Micromem

Brain plasticity that underlies memory function likely results from a balance between synapse formation, potentiation and removal. The synapse formation and potentiation occur mostly during wakefulness, while synaptic downscaling and removal take place mostly during sleep. Immune signaling molecules present in the healthy brain can interact with neurochemical systems including serotonin to contribute to the regulation of normal sleep. While it has been widely shown that sleep alterations impair learning, there remains much debate over the mechanisms involved. Recent studies revealed key tasks for microglia, the main immune cells in the brain, interactions with neurons during normal physiological conditions, especially in regulating the maturation of neural circuits and shaping their connectivity in an activity- and experience-dependent manner. However, their role in learning and memory remains elusive. Specifying the role of microglia in synaptic consolidation according to the sleep/wake cycle is undoubtedly a particular challenge to research. Consortium members have shown (i) that microglia motility can be modulated by serotonin, whose levels vary with arousal/sleep states, and (ii) that microglia dynamics is different in arousal vs. sleep states and (iii) that mice lacking 5-HT2B receptors, which is the main serotonin receptor expressed by microglia, display sleep and memory deficits. Together, these observations support the hypothesis that microglia and serotonin actively participate to memory consolidation by regulating synaptic plasticity, that microglia interact with synapses in different modes and potentially with different outcome during sleep and wakefulness, and that serotonin could be implicated in this switch. The role of microglia in learning and/or cognitive flexibility could therefore be more prominent during either the wakefulness or the sleep period. Exploring this hypothesis, the consortium will delineate the signaling pathways induced in microglia by serotonin, and show how serotonin participates to microglia dynamics and to synaptic plasticity. By multidisciplinary approaches combining the analysis of EEG (electroencephalogram) and in-vivo imaging, field potential in acute slices, behavior, conditional mutants, optogenetic and chemogenetic (DREADD) approaches, we propose to elucidate how a control of microglia by serotonin is implicated in synaptic and brain plasticity and if this occurs mainly during awake-learning phases, or asleep-consolidation phases and by which intracellular pathway. This proposed preclinical approach includes a totally new pathophysiological axis since no one has ever established a link between immune cells microglia, memory consolidation and sleep. Thus it may open new perspectives for pharmacological treatment of neuropsychiatric disorders, which are associated with microglia activation, and/or sleep alterations such as schizophrenia, autism and depressive disorders.