AG Neuroimaging und Neuroengineering des experimentellen Schlaganfalls
Dr. rer. nat. Markus Aswendt
Leiter der AG
Wir untersuchen die zellulären Grundlagen von Netzwerkveränderung, die zu Störungen der Motorik nach einem experimentellen Schlaganfall führen. Ein Schlaganfall ist die häufigste Ursache für eine Langzeitbehinderung, wobei motorische Defizite eine große Rolle spielen, die zu alltagsrelevanten Einschränkungen für die Patienten führen. Für diese chronische Phase nach einem Schlaganfall gibt es momentan keine wirksame Therapie. Unser experimenteller Ansatz verwendet neueste Methoden der Neurowissenschaften, die eine Langzeitbeobachtung von strukturellen und funktionellen Netwerkveränderungen und Rückschluss auf die zellulären Grundlagen der Motorik erlauben. Ziel der Untersuchungen ist die Charakterisierung zentraler Ursachen von Motordefiziten, wie z.B. spastischem Muskeltonus, und die Entwicklung neuer neuromodulatorischer und regenerativer Verfahren zur gezielten Verbesserung der Motorik.
Grafik: Uniklinik Köln
AG Neuroimiging and neuroengineering of experimental stroke
One third of stroke patients suffer from long-term disability and recovery of function is generally inclompete. By combining cutting-edge neurotechniques, such as in vivo MRI, viral tracing and light sheet microscopy, we seek to unravel the cellular and neural circuit mechanisms that underlie motor recovery after experimental stroke. Our studies dissect the development of motor deficits such as spastic muscle tone and develop novel neuromodulation and regeneration paradigms to enhance endogenous plasticity mechanisms and boost stroke recovery.
- Prof. Mathias Hoehn, In-vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Cologne, Germany
- Dr. Martin Schwarz, Functional Neuroconnectomics Group, Laboratory of Experimental Epileptology and Cognition Research, Department of Epileptology, University of Bonn, Germany
- Prof. Gary K. Steinberg and Dr. Michelle Cheng, Department of Neurosurgery, Stanford University School of Medicine
- Assistant Prof. Jennifer A. McNab and Dr. Christoph Leuze, Department of Radiology, Stanford University School of Medicine, Stanford, USA
- Assistant Professor Michael Zeineh and Dr. Maged Goubran, Department of Radiology, Stanford University School of Medicine, Stanford, USA
- Dr. Amit Jathoul, Molecular Biosciences Research Division, Cardiff University, United Kingdom
- Dr. Christian Roedel, Institute of Optics and Quantum Electronics
University of Jena, Germany
1) Spasticity after stroke
Spasticity is a common symptom after stroke, arising in about 30% of patients, and affecting the lower as well as upper limb. The spastic (abnormal) muscle tone appears in the first weeks after stroke onset and maladaptive processes lead to a manifestation of spasticity, which ultimately limits the success of rehabilitation. While previous studies investigated the abnormal intra-spinal processing, spasticity remains a result of damage to the primary motor regions. Therefore we are characterizing the cellular components and network changes which lead to spasticity after stroke to effectively develop opposing optogenetic and chemogentic stimulation paradigms.
2) Spontaneous recovery after stroke
Loss of function after stroke is caused by cell death and breakdown of the functional networks in the infarcted and connected brain regions. To some extent, the affected limb regains function, in a form of spontaneous recovery during the first 3 months after stroke. However, this recovery is generally incomplete and the underlying neural and molecular mechanisms are still unknown. In this project we are investigating brain/circuit activation patterns and analyse the transcriptome in the ipsi- and contralesional hemispheres of recovered vs. non-recovered mice after experimental stroke.
Optogenetic approaches to target specific neural circuits in post-stroke recovery.
Cheng, M., Aswendt, M., Steinberg G.K. "Optogenetic approaches to target specific neural circuits in post-stroke recovery." Neurotherapeutics 13.2 (2016): 325-340.
319.05 / U13 - Investigating neural and molecular mechanisms of spontaneous recovery in experimental stroke. Ito, M., Aswendt, M., Cheng, M., Ishizaka, S., Lee, A., Levy, S., Smerin, D., Wang, E., Steinberg, G.K. Neuroscience 2016, San Diego, USA.
3) Immune modulation for therapy of hyperglycemic stroke
The important role of infiltrating macrophages and brain-resident microglia for stroke recovery becomes more and more accepted. We are working on novel imaging techniques to noninvasively quantify certain immune cells in the brain and switch their polarization state. In this project, we seek to develop a novel therapy for hyperglycemic stroke. Hyperglycemia affects 30-40% of stroke patients and correlates with larger lesions, enhanced mortality and poorer outcome. Recently, it was found that hypgerglycemia leads to decreased levels of protective, non-inflammatory monocytes/macrophages, which are known to improve recovery. Our novel immune modulation paradigm is used to overcome the hyperglycemia roadblock of monocyte/macrophage polarization and improve stroke outcome.
Dynamic Modulation of Microglia/Macrophage Polarization by miR-124 after Focal Cerebral Ischemia
Hamzei, T., Kho, W., Aswendt, M., Collmann, F. M., Green, C., Adamczak, J., ... & Hoehn, M. (2016). Dynamic Modulation of Microglia/Macrophage Polarization by miR-124 after Focal Cerebral Ischemia. Journal of Neuroimmune Pharmacology, 1-16.
#PS 14 / 1 - Arginase1/iNOS expression and localization following miR-124 administration after focal cerebral ischemia in mice.
Hamzei, T., Kho, W., Aswendt, M., Hafeneger, C. Adamczak, J., Hoehn, M. EMIM 2015, Tübingen, Germany.
#PS 11 / 3 - Bioluminescence Imaging (BLI) of microglia polarisation in the living mouse brain using lentiviral vectors.
Collmann, F., Schäfer, C., Beyrau, A., Folz-Donahue, K., Aswendt, M., Kukat, M., Hoehn, M. EMIM 2016, Utrecht, Netherlands.
4) Software platform for registration and analysis of multimodal, whole brain neuroimaging data
Integrating in vivo imaging such as MRI and ex vivo analysis such as histology is key for the interpretation of imaging signatures and identification of the cellular correlate. In brain pathologies such as stroke, we are convinced that such an in vivo/ex vivo correlation will unravel the cellular signature of brain recovery and path the way for novel, targeted therapies. In order to merge in vivo MRI and histology in 3D, we make use of brain clearing techniques such as CLARITY and Fluo-BABB, which make whole brains accessible for microscopy while preserving structural integrity. In vivo and ex vivo data are co-registered with a segmented mouse brain atlas such as the Allen Brain Atlas or the AMBMC and processed for automatic analysis.
Whole-Brain Microscopy Meets In Vivo Neuroimaging: Techniques, Benefits, and Limitations
Aswendt, M., Schwarz, M., Abdelmoula, W. M., Dijkstra, J., & Dedeurwaerdere, S. (2016). Whole-Brain Microscopy Meets In Vivo Neuroimaging: Techniques, Benefits, and Limitations. Molecular Imaging and Biology, 1-9.
92.10 / KKK8 - Multimodal image registration and analysis via clarity-based light-microscopy (MIRACL). Goubran, M., Leuze, C., Hsueh, B., Aswendt, M., Ye, L., Tian, Q., Cheng, M., Steinberg, G.K, Deisseroth, K., McNab, J., Zeineh, M. Neuroscience 2016, San Diego, USA.
319.04 / U12 - Whole brain activation dynamics after stroke.
Levy, S., Aswendt, M., Hsueh, B., Sun, G., Ishizaka, S., Smerin, D., Cheng, M., Deisseroth, K., Steinberg, G.K. Neuroscience 2016, San Diego, USA.
92.14 / KKK12 - Methods for comparison of MRI and CLARITY data in human tissue specimen. Leuze, C., Goubran, M., Aswendt, M., Tian, Q., Hsueh, B., Zeineh, M., Deisseroth, K., McNab, J. Neuroscience 2016, San Diego, USA.
Abstract TP263: Whole Brain Screening of Cellular and Molecular Changes After Stroke
Aswendt, M., Hsueh, B., Ishizaka, S., Sun, G., Cheng, M., Deisseroth, K., & Steinberg, G.K. (2016).
Abstract TP263: Whole Brain Screening of Cellular and Molecular Changes After Stroke.
Aswendt, M., Hsueh, B., Ishizaka, S., Sun, G., Cheng, M., Deisseroth, K., Steinberg, G.K. International Stroke Conference 2016, Vancouver, Canada. Stroke, 47(Suppl 1), ATP263-ATP263.
Abstract: “Fiber orientation measurement using diffusion MRI and CLARITY on the same human brain tissue.”
Leuze, C., Goubran, M., Aswendt, M., Tian, Q., Hsueh, B., Deisseroth, K., McNab J. OHBM 2015, Geneva, Switzerland.
5) Molecular imaging of neural stem cell differentiation - a novel quantitative and noninvasive approach using imaging reporters
How can we quantify the fate of cultured or transplanted stem cells noninvasively? This fundamental question arises from our previous studies on stem cell-induced recovery processes in experimental stroke. We follow transplanted stem cells longitudinally upon transplantation into the mouse brain by noninvasive imaging techniques. However, while cell localization is thus possible, survival and differentiation of the graft cannot be detected. Yet, there is a great need to gain insight into graft-host reactions and the biological time profile of stem cell actions before stem cell therapy can be further translated. Approaches with conventional techniques reveal the cell status only upon sacrificing the animal and cannot be performed on the same sample, which prohibits the intra-individual time profile. We take a different approach towards quantitative monitoring of stem cell viability and differentiation for both, in vitro and in vivo conditions using bioluminescence reporters.
Adamczak J.*, Aswendt M.*, Kreutzer C., Rotheneichner P., Riou A., Selt M., Beyrau A., Uhlenküken U., Diedenhofen M., Nelles M., Aigner L., Couillard-Despres S., Hoehn M. (2017). Neurogenesis upregulation on the healthy hemisphere after stroke enhances compensation for age-dependent decrease of basal neurogenesis. Neurobiology of Disease, 99, 47-57.
Human neural stem cell intracerebral grafts show spontaneous early neuronal differentiation after several weeks.
Tennstaedt, A., Aswendt, M., Adamczak, J., Collienne, U., Selt, M., Schneider, G., ... & Kloppenburg, P. (2015). Human neural stem cell intracerebral grafts show spontaneous early neuronal differentiation after several weeks. Biomaterials, 44, 143-154.
A multi-modality platform to image stem cell graft survival in the naïve and stroke-damaged mouse brain.
Boehm-Sturm, P., Aswendt, M., Minassian, A., Michalk, S., Mengler, L., Adamczak, J., ... & Hoehn, M. (2014). A multi-modality platform to image stem cell graft survival in the naïve and stroke-damaged mouse brain. Biomaterials, 35(7), 2218-2226.
Boosting bioluminescence neuroimaging: an optimized protocol for brain studies
Aswendt, M., Adamczak, J., Couillard-Despres, S., & Hoehn, M. (2013). Boosting bioluminescence neuroimaging: an optimized protocol for brain studies. PloS one, 8(2), e55662.
Evaluating reporter genes of different luciferases for optimized in vivo bioluminescence imaging of transplanted neural stem cells in the brain
Mezzanotte, L., Aswendt, M., Tennstaedt, A., Hoeben, R., Hoehn, M., & Löwik, C. (2013). Evaluating reporter genes of different luciferases for optimized in vivo bioluminescence imaging of transplanted neural stem cells in the brain. Contrast media & molecular imaging, 8(6), 505-513.
Stem cell graft differentiation towards the glial lineage - Insights from optical in vivo imaging.
Aswendt, M., Tennstaedt, A., Michalk, S., Mezzanotte, L., Loewik, C., Hoehn., M. Neuroscience 2014 Washington DC, USA.
751.26 / MMM20 - Two-color bioluminescence for sensitive and quantitative discrimination of cell grafts in the mouse brain.
Aswendt, M., Vogel, S., Schäfer, C., Jathoul, A., Hoehn, M. Neuroscience 2016, San Diego, USA.
In vivo monitoring of cell differentiation and fate specification of human neural stem cells grafted into mouse brain.
Tennstaedt, A., Aswendt, M., Adamczak, J., Selt, M., Collienne, U., Kloppenburg, P. Hoehn, M. EMIM 2014, Antwerp, Belgium.
Two-color bioluminescence for sensitive and quantitative discrimination of cell grafts in the mouse brain.
Aswendt, M., Michalk, S., Schäfer, C., Jathoul, A., Pule, M., Hoehn, M. EMIM 2014, Antwerp, Belgium.
Novel in vivo fate mapping of intracerebral stem cell grafts shows localization, vitality, and neuronal differentiation.
Aswendt, M. Neuroprotection and Neurorepair 2014, Magdeburg, Germany.
Grafik: Uniklinik Köln