The Choroid Plexus as a Hub of Immune-Clock Interaction That Connects the Body to the Brain in Prematurity (1/3)

Circadian rhythm disruption has long standing associations with inflammation and disorders of the central nervous system. As an interface between the brain and the rest of the body, the choroid plexus is gaining renewed attention. The applicant and his team have discovered that the strongest circadian clock in the brain exists in the choroid plexus. Circadian rhythms are now being found in lymphocytes, and in parallel the tight junction regulations in the fluid barriers are understood to be circadianly modulated. Amidst these new findings, it was recently demonstrated that silencing circadian rhythmicity in the RORt-expressing resident lymphocytes of the gastrointestinal tract can impair its permeability control. The choroid plexus functions as the brain's hub of immune cells, and these emerging views point to a possibility that the brain-cerebrospinal fluid barrier is gated by a converging circadian checkpoint between lymphocytes and the choroid plexus epithelium. The developing brain is particularly vulnerable in this gating process as all of these components are not fully established. We have preliminary evidence showing suppression of the immune cell circadian clock component RORt alters circadian clock rhythmicity in the choroid plexus. By combining targeted genetic silencing of circadian clock and real-time circadian clock monitoring in lymphocyte species screened through immunophenotyping, we aim to assess how changing the lymphocyte landscape shifts the circadian rhythm of the choroid plexus and alters barrier function in prematurity models of enteropathy, retinopathy, and chronic antibiotics use. The proposed project is expected to reveal an immune-clock link in the premature brain barrier regulation that is potentially relevant to understanding altered brain development in preterm adults and potentially to neurodegeneration in this subject group.

Circadian rhythm； immune cells； choroid plexus； brain barriers； NICU； X-Brain