Forschung

In this Sinergia project funded by the Swiss National Science Foundation, we aim to consolidate the understanding of central nervous system (CNS) fluid physiology and how it changes with age, neuroinflammation and neurodegeneration – with direct relevance for the understanding of brain pathologies, including multiple sclerosis and Alzheimer’s disease. This research endeavor is a collaboration between the Interface Group, the Theodor Kocher Institute of the University of Bern and the Biomaterials Science Center of the University of Basel, in partnership with the French National Synchrotron Facility SOLEIL and the European Synchrotron Radiation Facility (ESRF).

Current understanding of CNS fluid homeostasis

Advances in intravital imaging technologies have enabled an unprecedented view into the fluid spaces of the central nervous system (CNS), challenging our current understanding of CNS fluid physiology and our brain’s immune privilege. But this has also led to a segregation of CNS research into microscopic investigations of biology in mice and macroscopic studies of biophysics in humans, without clear agreement on the production mechanisms, exit locations, driving forces and routes of CNS fluids.

The CNS fluid spaces and barriers are also of fundamental importance for CNS immune surveillance and the progression of neuroinflammatory diseases. In multiple sclerosis, lesions are first compartmentalized in periventricular areas or the perivascular spaces and only reach the CNS parenchyma proper once CNS barriers are breached. Understanding how neuroinflammation, neurodegeneration and changes in CSF dynamics are interlinked is a key requirement for the development of novel therapeutic strategies.

Our approach

We aim to establish a comprehensive understanding of CSF dynamics, associated transport processes, and corresponding CNS barriers in mouse models, and then analyze changes due to aging, neuroinflammation, and neurodegeneration. Our team consists of biologists, veterinarians, physicists, physiologists, neuroscientists, and engineers that bring together the required cross-disciplinary expertise. We will pursue our goals by a unique combination of technologies including new reporter mice, in vivo synchrotron radiation-based micro computed tomography (SRµCT), magnetic resonance imaging (MRI), near-infrared and two-photon fluorescence imaging of CSF pathways and CNS barriers, and computational modelling. Figure 1 shows sections of preliminary data obtained in vivo by SRµCT. Top panel: whole brain section. Bottom panel: olfactory bulbs and vicinity. Scale bars: 2 mm.

Related publications

1. Virtual histology of an entire mouse brain from formalin fixation to paraffin embedding. Part 2: Volumetric strain fields and local contrast changes G. Rodgers, W. Kuo, G. Schulz. M. Scheel, A. Migga, Ch. Bikis, Ch. Tanner, V. Kurtcuoglu, T. Weitkamp, B. Müller, Journal of Neuroscience Methods, 365, 109385 (2022).
2. Virtual histology of an entire mouse brain from formalin fixation to paraffin embedding. Part 1: Data acquisition, anatomical feature segmentation, tracking global volume and density changesG. Rodgers, W. Kuo, G. Schulz. M. Scheel, A. Migga, Ch. Bikis, Ch. Tanner, V. Kurtcuoglu, T. Weitkamp, B. Müller, Journal of Neuroscience Methods, 364, 109354 (2021).
3. Analysis of L-leucine amino acid transporter species activity and gene expression by human blood brain barrier hCMEC/D3 model reveal potential LAT1, LAT4, B0AT2 and y+LAT1 functional cooperationM. Taslimifar, M. Faltys, V. Kurtcuoglu, F. Verrey, V. Makrides, Journal of Cerebral Blood Flow & Metabolism, 42(1), 90 – 103 (2021).
4. Functional polarity of microvascular brain endothelial cells supported by neurovascular unit computational model of large neutral amino acid homeostasis M. Taslimifar, S. Buoso, F. Verrey, V. Kurtcuoglu, Frontiers in Physiology, 9(171), 1 – 14 (2018).
5. Barrier dysfunction or drainage reduction: differentiating causes of CSF protein increase M. Asgari, D. A. de Zélicourt and V. Kurtcuoglu, Fluids and Barriers of the CNS, 14(1), (2017).
6. Is posture-related craniospinal compliance shift caused by jugular vein collapse? A theoretical analysis M. Gehlen, V. Kurtcuoglu, M. Schmid Daners, Fluids and Barriers of the CNS, 14(5), 1 – 11 (2017).
7. Glymphatic solute transport does not require bulk flow M. Asgari, D. A. de Zélicourt, V. Kurtcuoglu, Scientific Reports, 6(38635 ), 1 – 11 (2016).
8. How astrocyte networks may contribute to cerebral metabolite clearance M. Asgari, D. A. de Zélicourt, V. Kurtcuoglu. Scientific Reports, 5, 15024 (2015).
9. Flow induced by ependymal cilia dominates near-wall cerebrospinal fluid dynamics in the lateral ventricles. B. Siyahhan, V. Knobloch, D. de Zélicourt, M. Asgari, M. Schmid Daners, D. Poulikakos, V. Kurtcuoglu Journal of the Royal Society Interface, 11, 20131189 (2014).
10. Arterial, venous, and cerebrospinal fluid flow: Simultaneous assessment with Bayesian multipoint velocity-encoded MR Imaging. V. Knobloch, C. Binter, V. Kurtcuoglu, S. Kozerke. Radiology, 270(2), 566 – 573 (2014).
11. Cerebrospinal fluid dynamics in the human cranial subarachnoid space – An overlooked mediator of cerebral disease. Part II: In vitro arachnoid outflow model. D. W. Holmann, V. Kurtcuoglu, D. M. Grzybowski. Royal Society Interface, 7(49), 1205 – 1218 (2010).
12. Mixing and modes of mass transfer in the third cerebral ventricle: A computational analysis. V. Kurtcuoglu, M. Soellinger, P. Summers, D. Poulikakos, P. Boesiger. ASME Journal of Biomechanical Engineering, 129(5), 695 – 702 (2007).
13. Computational investigation of subject-specific cerebrospinal fluid flow in the third ventricle and aqueduct of sylvius. V. Kurtcuoglu, M. Soellinger, P. Summers, K. Boomsma, D. Poulikakos, P. Boesiger, Y. Ventikos. Journal of Biomechanics, 40(6), 1235 – 1245 (2007).
14. Computational modeling of the mechanical behavior of the cerebrospinal fluid system V. Kurtcuoglu, D. Poulikakos, Y. Ventikos. ASME Journal of Biomechanical Engineering, 127(2), 264 – 269 (2005).