Anesthetics Modulate Cerebrospinal Fluid Efflux Pathways in Mice by Altering Perineural and Perivascular Spaces

The brain-wide glymphatic transport system facilitates cerebrospinal fluid (CSF) circulation and the clearance of metabolic waste, processes largely influenced by sleep and sleep-like anesthesia. Recent research indicates that different anesthetic agents modulate CSF dynamics in distinct ways; however, their effects on CSF efflux pathways remain unclear. This study utilized dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and structural MRI to investigate CSF efflux pathways in mice under three anesthesia protocols (n = 6 per group): isoflurane alone (ISO), isoflurane combined with dexmedetomidine (DEXI), and ketamine/xylazine (K/X). Additionally, blood vessel diameters and CSF volume fractions were quantified. Our results demonstrate that ISO induced vasodilation in the anterior brain, slowing CSF flow to the dorsal brain while substantially accelerating CSF efflux across the cribriform plate and nasal mucosa toward the nasopharyngeal lymphatic plexus compared with DEXI and K/X (p < 0.001). However, ISO reduced CSF outflow through the spinal subarachnoid space primarily due to a decreased spinal subarachnoid CSF volume (ISO vs. DEXI, p = 0.0373; ISO vs. K/X, p = 0.0436). K/X considerably impaired CSF efflux via the cervical ganglia relative to DEXI and ISO, likely resulting from a lower CSF volume fraction within the peri-cranial nerve space (ISO vs. K/X, p = 0.0328, K/X vs. DEXI, p = 0.023). In conclusion, different anesthesia protocols modulate CSF efflux pathways by altering perineural and perivascular CSF spaces. These findings suggest that anesthetic agents influence glymphatic function by modulating distinct CSF efflux routes.