Humberto Mestre - PhD Candidate
Advisor: Maiken Nedergaard, M.D., D.M.Sc.
Water is the principal component of all biological tissues. The brain is not an exception to this rule and has one of the highest water contents of any tissue type. Normal brain function depends on the precise balance within all the different fluid compartments that include intracellular and extracellular fluid, cerebrospinal fluid (CSF), and cerebral blood volume. When any one of these compartments becomes deranged, such as in cerebral edema, any abnormal accumulation of fluid can lead to herniation and death. The mammalian brain has evolved a global network of fluid conduits surrounding the blood vessels that perfuse it to allow for the rapid exchange of brain fluids. These perivascular spaces serve a multitude of roles in central nervous system physiology and form the basis for the glymphatic system. The flow of CSF through the glymphatic system aids in the clearance of metabolic waste from the parenchyma serving the role of the brain’s lymphatic system. This thesis aimed to understand the mechanisms that regulate flow within the brain. Chapter two of this thesis aimed to determine the anatomical structure and geometry of perivascular spaces in the murine brain. We developed a novel imaging modality to quantify flow within perivascular spaces for the first time. This technique demonstrated that perivascular fluid flow is pumped by arterial pulsations driven by the cardiac cycle and that arterial hypertension disrupts effective pumping slowing the flow. In chapter three, we developed a mesoscopic imaging platform to show that perivascular fluid enters the brain secondary to changes in plasma osmolarity. We then exploited this finding to improve the delivery of a monoclonal antibody targeted against amyloid plaques used in the treatment of Alzheimer’s disease. Astrocytes ensheathe virtually all cerebral blood vessels, forming the outside wall of the perivascular spaces. Their endfeet express high levels of the water channel aquaporin-4 (AQP4) and this unique, polarized distribution increases the influx of CSF to the brain. In chapter four we evaluated the dependence of perivascular transport on AQP4 expression uniting efforts with four independent research groups and using five different AQP4 knockout rodent lines to confirm the dependence of brain fluid transport on AQP4. In chapter five, we leveraged the newly developed imaging modalities from chapter two and three to evaluate how acute cerebrovascular diseases contribute to abnormal fluid flow within the brain. Mainly, we tested how acute ischemic stroke enhanced perivascular inflow of CSF to the brain. This abnormal state of fluid inflow caused the detrimental accumulation of CSF and triggered the onset of edema formation. More importantly, we identified that knocking out AQP4 reduced this effect and protected against edema fluid accumulation after stroke. The results of the present thesis provide novel insights into the principles governing fluid transport in the mammalian brain and developed innovative imaging techniques to further evaluate them. The goal of gaining further insight into these processes is to ultimately use our newly gained understanding to develop novel therapeutic interventions.
Apr 12, 2021 @ 9:00 a.m.
Host: University of Rochester School of Medicine and Dentistry
The Neuroscience Graduate Program