Peripheral injuries have an impact on brain function. For instance, chronic pain (e.g., due to joints inflammation) can lead to depression, anxiety and cognitive deficits, thereby reducing the life quality of patients. To date, the sequence of events that link the initial injury to dysfunction in the brain is not well understood, thereby limiting the access to therapies for patients.
The brain is protected from the rest of the body by specific structures known as brain barriers. Brain barriers prevent the free diffusion of molecules and cells from the periphery into the brain, thereby maintaining a highly controlled environment for proper neuronal function. Dysfunction of the brain barriers is associated with many human conditions, such as multiple sclerosis and neurodegenerative diseases. One of these brain barriers is constituted by the choroid plexus (CP), which regulates the production of the brain liquids, known as cerebrospinal fluid (CSF), and the transport of molecules and immune cells from the blood to the CSF and the brain.
Recent work by our consortium has identified enlargement of the CP in multiple sclerosis patients. In parallel, studies in animal models have shown that immune cells are recruited in the CP following peripheral injuries and that this precedes and exacerbates brain inflammation and damage. This supports the idea that the CP may be involved in several conditions associated with peripheral injuries, in addition to multiple sclerosis. However, it remains poorly understood whether and how the CP contributes to these conditions.
In our project, we will analyze data obtained from patients with multiple sclerosis and peripheral injuries, as well as animal models for these disorders. Our goal is to identify the recruitment and function of CP in health and disease, to discover biomarkers of CP dysfunction and to develop clinical interventions targeting the CP that could on the long term be implemented in patient diagnosis and treatment.
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.
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.
