Primary Supervisor: Catherine Hall, University of Sussex
Secondary Supervisor: Mariana Vargas-Caballero, University of Southampton
This project will investigate the effects on hippocampal neuronal and circuit function of a mild restriction in oxygen supply.
BACKGROUND: Chronic low-level vascular dysfunction occurs at the onset of a number of disease states such as Alzheimer’s disease, in which it may be linked with the onset of neuronal dysfunction. However, it is not currently known how a chronic mild reduction in ATP availability affects neuronal and circuit function, because previous stroke-related studies have looked at much larger changes in oxygen or blood flow. How a given neuron will be affected by a failure to generate sufficient ATP should depend on factors such as its basal activity level, number of synaptic inputs and action potential rate. Small changes in blood flow could therefore gradually initiate an energy crisis in certain neuronal populations, leading to further neuronal dysfunction and cognitive decline.
EXPERIMENTAL PLANS: This project will express excitatory DREADDs in hippocampal smooth muscle cells and pericytes to allow regionally-specific mild reductions in cerebral blood flow. At the University of Sussex, we will use in vivo 2-photon and haemodynamic recordings from awake mice to measure how blood oxygenation, brain energy metabolism and the activity of individual excitatory and inhibitory neurons and blood vessels are impacted by small reductions in hippocampal blood flow, and whether any changes are associated with behavioural impairments on spatial memory tasks. At the University of Southampton we will use field recordings and patch clamp in brain slices to investigate whether intrinsic (passive and active) neuronal properties and synaptic inputs (miniature and evoked currents) are affected by different durations of restriction of hippocampal blood flow in principal CA1 neurons compared against fast spiking interneurons.
Together these experiments will reveal how mild restriction in hippocampal blood flow changes neuronal function and whether it could initiate processes leading to progressive restriction of neuronal energy availability. It will impact on our understanding of processes that lead to neurodegeneration and cognitive impairment.