Primary Supervisor: Professor Alicia Hidalgo, School of Biosciences
Secondary supervisor: Dr Carolina Rezaval
PhD project title: Genetic and circuit mechanisms of structural brain plasticity and neurodegeneration in Drosophila
University of Registration: University of Birmingham
The brain changes throughout life, as we experience, learn, adapt and age. Neurons and glial cells make adjustments in cell size and shape (dendrites, axons), in synapses, and in cell number (cell death, or neurogenesis), throughout life. Structural plasticity enables change as we learn, remember and adapt to environmental change. Counteracting homeostatic mechanisms constrain the brain’s ability to change to stabilise circuits. The healthy brain is kept in balance between plasticity and homeostasis, resulting in normal behaviour. Exercise and learning increase plasticity, homeostatic processes occur during sleep, whilst brain diseases are linked to loss of this balance, e.g. brain tumours (e.g. gliomas), neurodegenerative diseases (e.g. Alzheimer’s and Parkinson’s), neuro-inflammation and psychiatric disorders (e.g. depression). Conversely, the homeostatic mechanisms that keep the brain stable also prevent the brain from recovering in disease. We want to understand how these forces operate in the brain. Structural plasticity reveals that structure and function are tightly linked in the brain. Thus, understanding these processes will reveal fundamental principles of how the brain works. In the longer-term, it will reveal how to help treat brain disease.
We tackle this big question by aiming to discover underlying genetic mechanisms, and investigating the interaction between gene networks, cell biology, neuronal activity, neural circuits and behaviour. In this project, we will not aim to learn how to cure or treat any particular disease. We will aim to understand how genes, neurons and glia in the brain can swing between promoting structural plasticity and neurodegeneration, and the consequences this has in behaviour.
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 (i.e. why we sleep). 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. It is an extremely exciting time to investigate neuroscience with the fruit-fly Drosophila, to discover fundamental principles about the brain, any brain, including the human brain.
To investigate molecular and genetic mechanisms of brain structural plasticity and neurodegeneration in the fruit-fly Drosophila.
Amongst other genes, we will investigate the function of Toll receptors, which can be responsible for structural plasticity, neurogenesis, neurodegeneration and neuro-inflammation.
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, 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.
- 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
- 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:e52743 DOI: 10.7554/eLife.52743
- See also: “How experience shapes the brain, https://elifesciences.org/digests/52743/how-experience-shapes-the-brain
- Anthoney N, Foldi I and Hidalgo A (2018) Toll and Toll-like receptor signalling in development. Development, 145, dev156018. Doi:10.1242/dev.156018
- Zhu, Pennack, McQuilton, Forero, Mizuguchi, Gu, Fenton and Hidalgo (2008) Drosophila neurotrophins reveal a common mechanism of nervous system formation. PLoS Biology 6, e284.
BBSRC Strategic Research Priority: Understanding the Rules of Life: Neuroscience and behaviour
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
Contact: Professor Alicia Hidalgo, University of Birmingham