Astrocytes, an abundant cell type in the central nervous system, are generally believed to play a homeostatic, supportive role for neurons. In the last two decades, a growing body of evidence suggests that they contribute actively to brain functions, including cognitive ones such as learning and memory. Our laboratory has recently shown that astrocytic mechanisms underlie long-term memory formation. Blocking glycogenolysis in the rat hippocampus impairs memory. In the adult brain, glycogen is stored in astrocytes, but not in neurons, and its breakdown produces lactate. We found that levels of lactate increase in the hippocampus following learning, and that blocking hippocampal transport of lactate from astrocytes to neurons blocks long-term memory formation and its underlying molecular activations. Lactate, but not equicaloric concentrations of glucose, rescues the amnesia suggesting that metabolic coupling between astrocytes and neurons via lactate is required for long-term memory formation. This project aims to further elucidate mechanisms of astrocyte-neuron metabolic coupling. Specifically, I hypothesize that astrocyte-neuron lactate transport is a general mechanism important for memory consolidation across brain regions and learning paradigms. The contribution of glycogenolysis and lactate transport to memory formation will be examined in various brain regions known to be critical for a fear-based learning task and a social learning task, respectively. Also, as the noradrenergic system has long been known to enhance memory, and studies in vitro suggest that glycogenolysis is stimulated by norepinephrine via astrocytic 2-adrenergic receptors, I hypothesize that -adrenergic receptors found on astrocytes mediate long-term memory formation. I will test this hypothesis using an in vivo, astrocyte-specific, viral-mediated knockdown strategy. Lastly, I will investigate the mechanisms by which lactate mediates memory consolidation after being transported into neurons. Beyond its function as an energy source, lactate is implicated in regulating cellular and organelle redox balance, as well as the generation of reactive oxygen species. Proteins that are known to be regulated by redox state and reactive oxygen species include sirtuins, a class of deacetylases involved in a number of cellular functions, of which SIRT1 is known to play a role in memory. I hypothesize that downstream targets of learning-induced astrocyte-neuron lactate coupling include sirtuins, and will test whether sirtuin expression is regulated by learning through astrocytic mechanisms. Astrocytic pathology is found in numerous brain diseases, including neuropsychiatric diseases affecting cognition, and thus the molecular pathways underlying astrocyte-neuron interactions are promising targets for therapeutic interventions. PUBLIC HEALTH RELEVANCE: Glial pathology is seen in every brain disease, from astrocyte activation in neurodegenerative disorders such as Alzheimer's disease, to abnormal astrocyte density in neuropsychiatric disorders such as depression and schizophrenia; however, the pathophysiological mechanisms underlying these changes are not well understood. Astrocytes play active roles in what were previously thought to be solely neuronal functions, from signal transmission and synaptic plasticity, to cognitive functions such as learning and memory. This project aims to elucidate the molecular mechanisms underlying this neuron-astrocyte interplay, a promising locus for potential therapeutic targets.