I grew up in Madrid, Spain, and carried out my first degree in Biological Sciences at the Universidad Complutense in Madrid. I obtained my DPhil from the University of Oxford (Madgalen College), on Drosophila developmental genetics with Phil Ingham. I subsequently obtained a post-doctoral fellowship from the Spanish Ministry of Science and Education to do a post-doctoral period, at the Universidad Autónoma de Madrid with Antonio García-Bellido. I returned to UK with a Marie Curie Human Capital and Mobility Fellowship to do a second post-doc at the Wellcome/CR-UK Institute, University of Cambridge, with Andrea Brand. After this, I was awarded a Wellcome Trust Research Career Development Fellowship to establish my independent research group at the Department of Genetics, University of Cambridge, into neuron-glia interactions in Drosophila. In 2001 I received an EMBO Young Investigator Award for my achievements as a young group leader. In 2002, I moved to the School of Biosciences, University of Birmingham. I became Reader in 2012, Fellow of the Royal Society of Biology in 2014, Professor of Neurogenetics in 2019, founder and Director of the Birmingham Centre for Neurogenetics in 2021 and Wellcome Trust Investigator in 2022. With my team, our research focuses on structural brain plasticity and regeneration using fruit-flies, and it is or has been funded by The Wellcome Trust, MRC, BBSRC, EU and multiple PhD scholarships.
Brain switch: degeneration, plasticity, regeneration
The healthy brain is in balance between structural plasticity, its ability to undergo change, and homeostasis, which constrains change within reasonable boundaries that enable appropriate behaviour. Experience-dependent structural plasticity and resulting circuit modifications could encode memory and enable adaptation to life challenges. Conversely, circuit degeneration with aging underlies the deterioration of brain function. Alterations in this balance result in brain disease, like psychiatric, neurodegenerative and brain tumours.
The main growth factors responsible for brain plasticity in mammals are the neurotrophins, functioning through p75 and Trk receptors, involving tyrosine-kinase signalling. Instead, Drosophila neurotrophins are ligands for Tolls and kinase-less Trk-like Kek receptors. Toll and human Toll-Like Receptors have a conserved function in innate immunity, whereas kinase-less Trks underlie psychiatric disorders, but their function remains little explored. We showed that Tolls function like neurotrophin receptors in the CNS, regulating cell survival and axon targeting. Together with Keks, they regulate structural synaptic plasticity – a novel mechanism not yet found in mammals.
There are nine Tolls, distributed throughout the distinct brain modules, in overlapping but distinct patterns. Toll signalling can result in distinct cellular outcomes, cell survival or cell death, quiescence or cell proliferation, including inducing adult neurogenesis. Through their spatial segregation and their ability to regulate cell number in various ways, Tolls are ideally placed to translate experience into structural brain change.
In fact, neurons expressing the Toll-6 ligand DNT-2 have unique arborisation patterns in each individual fly and these arborisations are modulated further by neuronal activity. Integrated in a dopaminergic circuit, DNT-2 neurons function as translators of experience valence into structural change. Our findings indicate that dopamine labels the circuits engaged in experience and DNT-2 with Toll-6 and Kek-6 receptors modify those circuits, preventing neurodegeneration and promoting structural plasticity, locomotion and memory. We are now asking how experience shapes the brain.