Cerebrospinal fluid (CSF) is increasingly recognized as an active regulator of brain function rather than a passive mechanical buffer. Beyond its classical roles in cushioning the brain and removing metabolic waste, CSF participates in a tightly coupled system linking neural activity, vascular dynamics, molecular signaling, and tissue mechanics. Here, we present an integrated theoretical framework that unifies three major conceptual strategies in contemporary CSF research: metabolic clearance, neuromodulatory signaling, and bidirectional coupling between fluid dynamics and neural activity. We argue that these processes form a closed-loop regulatory system in which brain state governs CSF flow, while CSF dynamics reciprocally shape neural function and long-term brain health. Disruptions to this integrated CSF-brain system underlie a wide spectrum of neurological disorders, including Alzheimer’s disease, stroke, sleep disorders, and hydrocephalus. By synthesizing evidence across scales and disciplines, this framework provides a coherent conceptual foundation for future experimental, diagnostic, and therapeutic advances targeting CSF physiology.
Yang et al. (Tue,) studied this question.