Project

Discipline

lymphatic; stroke; hemorrhage; brain edema; cerebrospinal fluid

Lead
Die Entwicklung eines Hirnödems nach einem hämorrhagischen Schlaganfall ist eine ernsthafte Komplikation in der Klinik. Aufgrund fehlender grundlegender Kenntnisse darüber, wie das Flüssigkeitsvolumen im Zentralnervensystem (ZNS) reguliert wird, sind die Mechanismen für die Entstehung eines Hirnödems jedoch noch unbekannt. Unsere Arbeit hat bei Mäusen den Nachweis erbracht, dass der Liquor, nachdem er in den Ventrikeln im Gehirn produziert wurde, vorwiegend entlang der Hirnnerven abfließt, um die Lymphgefässe ausserhalb des ZNS zu erreichen, und nicht in Richtung des Hirnparenchyms fliesst, wie in mehreren neueren Studien vorgeschlagen wurde.
Lay summary
Inhalt und Ziele des Forschungsprojekts  Im vorliegenden Projekt wollen wir mit Hilfe der Nah-Infrarot-Fluoreszenz-Bildgebung zeigen, dass die interstitielle Hirnflüssigkeit unter physiologischen Bedingungen entlang definierter Wege entlang der paravaskulären Räume und der Bahnen der weißen Substanz aus dem Parenchym austritt. Wir werden auch die wichtige Rolle hervorheben, die die paravaskulären Räume beim Flüssigkeitstransport zwischen dem Liquor und dem Hirn-ISF spielen, um die Flüssigkeitshomöostase des Hirngewebes zu kontrollieren. Schließlich werden wir die gewonnenen Erkenntnisse anwenden, um die Auswirkungen von Subarachnoidalblutungen und intrazerebralen Blutungen auf die Clearance von ZNS-Flüssigkeit in Mausmodellen unter diesen Bedingungen zu bewerten.    Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts  Es wird erwartet, dass diese Studien zur Etablierung eines Modells des extrazellulären Flüssigkeitsflusses innerhalb des ZNS beitragen werden, das unser Verständnis des hämorrhagischen Schlaganfalls und verschiedener anderer Neuropathologien verbessern wird.

Direct link to Lay Summary

Last update: 03.02.2020

Natural persons

Number	Title	Start	Funding scheme

The interrelationships of cerebrospinal fluid (CSF) and brain interstitial fluid (ISF) are incompletely understood. Recent studies have proposed the existence of a “glymphatic” system that flushes CSF through the parenchyma of the central nervous system (CNS). However, this concept remains highly controversial. Our own work in mice has presented evidence that CSF, after being produced in the ventricles within the brain, will clear predominantly along exiting cranial nerves to reach lymphatic vessels outside the CNS rather than flow towards the brain parenchyma. However, based on historical evidence, it is likely that the paravascular (or Virchow-Robin spaces) around cerebral blood vessels do play an important role in shuttling fluid between the CSF and brain ISF to control the fluid homeostasis of the brain tissue. Thus, the first aim of this project will be to demonstrate that the fluid flow within paravascular spaces is reversible depending on the osmotic forces present at the blood-brain barrier. This will be tested by altering the osmolarity of the blood to induce the formation or resorption of brain interstitial fluid. During these interventions, a recently developed through-skull near-infrared imaging technique will track the direction of flow of fluorescent tracers in the paravascular spaces on the surface of the brain. The work of the first aim will provide support for the concept that brain ISF, under physiological conditions, exits the parenchyma along defined routes through paravascular spaces or along white matter tracts to join CSF. However, due to the presence of potential anatomical barriers, it is unclear if solutes will be able to use the same routes to access the CSF or lymphatic system. Our second aim is to trace the pathways of solute clearance from brain ISF to the lymphatic system. We will inject, under carefully-controlled conditions, different molecular weight near-infrared labeled fluorescent tracers to evaluate if the size of the particle influences its ability to clear from the brain interstitial space. Hypoosmotic conditions will be induced in the blood to stimulate the production of interstitial fluid and to test if the clearance of solutes is increased. Information from these experiments will be used to develop in vivo techniques for clearance of interstitial solutes using magnetic resonance imaging. It is anticipated that the work from the first two aims will contribute to the establishment of a new model of CNS fluid flow that will improve our understanding of several different neuropathologies and enhance CNS drug delivery strategies.We will then test the CNS fluid model in mouse models of subarachnoid and intracerebral hemorrhage. Brain edema after hemorrhagic stroke is a serious clinical issue with no established treatments to prevent the dangerous increases in intracranial pressure that occur in these patients, in many cases resulting in death many days after the initial stroke. Several observations from clinical studies or animal models have indicated that altered CSF flow occurs after hemorrhage. Therefore, the third aim of the project is to evaluate how subarachnoid and intracerebral hemorrhage affect the fluid circulation of CSF and ISF. Of key interest is to determine if red blood cells can clear intact from the subarachnoid space or if degradation of these cells must take place within the CNS, with resultant inflammatory effects. These studies in hemorrhagic stroke models will provide novel insights into the development of brain edema in patients with these conditions and may lead to new therapeutic strategies.