Immune mechanisms in Environment-induced brain plasticity: Role of T cell-ILC Crosstalk

Neuroplasticity is the essential ability of the brain to respond and adapt to extrinsic and intrinsic stimuli, and it is strongly influenced by the environment we live in. Exposure to e nvironmental enrichment (EE) leads to neurological changes paralleled by changes in the immune system. EE promotes neurogenesis, neuroplasticity, and ameliorates neuroinflammation in both rodents and humans. Microglia and brain T cells also adapt their phenotype and T cell number increases, suggesting a connection between neural activity and immune response. How brain T cells or other lymphoid cells and microglia are able to respond to EE and eventually modify the brain is unknown. I hypothesize that EE instigates a neuroimmune crosstalk between lymphoid cells and microglia to support the neuronal changes. To test this, I will use high-dimensional spectral flow cytometry and CITE-seq to map the changes in the intercellular communication networks induced by exposure of mice to EE and identify key cellular and molecular mediators. Next, I will combine depletion tools and genetic models to assess the specific role of different subsets of lymphocites in EE-induced brain plasticity. The final ambition of this project is to identify key molecular targets mediating EE-induced lymphocites-microglia crosstalk. I will then use a gene therapy approach to deliver candidate biologics to the brain. Using a mouse model of Autism, I will provide impactful proof-of-concepts for the ability of immune molecular mediators to stimulate pathways of brain plasticity and mimic the benefits of environmental enrichment in neuropathology.