The brain's energy supply must match its moment-to-moment workload, but the cellular machinery that orchestrates this delivery remains poorly understood. This research programme investigates three specific mechanisms: how star-shaped glial cells called astrocytes use a signalling molecule (cAMP) to deliver fuel on demand, how carbon dioxide levels control blood flow in the brain, and how mitochondria in astrocytes produce nitric oxide when oxygen runs low. By genetically blocking key components of these pathways in rats and mice, then recording neuronal activity, blood flow, and vessel responses with two-photon microscopy and MRI, the team aims to identify the molecular levers that couple energy supply to neural computation. This is fundamental science—there is no immediate clinical application. However, a clearer picture of how the brain manages its energy budget could eventually inform strategies to preserve cognitive function during ageing or after stroke, when metabolic support falters. Past discoveries in brain energy metabolism, such as the role of lactate shuttling, have already reshaped understanding of memory and neurodegeneration; this work extends that foundation.
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This research programme explores the cellular and molecular mechanisms responsible for metabolic support of neuronal computation in the brain. Experimental studies are designed to answer the following fundamental questions: (Q1) What are the mechanisms responsible for on-demand delivery of metabolic substrates to support the variable level of neuronal activity? (Q2) What are the mechanisms underlying metabolic control of cerebral blood flow? (Q3) What are the brain mechanisms of adaptation to acute metabolic insufficiency? These questions are addressed by focusing on three metabolic mechanisms/signalling pathways: (i) mediated by cAMP in astrocytes, (ii) underlying the effect of CO2 on brain vasculature, and (iii) responsible for mitochondrial production of nitric oxide by astrocytes in low oxygen conditions. Key identified component(s) of the hypothesised mechanisms will be blocked genetically, followed by two-photon optical recordings of the activities and interactions between neurons, astrocytes and cerebral vasculature, electrophysiological assessment of synaptic function, recordings of cerebral blood flow and cerebrovascular reactivity using MRI, physiological and behavioural phenotyping in experimental animals (rats and mice). This research is expected to advance our understanding of brain energy metabolism and may prove to be important for the development of preventive and therapeutic strategies to maintain cognitive health and promote brain longevity.
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