Glymphatic flow diurnal variation in the brain inhibited by circadian rhythm disruption and recovered by arginine vasopressin administration

Sleep is among the most fundamental of all behaviors, yet its restorative, homeostatic processes are not understood. Mounting evidence reveals that restorative sleep removes brain toxins and metabolites and, in turn, alters physiology and metabolism significantly. However, to date, (i) the basis of the process, (ii) counteracting effects of wakefulness periods, (iii) integrative processes from molecular to behavior levels during restorative sleep remain unexplained. The glymphatic system is a network of perivascular spaces surrounding the vasculature in the brain (Iliff et al., 2012a). The cerebrospinal fluid (CSF) passes from the subarachnoid space surrounding the brain and passes into these PVS. Aquaporin-4 (AQP4) channels on the glial cells surrounding the PVS move CSF into the brain parenchyma. Large proteins and metabolic waste products are removed through this flow. Little is known about whether day-night circadian rhythms of physiology affect the glymphatic flow and, consequently, metabolic waste clearance. We hypothesize that there is a diurnal variation of the glymphatic flow that is mitigated by circadian rhythm disruption. Through this flow, CSF entering the interstitial space removes large protein molecules and metabolic waste products, such as amyloid β, from the brain parenchyma (Iliff et al., 2012a). CSF together with interstitial fluid that has washed out from between the cells flows into the perivascular spaces around the veins and is discharged outside the brain (Iliff et al., 2012a). Circadian rhythms, biological processes that display an endogenous, near 24-h oscillation, significantly affect brain physiology, including alterations in sleep architecture (Karatsoreos et al., 2011) (Phillips et al., 2015). Circadian disruption, the continuous shifting of physiology on a 20-h day-night cycle, models non-restorative sleep. In addition, glymphatic flow differs between sleep and awake states, increasing significantly during sleep (Xie et al., 2013). However, it is not known whether or how circadian rhythms affect glymphatic flow. People with circadian rhythm disruption generally wake up feeling less refreshed, similar to the effects of sleep disruption. This observation brings up the question of what effects circadian rhythm disruption could potentially exert on glymphatic fluid transport in the brain and consequently on metabolic waste clearance. Furthermore, elderly patients suffering from neurodegenerative diseases, including Alzheimer’s patients, exhibit altered circadian physiology as well as disrupted sleep. If circadian rhythm disruption negatively affects the fluid transport in the brain and in turn causes waste product accumulation that leads to neurodegenerative disease, is there a way we could reverse that using the glymphatic system itself as a drug delivery model?

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Neuroscience

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2023

Author dc:creator

• Hamed, Eman Elhag Abdel

Contributors dc:contributor

• Gillette, Martha
• Kong, Hyunjoon
• Sutton, Bradley
• Christian-Hinman, Catherine

• Glymphatic System
• Circadian Rhythm
• Circadian Rhythm Disruption
• Arginine Vasopressin
• Magnetic Resonance Imaging
• Mri
• Hippocampus
• Suprachiasmatic Nucleus
• Scn
• Brain Fluid Transport
• Neurodegeneration
• Neuroscience
• Pharmacology
• Biomedical Engineering

Statement dc:rights

• © 2022 Eman Elhag Abdel Hamed

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/120477

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F120477