In all animals, the optimal functioning of the nervous system at every stage of life is essential to support appropriate behaviour. Impairments in this function are associated with neurodevelopmental and/or neurodegenerative conditions, which have a significant impact on quality of life. However, how such function is maintained throughout life remains poorly understood.
Neurons that underlie adult behaviours are largely established during early embryonic development. A key challenge is the lifetime maintenance of their function. This is because the nervous system changes in response to developmental cues, environmental shifts, and disease. Once established, neurons must strike a balance between stability and adaptability (plasticity): stability preserves essential properties such as neuronal activity and neurotransmitter release, while plasticity enables the remodelling of specific features, such as neurite arborisation or synapse density. Evidence suggests that these processes are regulated by intrinsic programmes (i.e. gene regulatory factors) and extrinsic stimuli (e.g. neuronal activity).
This raises two central questions for neuroscientists:
- How do neurons regulate the balance between stability and plasticity throughout life?
- How do alterations in these regulatory mechanisms contribute to, or arise from, disease?
Our research addresses these questions through two major aims:
Aim 1. Control of neuronal physiology and plasticity by gene regulators from development
Our previous work in Drosophila showed that neuronal activity and motor function require specific gene regulators, including homeodomain-containing transcription factors (e.g. Hox gene Ubx) and post-transcriptional repressors such as microRNAs. These regulators are known for their activation early in development, where they control processes such as progenitor proliferation and neuronal differentiation. Using a range of techniques to manipulate gene expression with spatiotemporal precision in vivo. We are now investigating the significance of additional developmental transcription factors and microRNAs in regulating neuronal activity and subcellular organisation. This includes aspects such as neuronal signalling, neurite morphology, and synapse organisation. Through a combination of transcriptomics, proteomics, mutagenesis, and bioinformatics, we aim to determine how transcription factors active during development relate to neuronal activity and contribute to the maintenance of neuronal function and behaviour throughout life. Ultimately, we will explore whether these mechanisms are conserved in mammalian neurons and assess their roles in disease models.
Aim 2. Developmental pathways and neurological disorders
It has become increasingly clear that the loss of neuronal structure or function in neurological conditions is associated with both genetic and environmental factors. These factors are present from birth or hatching and, in various ways, may influence the molecular programmes, biology, and physiology of neurons throughout life. This is particularly evident in Parkinson’s disease (PD), a neurodegenerative disorder characterised by motor impairments. However, the emergence and progression of PD pathophysiology remain poorly understood. Our aim is to identify early neuronal changes that contribute to the structural and functional deficits underlying motor impairments in the disease. To this end, we are studying developmental gene regulators and their associated pathways in Drosophila models of PD, using a range of genetic tools to explore neurite or synapse integrity and calcium signalling, alongside molecular biology techniques—many of which we are developing in collaboration with, or learning from, our partners.
We address these questions in the locomotor system
Locomotion is an evolutionarily innate and conserved motor activity that enables animals, including flies, to support diverse behaviors such as foraging, escaping predators, mating, and navigating their environments. It manifests in various forms such as crawling and walking. This recurrent motor activity relies on the sequential activation of motor neurons innervating body and limb muscles, with careful modulation by functional circuits (Central Pattern Generator, CPG) within the spinal cord, which receives commands from the brain. While the locomotor system undergoes maturation and adaptation, its neural circuits are established during embryonic development. All these features of the locomotor system, makes it a powerful model for investigating the mechanisms that sustain neuronal function and behaviour throughout life, as well as identifying the role of developmental pathways in this process. Many neurodegenerative disorders, such as Parkinson’s, Huntington’s and ataxia, primarily manifest as motor deficits. By studying neuronal maintenance in the locomotor system, we can identify early and key molecular and cellular signatures that underlie neurodegeneration, offering potential biomarkers and therapeutic targets.
Genetics
We use Drosophila's advanced genetic tools to label and manipulate motor circuits
Optogenetics
We manipulate specific neuronal subsets to link their activity to a motor action.
In vivo imaging
We use calcium imaging to record populations of neurons in action.
Behaviour
We study the genetics and molecular programs that control locomotor behaviors in flies at different developmental stages: embryo, larva, and adult.
Molecular biology
We employ state-of-art techniques associated with transcriptomics, proteomics and immunohistochemistry
to explore gene expressions in the brain.
Machine learning
Camera system and machine learning are used together to record and analyse how body parts move when an animal is behaving.