2022-PRESENT DNA damage repair and neurodegeneration
How do unrepaired DNA single-strand breaks (SSBs) - breaks in one strand of the DNA double helix - trigger neurodegeneration? We will employ a combination of molecular, cellular, and physiological experimental models to build on our recent discoveries and define at the mechanistic level how SSBs cause defects in neuronal function in vitro and in vivo, and how such defects lead to neurological disease. Although we are focusing on experimental models of rare genetic diseases to address our scientific questions, the relevance of this work will likely extend to other common degenerative diseases and even to the normal ageing population. Collaboration with Caldecott Lab, Sussex. MRC-funded.
2021-PRESENT Maximizing survival when hungry: computing behavioural priorities
Applying the latest advances in posture-tracking, multi-electrode recording and whole-CNS imaging we will determine how behavioural prioritization is computed according to motivational state and adaptively modulated to maximize survival. We will also establish how threat-conflict is resolved at the neuronal level, allowing animals to select appropriate actions when faced with threats from both predation and starvation. Collaboration with Kemenes and Baden Labs, Sussex.
2020-PRESENT Nanoscale readout of in vivo synaptic activity for functional connectomics
Large-volume ultrastructural mapping approaches yield detailed circuit wiring diagrams but lack an integrated synaptic activity readout which is essential for functional interpretation of the connectome. This project aims to resolve this limitation by combining functional synaptic labelling in vivo with focused ion-beam scanning electron microscopy (FIBSEM) and machine learning-based segmentation. Our approach generates high-resolution near-isotropic three-dimensional readouts of activated vesicle pools across large populations of individual synapses in a volume of tissue, opening the way for detailed functional connectomics studies. Collaboration with Hausser Lab, UCL and Funke Lab, Janelia Research Campus. BBSRC-funded.
2019-PRESENT Hypothalamic synaptic substrates regulating feeding behaviour
Synapses are key control points for implementing stable adjustments in information flow in brain circuits. Here we are characterizing a form of synaptic plasticity in the arcuate nucleus, a hypothalamic brain region containing circuits that critically change their signalling properties with appetitive state (hunger/satiety) to regulate feeding behaviour (eat/not eat). This accessible circuit is highly-advantageous for investigation, with orexigenic and anorexigenic compounds substituting for feeding motivation and the full cellular expression of hunger state retained in brain slices. Collaboration with Branco Lab, Sainsbury Wellcome Centre.