ELUCIDATING THE NEUROMODULATORY FUNCTION OF CEREBROSPINAL FLUID

Cerebrospinal fluid (CSF) is a clear liquid that fills the brain and spinal cord of vertebrates. Traditionally viewed as a passive medium that provides nutrients, removes waste, and cushions the brain, CSF is now emerging as an active regulator of brain physiology. Notably, disruptions in CSF composition or dynamics have been linked to neurological conditions such as anxiety, autism spectrum disorders, and dementia. Despite this growing recognition, the mechanisms underlying CSF production, circulation, and neuromodulatory function remain poorly understood.
Using genetic, imaging, and histological approaches, we first demonstrated that zebrafish possess an evolutionarily conserved ventricular system composed of interconnected ventricles lined by ciliated ependymal cells and CSF-producing choroid plexus. We then identified several physiological drivers of CSF flow within the ventricles, including ependymal cilia activity, cardiac pulsatility, body movements, and choroid plexus secretion, which mirror the mechanisms observed in mammals. By genetically manipulating cilia and choroid plexus function, we discovered that CSF dynamics play a crucial role in shaping brain physiology through their impact on neural and astroglial networks.
We are now investigating the molecular pathways that link altered CSF dynamics to changes in brain activity, neuronal circuit maturation, and behavior. To accomplish this, we combine proteomics with in vivo brain activity monitoring and behavioral assays in zebrafish with ablated choroid plexus and perturbed CSF flow. Our long-term goal is to elucidate how CSF dynamics regulate brain function in both healthy and pathological conditions.