BrainEnergyControl · Quantifying control of brain energy supply by the neuron-glia-vasculature unit

Quantifying control of brain energy supply by the neuron-glia-vasculature unit

The relationship between neuronal activity, blood flow and metabolism provides the basis for the functional brain imaging techniques widely in use today. Local changes in glucose utilization, oxygen utilization, blood flow and hemoglobin oxygenation are taken as indicators of the activity of neuronal pathways during behavioral tasks or mental states. Surprisingly however, the cellular mechanisms that underlie the coupling between neuronal activity, glial cells and cerebral blood flow are poorly understood. Unlike in other tissues, a complex flow of information between neurons, astrocytes, pericytes, microglia and arteriolar smooth muscle cells regulates blood flow. Elucidation of the mechanisms coupling brain energy use to energy supply is essential for understanding how brain imaging data relate to neural function and for using these data to identify mechanisms of neuropsychiatric disorders such as depression, Alzheimer’s disease or schizophrenia, in which alterations in neurometabolic function are detected. These mechanisms are also of great therapeutic and economic importance because of their relevance to treating stroke and other disorders of brain blood flow. Using a combination of mathematical modeling and in vitro imaging experiments, this project investigated the relations between energy consumption, information flow in neuronal circuits, the regulation of glial cell activity by extracellular metabolic signals and the trafficking of metabolites between neurons and glial cells. In this project, we demonstrated that, for information being transmitted at a synapse in the presence of noise, a low release probability at synapses is the optimal solution to maximize the information transmitted per metabolic cost. This provides an exciting explanation for the previously poorly understood fact that synapses are extremely unreliable, often only releasing neurotransmitter 25% of the times that a presynaptic action potential arrives. Similarly, we demonstrated, in rat lateral geniculate nucleus relay cells, that the amplitude of postsynaptic currents is not set to maximize the amount of information transmitted across the synapse, but to maximise the ratio of information transmitted to postsynaptic energy consumption. These results suggest the existence of homeostatic mechanisms that regulate both energy consumption and information transfer at synapses. Second, we built a model of metabolic interactions of the neuron-glia-vasculature ensemble. This model provides a template for large-scale simulations of this ensemble and for the first time integrates the respective timescales at which energy metabolism and neuronal excitability occur. These findings provide a quantitative mathematical description of the metabolic activation in neurons and astrocytes, as well as of the macroscopic measurements obtained during brain imaging. Third, we extended our understanding of brain energy use by examining the ATP used on non-signalling tasks in the brain. These are thought to consume to 25-50% of the brain’s ATP but the details have been unclear. We have shown that most of this non-signalling energy use is expended on turnover of the actin and microtubule cytoskeleton. Fourth, as an offshoot of our studies of the energy-supply molecule ATP, we investigated ATP-mediated signaling in rodent brain slices and its role in controlling the function of another type of glial cell, microglia. We first determined that a two-pore domain potassium channel determines the resting membrane voltage of microglia in situ and that this channel controls their motility. Interestingly, this channel is totally inhibited by gaseous anesthetics and by hypoxia. The suppressive effect of gaseous anesthetics on microglial surveillance suggests that brain immune function may be suppressed in clinical situations using these agents, while the expected suppressive effect of hypoxia on surveillance could explain the synergy of hypoxia and infection in causing brain damage.

Data: CORDIS, © European Union