ChorNEXUS:

Principles of choroid plexus-mediated brain-body interactions in the context of systemic pathologies

Behavioral responses are based on a continuous bidirectional communication between the body and the central nervous system (CNS). The choroid plexus (CP), a specialized epithelial-endothelial tissue in the brain, provides an interface between the blood and the CNS. It functions as the blood-cerebrospinal fluid (CSF) barrier, the CSF secretory organ, and a site for immune surveillance. Thereby, the CP is perfectly positioned for regulating brain-body interactions. Yet, how the CP senses and responds to this flow of information in health and disease is poorly understood. It is also unclear whether the CP can be targeted for clinical interventions of brain diseases. The primary objective of ChorNEXUS is to investigate the principles of CP-mediated brain-body interactions in peripheral and systemic pathologies, that have been associated with CP recruitment. We will study how the CP senses, processes, and responds to selective stimuli, and how this information influences neural circuits in view to identify biomarkers and targets for clinical interventions. ChorNEXUS is a multidisciplinary project combing research in preclinical models (mouse, rat and zebrafish) and humans to identify: 

(1) the impact of peripheral injuries on the CP and the brain, 

(2) how CP alterations lead to maladaptive brain plasticity and disease, 

(3) markers of CP dysfunction for diagnostic purpose, and 

(4) CP interventions, targeting the neuroprotective properties of CP, for treatment of brain disorders. 

Evidence from the literature and our consortium suggests that CP is recruited in the context of several inflammatory and non-inflammatory pathologies, including multiple sclerosis, systemic infection, and peripheral injuries, such as neuropathic pain. As the cellular and molecular mechanisms involving the CP cannot be tackled in humans, these aspects will be covered using preclinical models of diseases. We chose preclinical models in which we have preliminary evidence of the implication of the CP in the pathology, which include neuropathic pain (mouse), inflammatory pain (mouse), and postnatal systemic stress of infectious origin (rat and zebrafish). We will then relate our preclinical models to patients with the following clinical diagnostics: chronic neuropathic pain, chronic inflammatory pain (inflamed joints), pediatric systemic infection and multiple sclerosis. By combining preclinical expertise in CP, CSF, and neuronal physiology with the clinical management of patient cohorts with peripheral injury diseases, ChorNEXUS is well positioned to identify the overarching principles of CP-mediated brain regulation in health and disease. This will be instrumental for future development of diagnostics and therapies.