Illuminating body-brain communication channels at the choroid plexus and their impact on brain physiology.

ongoing

In contrast to other organs, the brain is surrounded by a system of specialized anatomical barriers isolating it from direct contact with immune cells and microbial products present in the blood. However, such factors do dynamically shape brain function in homeostasis and disease. Because of this unusual anatomy, the pathways of blood-brain communication are still poorly understood, while this understanding would provide a fundamental insight into brain function regulation, and enrich the current knowledge of neurological disease mechanisms. My previous work suggests that the choroid plexus (CP) is a central player mediating the influence of immune and microbial signals on the brain. The CP epithelium is a monolayer barrier tissue, which on the side facing the blood has the ability to sense such peripheral factors, and on the side facing the brain, produces the cerebrospinal fluid (CSF)–a liquid carrying nutrients and signaling molecules, which contacts nearly all brain cells, and ensures brain homeostasis. I therefore hypothesize that peripheral immune and microbial factors may shape brain function indirectly, via regulation of the CSF properties at the CP epithelium. Based on our preliminary data, and building on my past expertise in CP biology, neuroscience and immunogenomics, here I propose an interdisciplinary project BrainGate, striving to illuminate the physiological mechanisms and roles of gut-blood-CP-brain communication axis during post-natal development (Aim 1), under conditions of microbiota perturbation (Aim 2) and along the circadian cycles (Aim 3). By developing new tools for CP-specific genetic perturbation and combining them with approaches of spatial transcriptomics and behavioral readouts in mouse models, this project will reveal fundamental principles of physiological regulation of brain development, function and maintenance and pave the way for future investigation of the gut-blood-CP-brain communication circuit in neurological disease.