Interactions between neurons and glia are at the heart of healthy neurophysiology, and breakdown of communication between these cell types is implicated in a wide range of neurodegenerative conditions. Trauma, infection or chronic neurodegeneration of the brain and spinal cord is associated with a pronounced glial response. Activation of astrocytes leads to a phenotypic switch in cell function from quiescent and largely supportive roles, to an active immune response termed reactive gliosis. Gliosis can be neuroprotective or exacerbate neuronal damage and degeneration, but an experimental challenge in understanding this duality is the complex milieu of signalling factors and cells in the intact brain. To date, most studies that have attempted to understand the role of astroglia in neurodegeneration have used mutant or transgenic animals that model disease pathology, such as the SOD1G93A model of ALS (in which astrocytes have been clearly implicated in non-cell autonomous degeneration of motor neurons). These studies inevitably carry a significant burden of animal morbidity and mortality.
The aim of this project is to develop an in vitro microfluidics system that allows for compartmentalization of neuronal somata and axons, and the addition of astrocytes to these compartments individually. A key goal is to use 3D culture techniques, by suspending the cells in hydrogel or nanofiber matrices, to mimic a more physiological extracellular environment within which astrocytes adopt a non-reactive phenotype (in contrast to conventional 2D cultures). This would allow for investigations into how astrocytes interact with neuronal somata and axons undergoing degeneration due to injury or toxicity, before and after controlled induction of gliosis. This would result in a superior in vitro model for investigating neuron-glial interactions during neurodegeneration, reducing the need for ex vivo experiments using transgenic animal models.
Dobson KL et al. (2018). Distribution of vesicle pools in cerebellar parallel fibre terminals after depression of ectopic transmission. PLOS ONE 13(7):e0200937. doi: 10.1371/journal.pone.0200937
Principal investigatorDr Tomas Bellamy
InstitutionUniversity of Nottingham
Co-InvestigatorDr Noah Russell
Dr Federico Dajas-Bailador