Summary
The glymphatic and lymphatic systems are essential for waste drainage and fluid homeostasis of the central
nervous system (CNS). It has therefore been hypothesized that therapeutic efforts to maintain or accelerate
glymphatic/lymphatic functions throughout the life-span would be beneficial for preventing cognitive dysfunction.
Intriguingly, simple physiological maneuvers such as changes in body posture and/or deep-inspiratory breathing
affect the two systems and might therefore be therapeutically beneficial for sustaining a healthy brain. However,
an inherent problem in advancing such complementary therapeutics is the lack of knowledge pertaining to the
coupling between the two systems. The goal of our application is to uncover the mechanistic and physiological
controllers of the glymphatic/lymphatic coupling. A comprehensive investigation based on in vivo imaging, novel
computational fluid dynamic analysis and “omics” mapping of the lymphatic fluid will be used to test the
hypothesis that advective/diffusion transport modes of the glymphatic system operates synergistically with the
lymphatic system for optimal waste drainage and control of CNS fluid homeostasis via specific pathways such
as the Renin-Angiotensin system. We further hypothesize that physiological states (deep-inspiratory breathing,
body posture, stress/relaxation, etc.) differently affect aspects of glymphatic/lymphatic functioning and could be
externally modulated for health benefits. In SA1 we will address the important question of how the glymphatic
and lymphatic networks interconnect and regulate brain waste drainage in physiological conditions. By using
imaging and computational fluid dynamics analysis, in parallel with hemodynamic and intracranial pressure
monitoring we will map the advective/ diffusive solute transport of the glymphatic/lymphatic systems and their
response to key physiological parameters. Additionally, we will quantitatively map brain waste drainage to the
cervical lymph nodes under simple physiological manipulations such as ‘deep’ breathing using nasal continuous
positive airway pressure (CPAP). In SA2 we will address the consequences of physiological and mechanical
stressors on brain-lymphatic coupling and solute drainage. Specifically, we will use complementary therapeutic
approaches such as changes in body posture and animal models of spontaneous central and obstructive apnea
and test their modulatory roles on brain glymphatic function and lymph drainage. In SA3 we will perform a
comprehensive biochemical and biophysical analysis of the cerebrospinal fluid (CSF) and lymph, collected
through micro-cannulation under different physiological conditions, to map the molecular feed-back mechanisms
involved in CSF homeostasis and fluid drainage. Overall, our highly innovative proposal aims at a rigorous
characterization of the physiological mechanisms regulating the cross-talk between the glymphatic/lymphatic
systems and their role in CNS fluid control and brain waste drainage. An additional and crucial strength of this
application is the complementary expertise of the team, which is conducive to the execution of biochemical and
biophysical integrative experiments which, would not be possible to perform in isolation, by a single laboratory.