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How experience and behaviour change the brain in Drosophila

Primary Supervisor: Professor Alicia Hidalgo, School of Biosciences

Secondary supervisors: Dr Carolina Rezaval

PhD project title: How experience and behaviour change the brain in Drosophila

University of Registration: University of Birmingham

Project outline:

Why is sport good for the brain? Why do we learn more easily when we are little? Why are we likely to get depressed if we are long-term alone in the dark? Why do we sleep? Does brain function, and therefore behaviour, depend on physical changes to cells?

Experience modifies the brain. The brain can change throughout life, as we learn, adapt and age. Structural plasticity enables change as we learn and adapt to environmental change, perhaps encoding memory across the brain. Structural homeostasis constrains the brain’s ability to change, thus maintaining neural circuits stable. The healthy brain is kept in balance between structural plasticity and homeostasis, resulting in normal behaviour. Exercise and learning increase structural plasticity, sleep promotes homeostasis, whilst brain diseases are linked to loss of this balance, such as 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 slow down learning and prevent the brain from recovering in injury and disease. The brain controls behaviour, which thereafter is a source of new experience. Thus experience and behaviour are entangled in a feed-back loop that can affect the brain. We want to understand whether physical changes to neurons and glia are fundamental for determining how the brain works, the connectivity patterns that can form and the resulting brain function - that is, behaviour.

The structural changes regulated by plasticity and homeostasis could encompass changes in neurons and glial cells, including adjustments in cell number (cell death, or neurogenesis), cell size and shape (for example of dendrites, axons), in connectivity patterns, in synapse formation and elimination, throughout life. However, this remains little investigated. The underlying molecular mechanisms are mostly unknown. And it is also unknown what the consequences of brain structural changes are for behaviour.

Understanding these processes will help us answer how the brain works, how we can maintain brain health and treat brain disease.

We tackle this big question using the fruit-fly Drosophila as a model organism. We aim to discover the link between brain structural change and behaviour and the underlying genetic and molecular mechanisms. We will not aim to learn how to cure or treat any particular disease. We will ask which living conditions (e.g. light vs. darkness), experiences (e.g. stress, reward) and behaviours (e.g. isolation or living in groups) are conducive to brain plasticity and which ones to neurodegeneration or behavioural impairment found in brain disease. We will aim to understand how genes, neurons and glia in the brain can swing between promoting structural plasticity and degeneration, 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. 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.

Objective:

To investigate how experience and behaviour modify the brain 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, and recording and analysing fruit-fly behaviour.

References:

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

  1. Guiyi Li and Alicia Hidalgo (2021) The Toll route to structural brain plasticity. Frontiers in Physiology. Frontiers in Physiology DOI: 10.3389/fphys.2021.679766 https://doi.org/10.3389/fphys.2021.679766
  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

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, activity profiles, analysis of social interactions, optomotor response, learning and memory

Contact: Professor Alicia Hidalgo, University of Birmingham