Dysfunction of cell signalling in the aging brain: implication in brain metabolism and behaviour

Metabolic communication between the brain cells, neurons and glial cells, is crucial to sustain brain cognitive functions, such as memory formation and learning. The main model of metabolic communication in the brain is the astrocyte–neuron lactate shuttle, wherein glial cells uptake glucose from the blood stream and transform it via aerobic glycolysis (in the presence of oxygen) to lactate, which is then shuttled to neurons as an energy substrate. The production of lactate in glial cells is regulated by neuronal activity. One of the most important regulators of the brain metabolism on-demand is the locus coeruleus-noradrenergic system that controls brain energy metabolism and many aspects of cognition, including memory formation and learning. Noradrenergic system releases noradrenaline, which via activation of adrenergic receptors and intracellular Ca2+ and cyclic adenosine monophosphate (cAMP) signals triggers uptake of glucose, aerobic glycolysis and lactate production in glial cells and subsequent metabolic support of neurons. The noradrenergic system function declines during aging, which may contribute to dysregulation of metabolism in the aging brain and to cognitive decline. In the project we will monitor brain cell metabolism during aging and try to identify the cell type and the signalling pathway in the glia-neuron metabolic loop responsible for the dysregulation of brain metabolism and associated cognitive decline and behaviour changes. We will investigate whether nutrient uptake into brain cells and the regulation of cellular metabolism by the noradrenergic Ca2+ and cAMP signals become impaired in the aging brain. We will perform experiments in the brain of transgenic Drosophila melanogaster (ex vivo) and in the brain tissue slices from C57BL/6J mouse (in situ) expressing genetically encoding intracellular fluorescent sensors for Ca2+ and metabolites (cAMP, glucose, lactate) selectively in neuronal or glial cells. We will expose the brain tissue to elevated extracellular glucose and lactate concentrations and test whether the uptake of nutrients into neurons and glial cells differs between young and old animals. We will then expose Drosophila brains and mouse brain tissue slices from young and aged animals to octopaminergic (analogous to mammalian noradrenergic) and noradrenergic stimulation, respectively. Alterations in the intracellular Ca2+ and cAMP signals and metabolites in brain cells upon stimulation will be measured with a real-time fluorescence microscopy. We will then examine if expression of adrenergic-like receptors is altered in the aged Drosophila brains and by using genetical tools try to rescue the age-related decline in locomotion behaviour with restoring the normal receptor expression level in the aging brains. Restoring normal cell signalling and metabolism in the ageing brain could represent a new therapeutic strategy for the treatment of cognitive decline and related behaviour changes.