between gene networks, cell biology, neuronal activity and behaviour - in the healthy brain. 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 the 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 (e.g. optogenetics) 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. It is an extremely exciting time to investigate neuroscience with the fruit-fly Drosophila, to discover fundamental principles about the brain, including the human brain.

Objective:
To investigate molecular and genetic mechanisms of brain structural plasticity and neurodegeneration in the fruit-fly Drosophila.

Methods:
We will use a combination of genetics, molecular cell biology including CRISPR/Cas9 gene editing technology and transgenesis, microscopy, including laser scanning confocal microscopy and calcium imaging of neuronal activity in time-lapse, computational imaging approaches for analysis of images and movies, stimulating and inhibiting neuronal function in vivo using optogenetics and thermogenetics, and recording and analysing fruit-fly behaviour. Ultimately, the findings from our research will have implications beyond Drosophila, with an impact also in understanding how any brain works, in health, injury or disease, including the human brain.

Funding Notes

For UK/EU nationals, please apply via MIBTP Programme. For all other applicants, self-funded applicants and those who have access to international scholarship applications, please contact directly Prof. A. Hidalgo directly at .

References

http://www.biosciences-labs.bham.ac.uk/hidalgo/Alicia_Hidalgo_Lab_Home.html

Anthoney N, Foldi I and Hidalgo A (2018) Toll and Toll-like receptor signalling in development. Development, 145, dev156018. Doi:10.1242/dev.156018

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 JCB selected “One of Top 10 articles of 2017”; JCB Selected for special collection on Cellular Neurobiology 2018 as “one of the most exciting findings in cellular neurobiology”.

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 neurotrophin receptors in the Drosophila melanogaster CNS. Nature Neuroscience 16, 1248-1256

Zhu, Pennack, McQuilton, Forero, Mizuguchi, Gu, Fenton and Hidalgo (2008) Drosophila neurotrophins reveal a common mechanism of nervous system formation. PLoS Biology 6, e284.

How good is research at University of Birmingham in Biological Sciences?

FTE Category A staff submitted: 42.80

Research output data provided by the Research Excellence Framework (REF)

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