Water exchange rates measure active transport and homeostasis in neural tissue

Abstract

For its size, the brain is the most metabolically active organ in the body. Most of its energy demand is used to maintain stable homeostatic physiological conditions. Altered homeostasis and active states are hallmarks of many diseases and disorders. Yet there is currently no reliable method to assess homeostasis and absolute basal activity or activity-dependent changes non-invasively. We propose a novel, high temporal resolution low-field, high-gradient diffusion exchange NMR method capable of directly measuring cellular metabolic activity via the rate constant for water exchange across cell membranes. Using viable ex vivo neonatal mouse spinal cords, we measure a component of the water exchange rate which is active, i.e., coupled to metabolic activity. We show that this water exchange rate is sensitive primarily to tissue homeostasis and viability and provides distinct functional information in contrast to the Apparent Diffusion Coefficient (ADC), which is sensitive primarily to tissue microstructure but not activity. SIGNIFICANCE STATEMENTDespite what physiology text-books may report, water transport across membranes is not only a passive process. However, current understanding is limited because standard techniques can only measure net flux (the difference between water moving in and water moving out). Even so, water is constantly exchanging between the inside and outside of cells and organelles without net flux during homeostasis. We developed a Magnetic Resonance method able to "see" water molecules exchanging on shorter timescales than could be observed before. In neural tissue we find most water exchange is active, that is, linked to ATP-driven processes. This method may one day be translated to clinical MRI applications for measuring cellular function and activity in the human brain and body.