DESCRIPTION (provided by applicant): Memory consolidation is the process by which the newly learned information, which exists in a labile state, becomes a long-lasting memory that is resistant to disruption2,3,4. Long-term memory consolidation requires de novo protein synthesis, and it is very likely that dendritic protein synthesis is also involved in this process5. Long-term potentiation (LTP) is a persistent increase in synaptic strength, and is considered a cellular correlate for long-term memory8. Like memory consolidation, late forms of LTP (L-LTP) also require protein synthesis, and have been shown to specifically require dendritic protein synthesis as well as somatic protein synthesis9. Memories of emotional experiences such as those produced in the fear conditioning-based inhibitory avoidance (IA) paradigm, are subject to modulation by various hormones35. Noradrenaline is released from the locus coeruleus during arousal and enhances memory via ¿-adrenergic receptors41. The same is true in regards to LTP, which is likewise modulated by noradrenaline10,50. Recent evidence from our laboratory and others suggest that astrocytes play a larger role in both learning and memory and LTP than previously thought. By contributing lactate to neurons through glycogenolysis and transfer via monocarboxylate transporters, astrocytes are critical to memory consolidation and LTP maintenance (see preliminary data). Interestingly, ¿-adrenergic receptors are present on astrocytes and have also metabolic effects in astrocytes when stimulated15,16,37,38,39,40. This project will test the contribution of astrocytes to long-term memory and LTP. Specifically, it will test the hypothesis that astrocytes critically contribute to memory formation by providing astrocytic-neuronal coupling through lactate that supports the high-energy demands associated with activation of dendritic protein synthesis. Furthermore, it will test the hypothesis that the noradrenergic-dependent modulation of memory is mediated by the astrocytic-neuronal coupling. PUBLIC HEALTH RELEVANCE: The contribution of astrocytes to brain diseases is vast and still very underexplored, but astrocytic and microglial activation has been reported in several neurodegenerative disorders, including AIDS dementia complex, Alzheimer's disease and amyotrophic lateral sclerosis66. This transition may be accompanied by functional deregulation and even degeneration of the astrocytes with the consequent disruption of the crosstalk normally occurring between these cells and neurons67. Thus, incorrect neuron-astrocyte interactions may be involved in neuronal derangement and contribute to disease development, and elucidating the mechanisms that underlie the astrocyte-neuronal coupling in cognitive functions including learning and memory should enable us to better understand normal brain function and identify potential molecular targets for therapeutic intervention in several disorders.

Project Narrative The contribution of astrocytes to brain diseases is vast and still very underexplored, but astrocytic and microglial activation has been reported in several neurodegenerative disorders, including AIDS dementia complex, Alzheimer's disease and amyotrophic lateral sclerosis66. This transition may be accompanied by functional deregulation and even degeneration of the astrocytes with the consequent disruption of the crosstalk normally occurring between these cells and neurons67. Thus, incorrect neuron-astrocyte interactions may be involved in neuronal derangement and contribute to disease development, and elucidating the mechanisms that underlie the astrocyte-neuronal coupling in cognitive functions including learning and memory should enable us to better understand normal brain function and identify potential molecular targets for therapeutic intervention in several disorders. !