Role of Border-Associated Macrophages in neurocognition

The field of neuroimmunology is rapidly advancing, revealing that the brain does not function alone; immune cells play a significant role in modifying our behaviour in health and disease. While the brain itself lacks most immune cell types apart from microglia, the question arises: how do immune cells communicate with neurons and influence brain function? Interestingly, recent data indicate that the brain borders contain a massive network of immune cells, including border-associated macrophages (BAM). Using innovative depletion strategies based on transcranial drug delivery in mice and genetic models targeting BAM, my team discovered that in the absence of BAM, proliferation and activation of neuronal cells decrease in the hippocampus, a brain region crucial for memory. The goal of ‘BAMneuro’ is to understand how BAM support neurogenesis, neuronal activation and if this promotes memory, in health and disease. To this end, I will combine bioinformatic, transcriptomic, proteomic and metabolic techniques to identify candidate molecules allowing BAM to communicate with neurons and boost neuronal functions. I will then analyse BAM-derived ligands in vitro for their capacity to stimulate neuronal functions using neurosphere assays, calcium imaging and electrophysiology. I will inactivate BAM-derived ligands in vivo using conditional knock-out mice and siRNA-loaded liposomes, both engineered to target BAM while sparing microglia, and assess neuronal functions in presence or absence of BAM ligands. Additionally, since cognitive functions are significantly impacted by infection and inflammation, I will study BAM neurocognitive properties following peripheral exposure to microbial challenge such as lipopolysaccharide and influenza. I plan to restore BAM-to-neuron communication if proven disrupted. By discovering new players controlling brain functions from the ‘outside’, this work should provide major conceptual and therapeutical advances in the field of neuroimmunology.