Does the brain change as we go through life and does this depend on our experiences? What is the impact in the brain of stimulation, activity, exercise or immobility, lack of stimulation, isolation, ageing? If the brain can change with experience, why can't we regenerate brain or spinal cord after injury or disease (as they are extreme experiences)? if we could understand how cells respond to change, could we encourage cells to drive regeneration and repair after injury and disease? And when the mechanisms fail, are these common processes responsible for brain decline in ageing, brain tumours and neurodegeneration?
We will address these questions using the fruit-fly Drosophila as a model organism, as it is the most powerful genetic model organism. Drosophila genetics has for over a century provided ground-breaking discoveries of immense relevance for human health. Drosophila research has resulted in six Nobel Prizes, ranging including the discovery of the chromosomal basis of inheritance, the neural circuit basis of olfaction, the universal mechanism of innate immunity and biological clocks.
The Drosophila genome was the first complex genome to be sequenced. Now, all the fruit-fly brain neural circuits have been virtually completely mapped at transmission electron microscopy resolution, way ahead of the mapping of neural circuits in the mouse or human brain. There are cutting edge genetic and molecular (e.g. CRISPR/Cas9 gene editing) tools, to switch genes on or off in vivo, to visualise and manipulate neurons, glia and neural circuits. Using thermo- and optogenetics, it is possible to activate or silence neurons with temperature or light, and test the consequences on dendritic and axonal arbours, synapses, glia and behaviour.
It is possible to identify single neurons, to see them and manipulate them, test when, whether or how their arborisations and connectivity patterns could change. High, single cell resolution is also available for the visualisation and manipulation of glial cells. And it is possible to test and work out how distinct neural circuits deliver distinct behaviours. None of this can be done at this resolution with any other model organism. Importantly, investigating plasticity and regeneration, injury and repair in fruit-flies does not raise ethical issues. The fruit-fly life cycle is short and experiments can be carried out swiftly. The project will aim to test cellular and molecular mechanisms of structural plasticity and regeneration in the adult fly brain.
We will investigate underlying molecular mechanisms, glial and neural circuits involved. We will test: how cells respond to injury, neuronal activation and neuronal silencing; how cells respond to genetic manipulations in these conditions, whether they improve or worsen the effects; whether we can induce cellular reprogramming in vivo to enable plasticity, regeneration and repair; and whether and how adult neurogenesis, neuronal activity and behaviour enable or drive integration of neurons into functional neural circuits.
The discoveries we make with Drosophila will be impactful, for the understanding of fundamental principles of how any brain, including the human brain, works and responds to change. It will provide insights into understanding what goes wrong in brain damage and disease, from psychiatric disorders to brain tumours and neurodegenerative diseases. To find out more, visit our website: https://more.bham.ac.uk/hidalgo/