JUL 2023 NEW GRANT: a new eFIBSEM platform for connectomics (MRC)
JUL 2022 NEW GRANT: Readout of synaptic function in large brain volumes using eFIBSEM (Leverhulme Trust)
This work, a collaboration with the Hausser (UCL) and Racca (Newcastle) labs, will use the latest generation of FIBSEM ("enhanced-FIBSEM") to characterize the relationship between synaptic ultrastructure and function in visual cortex. This technology allows us to examine questions in extraordinarily large volumes (100x100x100 microns) providing profoundly new insights into the organizational principles of synaptic function.
APR 2022 NEW PAPER: Amyloid-β-42 and disruption of synaptic vesicle pool organization (CEREBRAL CORTEX)
Our findings suggest that organizational and dynamic features of functional vesicle pools can be targets in Aβ-driven synaptic impairment. Treatment with levetiracetam, an antiepileptic that dampens synaptic hyperactivity, partially rescues these transmission defects suggesting that interventions to relieve the overloading of vesicle retrieval pathways might have promising therapeutic value. LINK
FEB 2022 NEW GRANT: Impact of DNA single-strand breaks on neuronal function and neurological disease (MRC)
Collaboration with Prof. Keith Caldecott funded by a 5-year Programme Grant. The work will involve iPSC-derived human neurons, DNA damage response-defective mouse models, and a range of cutting edge technologies for neural function analysis and genome stability in SSB-induced disease models. We will identify and exploit novel drug-like molecules (e.g. novel PARP inhibitors in collaboration with AstraZeneca) for potential future therapeutics.
JAN 2022 NEW PAPER: Non-telecentric two-photon microscope design (NAT COMMS)
Diffraction-limited two-photon microscopy permits minimally invasive optical monitoring of neuronal activity. However, most conventional two-photon microscopes impose constraints on the size of the imaging field-of-view and shape of the effective excitation volume. Here, employing a non-telecentric optical design, we present a low-cost, easily implemented and flexible solution to address these limitations, offering a several-fold expanded three-dimensional field of view. LINK
DEC 2021 NEW GRANT: Functional connectomics using Focused Ion Beam Scanning EM, FIBSEM (BBSRC)
The project is a collaboration with Michael Hausser (UCL) and Jan Funke (Janelia), applying methods developed in our lab to map synapses activated by visual input in vivo at nanoscale resolution in large brain volumes. The work will also use superhuman machine-learning analysis tools to offer new insights into how the brain computes information and drives behaviour.
NOV 2021 PHD STUDENTSHIP: Synaptic Dysfunction in Alzheimer’s Disease
Join us! Funded by the South Coast Doctoral Training Program, this project will use cutting-edge techniques, including optical imaging, electrophysiology, electron microscopy and machine-learning analysis approaches, to identify how synapses go wrong in models of Alzheimer’s disease.
JUL 2021 NEW PREPRINT: Ultrastructural readout of in vivo synaptic activity for functional connectomics (BIORXIV)
Here we combine 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. LINK
JUL 2021 NEW GRANT: Maximizing survival when hungry: neural mechanisms for computing behavioural priorities (BBSRC)
New funding aimed at uncovering the cellular mechanisms of decision-making in relation to motivation and threat uing a simple molluscan model system, Lymnaea stagnalis. It builds on our recent major publications in Science Advances (2018) and Nature Comms (2016).
JAN 2021 NEW PAPER: DNA damage and neurological dysfunction (EMBO REPORTS)
Defects in DNA single-strand break repair (SSBR) are linked with neurological dysfunction but mechanisms are poorly understood. We show that hyperactivity of the DNA strand break sensor protein Parp1 in mice with the central SSBR protein Xrcc1 conditionally deleted (Xrcc1Nes-Cre) results in lethal seizures and shortened lifespan. Defects are prevented by Parp1 inhibition and/or deletion and extend lifespan. Our findings highlight PARP inhibition as a possible therapeutic approach in XRCC1-mutated neurological disease. LINK
JAN 2020 NEW PAPER: Nanoscale remodeling of vesicle pools in plasticity (CELL REPORTS)
We investigated whether modulation of vesicle pools accompanies Hebbian long-term potentiation (LTP) and contributes to synaptic strengthening. We used a nanoscale readout of functionally recycled vesicles in natively wired hippocampal circuits. We found that recycled vesicle pools expand after plasticity induction and changes in the spatial organization of vesicles accompany potentiation suggesting there is a presynaptic locus of LTP encoded in functionally recycled vesicle pool organization. LINK