Contextual fear memory: consolidation by the combined action of serotonin and microglia. – FEARMISER

Contextual fear memory is a conserved, still mysterious, process allowing vital response to dangerous situations. Microglia, which are the resident macrophages of the brain, are known to contribute to synaptic remodeling, by eliminating or promoting the appearance of synapses, and it has recently been shown that they also exert an inhibitory control over the activity of neurons. They can therefore potentially contribute to memory processes, but upstream signals regulating their actions on neurons and synapses are unknown. The neuromodulator serotonin is a good candidate, given its role in plasticity and our identification of functional serotonin receptors in microglia, the 5-HT2BR subtype. We have shown that serotonin, when applied locally to acute brain slices, induces an attraction of microglial processes, which depends on these 5-HT2B receptors. Recently, we have also shown that in the absence of this receptor since birth, microglia are more reactive, and in case of peripheral inflammation, the induced neuroinflammation is stronger and takes longer to resolve. Thus, serotonin has both acute and long-term effects on microglia, both on their morphology and function. Finally, our unpublished results indicate that when this receptor is inactivated in microglia, from adulthood onwards in order to avoid developmental effects, mice can learn to memorise an association between a context and a danger, but this contextual fear memory is not reinforced, not consolidated, beyond 1.5 hours. Morevoer, in these mice, the increase in dendritic spines density which is normally induced 48h after contextual fear conditioning, is not observed. Our working hypothesis is thus that microglia and serotonin work together to allow contextual fear memory consolidation, the microglia being regulated, engaged, by 5-HT in the hippocampus to act on neurons.
Combining sophisticated genetic and viral models (conditional KOs and GFP expression in microglia, biosensors to detect changes in serotonin levels in vivo in behaving animals, optogenetics to stimulate serotonergic neurons, viral infections to locate dendritic spines in hippocampal neurons), cutting-eddge in vivo imaging approaches (fiber photometry, GRIN lenses and multiphoton imaging in the hippocampus on awake animals), and transcriptomic and translatomic approaches, we will investigate the provocative hypothesis that microglia, under the timely control of 5-HT, contributes to contextual fear memory consolidation. One of our goals will be to understand the mechanisms by which microglia, under the control of serotonin, modulates the stability of synapses and thereby contributes to the consolidation of fear memory. Finally, along these experiments, we will develop a microglial activation reporter system in order to be able to identify and tag, specifically, the microglial cells which are actively engaged upon fear conditioning. This would allow to follow and study them specifically, and to compare them to other microglial cells that have not been activated by fear conditioning. We aim at producing a versatile mouse system that may have many more applications for studying activated microglial cells in other contexts, like stress, addiction, inflammation.
Our results, by documenting the involvement of microglia and serotonin in the consolidation of contextual fear memory, will suggest new therapeutic targets to treat emotional memory disorders, for example post-traumatic stress disorders, in which contextual emotional memory is abnormally generalized. Moreover, they could open to fascinating hypotheses about the potential modulation of this memory and thus of our behaviour by situations such as infection, stress, and changes in microbiota, which are known to affect microglia.