Modulation of memory encoding by the blood-brain barrier

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Emotions strongly influence cognitive processes such as learning and memory in humans and animals. The vast majority of behavioral studies are neuron-centric however accumulating evidence suggest involvement of other biological systems yet to explore. The main research goal of my NSERC research program is to understand how the peripheral immune system interacts with the brain neurovasculature to modify neuronal circuits involved in memory processes. I propose to combine the expertise I developed in brain and membrane plasticity, memory formation and emotional response to decipher the mechanisms involved. The blood-brain barrier (BBB) represents the ultimate frontier between the brain and peripheral immune signals. Still, we know very little on how circulating inflammatory mediators influence the BBB, brain cell circuits and ultimately behaviors in different environmental context under normal conditions. Emotional experience can have a negative or positive valence, for example if it is associated with fear or reward, respectively. The brain is an immunologically privileged site and peripheral immune cells and mediators such as proinflammatory cytokines have a very limited access to it. However, we showed that negative emotional experience induces changes in BBB permeability and loss of tight junction proteins promoting infiltration of inflammatory signals. Our preliminary data revealed significant correlations between levels of cytokines and expression of Major facilitator super family domain containing 2a (Mfsd2a), a membrane transport protein critical for BBB formation and integrity. These findings provide a basis to this proposal and raises questions about the role played by endothelium transport mechanisms in infiltration of peripheral immune signals and a potential link between emotion-driven immune responses, BBB integrity and formation of positive or negative memories. To tackle these fundamental questions, we will combine behavioral assessments to morphological and functional studies. For our first short-term objective we propose to evaluate how emotion-driven memory formation affects blood cytokine profile, BBB morphology and molecular properties. For the second short-term objective we propose to manipulate expression of genes involved in BBB integrity and transport and determine how it affects memory formation and cytokine infiltration into the brain. The BBB is perfectly located to carry on peripheral immune signals to neighboring glial cells and neurons affecting their biology and ultimately emotional valence and memory processes. Our research program will aim to understand how neurovascular adaptations and immune responses affect behavioral encoding and if these systems can be manipulated to promote positive bias and normal memory formation. Requested funds will advance knowledge of fundamental aspects related to cognition and expose the next generation of scientists to a dynamic research environment and cutting-edge technologies.