Scientific Research Institutes > University Institutes > Experimental Neuroregeneration

Institute for Experimental Neuroregeneration

Director: Univ.-Prof. Dr. Sébastien Couillard-Després



The Research Institute for Experimental Neuroregeneration was founded in August 2013 as part of the Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS) at Paracelsus Medical Private University.

The objective of the research work is the restoration of the functions which have been lost as a result of traumas or diseases of the central nervous system. In particular, the restoration of the motor and sensoric functions after an injury of the spinal cord.

In the central nervous system itself, regenerative capabilities have already been proven. However, they are not sufficient to significantly restore the lost functions after an injury of the spinal cord. Therefore, we perform research on the development of new substances and therapies which increase the intrinsical regenerative capabilities of the central nervous system. Also the use of stem cells and precursor cells of the own body within the framework of the regenerative therapies is increasingly researched. These cells are in a position to replace the lost neurons and glial cells and can, in addition, convert the lesion environment into a pro-regenerative environment.


The focus points of our research:

  • Therapies with adult stem cells
  • Pre-clinical models of the transverse spinal cord syndrome
  • Stimulation of the endogenous neurogenesis and gliogenesis

Projects

Pre-clinical models of injuries of the spinal cord and therapy development

Damages of the spinal cord represent grave injuries which in most cases have life-long consequences for the respective affected persons.

The pathophysiology of the transverse spinal cord syndrome can be seen as a two-part event. After the initial trauma per se, which leads to tissue laceration, petechial bleeding and finally to the cell death, the internal bleeding and the degradation products of the cells within the injured spinal cord cause a number of secondary damages, which include ischemia, excitotoxicity, forming of oedemas and strong inflammatory component. After a certain amount of time, a scar with pseudo-cyst is formed – depending on the size of the injury. This process helps, on the one hand, to contain the pathological process and preven the further spreading of the problem but, on the other hand, it makes a potential neuro-regeneration difficult.

In various pre-clinical models of spinal cord injuries, we research the effect of potential neuro-protective and neuro-regenerative therapies. Here belong, on the one hand, the administration of various flavonoids such as the prenylflavonoid ENDF1, as well as cell-based therapies. After the respective therapy, the locomotor and sensoric progress is evaluated, as well as the effect on inflammatory processes, the formation of scars and the axonal regeneration are studied.


Immature nerve cells in the central nervous system of adult persons: alternative form of neurogenesis in adult persons

The neurogenesis in adult persons, the new formation of nerve cells, is observed in the brain of adult mammals in two neurogeneous niches, the gyrus dentatus in the hippocampus and the subventricular zone along the lateral ventricle. In addition, neuronal cells of the precursor type were proven in the further regions of the brain. For example, in the cortex piriforms, a region which, among other things, participates in the processing of odors, cells were found, which are the same as immature neurons. Until now it is only known that these cells develop before birth and remain dormant in immature state. In older individuals, the number of these sells decreases significantly. The fate of these cells, either cell death or maturing into another cell type, could not be determined until now due lack of adequate methods. For this purpose, we have recently generated a transgenic model (DCX-CreERT2/Flox-EGFP), in which doublecortin-expressed cells could be marked permanently with a green referent by the addition of tamoxifen. The purpose of this project is to analyse these immature cells – their ultrastructure, their electro-physiological activity, their fate, their origin, their effect on the behaviour and their existence in humans and animals.

In the analysis of the cortex piriforms we could show that the previously immature cells do not die but mature locally to glutamatergic pyramidal cells. Furthermore, it could be shown that the cells have matured both morphologically and functionally. The immature neurons of the cortex piriforms and the cells, into which they can develop, can be studied electro-physiologically in acute-type cut with the help of a transgenic model. During the electro-physiological measurements, the cells are filled with biocytin. In this way, the identity of the studied cells can be clearly determined and described further with the help of immunhisto-chemistry and electron microscopy. In order to identify these cells in various species, including man, we also use electron microscopy. Consequently, this project will show whether the neurogenic capacity of the human brain has been seriously underestimated and whether there is a limited reservoir of immature nerve cells, which build additional new neurons and thus can keep the ageing brain in a more plastic condition as it was accepted until now.


Induced oligodendrogenesis of adult neural stem cells by means of mesenchymal stem sells - researching the signal path

The stem cells exist in grown-up organisms in different tissues and can rebuild injured or destroyed tissues. Well-known examples are the mesenchymale stem cells (MSCs) which are present in the bone marrow. However, the central nervous system (ZNS), too,contains a stem cell pool, the so-called neural stem cells (NSCs), which can be differentiated in the astrogenic, oligodendrogenic or neuronal line. Demyelinating diseases such as, for example, multiple sclerosis, lead to damage of the myelin layer, which is built by the oligodendrocytes, and further on to a loss of the nerve function. The own potential of the regeneration decreases with the duration of the disease and the age of the affected person. Effective therapies, which stop the process of the disease or improve the regeneration, do not exist at present.

It could be shown in in-vitro experiments that soluble factors, which are secreted by the MSCs, can make the NSCs to differentiate in oligodendroglial direction. However, the molecular mechanisms and the signal-transduction paths, through which this effect takes place, are not known at present. Our goal is to find out through which signal-transduction path the oligodendrogenesis, which is induced by the MSCs, is mediated, in order to find a possible therapy for improving the regeneration. With the help of NSC cultures, various signal paths are tested in vitro and are eliminated by means of specific inhibitors. In this way it is researched which signal path has a direct effect on the MSCs-induced oligodendrogenesis. Through the knowledge of a main signal path in the oligodendrogenesis, new phrarmacological applications for the remyelinisation could be developed.


Flavonoids: Neuro-regenerative substances for damaged nervous system

The flavonoids, a class of secondary plant metabolites, already show many positive effects on the human organism. Consequently, nutrition rich in flavonoids reduced the loss of memory in Morbus Alzheimer's. In addition, certain flavonoids had antidepressive and anxiolytic effects in studies on animals. Humulus lupulus L., generally known as common hop, is a plant which is very rich in flavonoids. In various in vitro experiments of our work group, we were able to prove an increased neuronal differentiation rate after the treatment of neural stem cell cultures with some of these flavonoids. In addition, some flavonoids have induced a strong growth and offshoots of neurites and they had a neuroprotective effect. On the basis of these results, the flavonoids are researched in vivo for their pharmacological effect and their area of application in the central nervous system is researched.

In our current projects, we occupy ourselves with the question about whether ENDF1 affects the neurite growth of neurons of the dorsal root ganglia as well as the complexity of these neurites. In the first experiments, we could determine that ENDF1 shows a positive effect on the growth of the neurites and eliminates fully or partially the growth-retarding effect of the various naturally existing inhibitors. The molecular mechanisms behind this effect are a central area of our research.

Publications

2015

Analysis of neurogenesis during experimental autoimmune encephalomyelitis reveals pitfalls of bioluminescence imaging. Ayzenberg I, Schlevogt S, Metzdorf J, Stahlke S, Pedreitturia X, Hunfeld A, Couillard-Despres S, Kleiter I. PLoS One. 2015 Mar 17;10(3):e0118550. doi: 10.1371/journal.pone.0118550. eCollection 2015.

Reduction in subventricular zone-derived olfactory bulb neurogenesis in a rat model of Huntington's disease is accompanied by striatal invasion of neuroblasts. Kandasamy M1, Rosskopf M2, Wagner K1, Klein B, Couillard-Despres S, Reitsamer HA, Stephan M, Nguyen HP, Riess O, Bogdahn U, Winkler J, von Hörsten S, Aigner L. PLoS One. 2015 Feb 26;10(2):e0116069. doi: 10.1371/journal.pone.0116069. eCollection 2015.

Lesion-Induced Accumulation of Platelets Promotes Survival of Adult Neural Stem / Progenitor Cells. Kazanis I, Feichtner M, Lange S, Rotheneichner P, Hainzl S, Öller M, Schallmoser K, Rohde E, Reitsamer HA, Couillard-Despres S, Bauer HC, Franklin RJ, Aigner L, Rivera FJ. Exp Neurol. 2015 Mar 24;269:75-89. doi: 10.1016/j.expneurol.2015.03.018. [Epub ahead of print]

Neurodifferentiating potential of 8-prenylnaringenin and related compounds in neural precursor cells and correlation with estrogen-like activity. Urmann C, Oberbauer E, Couillard-Després S, Aigner L, Riepl H. Planta Med. 2015 Mar;81(4):305-11. doi: 10.1055/s-0034-1396243. Epub 2015 Feb 25.

 

2014

Acute and chronic evolution of MRI findings in a case of posterior spinal cord ischemia. Grassner L, Klausner F, Wagner M, McCoy M, Golaszewski S, Leis S, Aigner L, Couillard-Despres S, Trinka E. Spinal Cord. 2014 Jun;52 Suppl 1:S23-4. doi: 10.1038/sc.2013.165. Epub 2014 Jan 14.

Cerebrolysin protects PC12 cells from CoCl2-induced hypoxia employing GSK3? signaling. Hartwig K, Fackler V, Jaksch-Bogensperger H, Winter S, Furtner T, Couillard-Despres S, Meier D, Moessler H, Aigner L. Int J Dev Neurosci. 2014 Nov;38:52-8. doi: 10.1016/j.ijdevneu.2014.07.005. Epub 2014 Aug 2.

Lactation-induced reduction in hippocampal neurogenesis is reversed by repeated stress exposure. Hillerer KM, Neumann ID, Couillard-Despres S, Aigner L, Slattery DA. Hippocampus. 2014 Jun;24(6):673-83. doi: 10.1002/hipo.22258. Epub 2014 Feb 19.

Intrinsically active and pacemaker neurons in pluripotent stem cell-derived neuronal populations. Illes S, Jakab M, Beyer F, Gelfert R, Couillard-Despres S, Schnitzler A, Ritter M, Aigner L. Stem Cell Reports. 2014 Feb 20;2(3):323-36. doi: 10.1016/j.stemcr.2014.01.006. eCollection 2014.

TGF-beta signalling in the adult neurogenic niche promotes stem cell quiescence as well as generation of new neurons. Kandasamy M, Lehner B, Kraus S, Sander PR, Marschallinger J, Rivera FJ, Trümbach D, Ueberham U, Reitsamer HA, Strauss O, Bogdahn U, Couillard-Despres S, Aigner L. J Cell Mol Med. 2014 Jul;18(7):1444-59. doi: 10.1111/jcmm.12298. Epub 2014 Apr 30.

Age-dependent and differential effects of Smad7?Ex1 on neural progenitor cell proliferation and on neurogenesis. Marschallinger J, Krampert M, Couillard-Despres S, Heuchel R, Bogdahn U, Aigner L. Exp Gerontol. 2014 Sep;57:149-54. doi: 10.1016/j.exger.2014.05.011. Epub 2014 May 24.

Hippocampal neurogenesis and antidepressive therapy: shocking relations. Rotheneichner P, Lange S, O'Sullivan A, Marschallinger J, Zaunmair P, Geretsegger C, Aigner L, Couillard-Despres S. Neural Plast. 2014;2014:723915. doi: 10.1155/2014/723915. Epub 2014 May 22.

Rat choroidal pericytes as a target of the autonomic nervous system. Schrödl F, Trost A, Strohmaier C, Bogner B, Runge C, Kaser-Eichberger A, Couillard-Despres S, Aigner L, Reitsamer HA. Cell Tissue Res. 2014 Apr;356(1):1-8. doi: 10.1007/s00441-013-1769-5. Epub 2013 Dec 14.

Characterization of dsRed2-positive cells in the doublecortin-dsRed2 transgenic adult rat retina. Trost A, Schroedl F, Marschallinger J, Rivera FJ, Bogner B, Runge C, Couillard-Despres S, Aigner L, Reitsamer HA. Histochem Cell Biol. 2014 Dec;142(6):601-17. doi: 10.1007/s00418-014-1259-1. Epub 2014 Aug 20.

 

2013

Chroman-like cyclic prenylflavonoids promote neuronal differentiation and neurite outgrowth and are neuroprotective. Oberbauer E, Urmann C, Steffenhagen C, Bieler L, Brunner D, Furtner T, Humpel C, Bäumer B, Bandtlow C, Couillard-Despres S, Rivera FJ, Riepl H, Aigner L. J Nutr Biochem. 2013 Nov;24(11):1953-62. doi: 10.1016/j.jnutbio.2013.06.005. Epub 2013 Sep 24. PMID:24070601

Transforming growth factor-?1 primes proliferating adult neural progenitor cells to electrophysiological functionality. Kraus S, Lehner B, Reichhart N, Couillard-Despres S, Wagner K, Bogdahn U, Aigner L, Strauß O. Glia. 2013 Nov;61(11):1767-83. doi: 10.1002/glia.22551. Epub 2013 Aug 30. PMID: 24038377

Neurogenesis and neuronal regeneration in status epilepticus. Rotheneichner P, Marschallinger J, Couillard-Despres S, Aigner L. Epilepsia. 2013 Sep;54 Suppl 6:40-2. doi: 10.1111/epi.12274. PMID: 24001070

Sex-dependent regulation of hippocampal neurogenesis under basal and chronic stress conditions in rats. Hillerer KM, Neumann ID, Couillard-Despres S, Aigner L, Slattery DA.Hippocampus. 2013 Jun; 23(6):476-87. doi: 10.1002/hipo.22107. Epub 2013 Mar 18.PMID: 23504963

Boosting bioluminescence neuroimaging: an optimized protocol for brain studies. Aswendt M, Adamczak J, Couillard-Despres S, Hoehn M. PLoS One. 2013;8(2):e55662. doi: 10.1371/journal.pone.0055662. Epub 2013 Feb 6. PMID: 23405190

LC-MS/MS identification of doublecortin as abundant beta cell-selective protein discharged by damaged beta cells in vitro. Jiang L, Brackeva B, Stangé G, Verhaeghen K, Costa O, Couillard-Després S, Rotheneichner P, Aigner L, Van Schravendijk C, Pipeleers D, Ling Z, Gorus F, Martens GA. J Proteomics. 2013 Mar 27;80:268-80. doi: 10.1016/j.jprot.2012.12.031. Epub 2013 Jan 19. PMID: 23337804

Hippocampal neurogenesis and ageing. Couillard-Després S. Curr Top Behav Neurosci. 2013;15:343-55. doi: 10.1007/7854_2012_232. Review.PMID: 23065635

Bortezomib alters microtubule polymerization and axonal transport in rat dorsal root ganglion neurons. Staff NP, Podratz JL, Grassner L, Bader M, Paz J, Knight AM, Loprinzi CL, Trushina E, Windebank AJ. Neurotoxicology. 2013 Sep 12; 39C:124-131. doi: 10.1016/j.neuro.2013.09.001. PMID: 24035926

Team and contact

Univ.-Prof. Dr. Sebastien Couillard-Despres, Ph.D.
Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS)
Institute for Experimental Neuroregeneration

Director

Mobile: +43 699 14420058
Mail: s.couillard-despres@pmu.ac.at
Publications
Rosemarie Granig, MBA
Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS)
Institute for Experimental Neuroregeneration

Assistant to the Director

Phone: +43 662 2420-80831
Mail: rosemarie.granig@pmu.ac.at
Dr. Bruno Benedetti, Ph.D.
Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS)
Institute for Experimental Neuroregeneration

Senior Post Doc

Phone: +43 662 2420-80835
Mail: bruno.benedetti@pmu.ac.at
Publications
Lara Bieler, MSc
Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS)
Institute for Experimental Neuroregeneration

Ph.D.-Student Scient.Med.

Phone: +43 662 2420-80835
Mail: lara.bieler@pmu.ac.at
Publications
Christina Kreutzer, MSc
Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS)
Institute for Experimental Neuroregeneration

Technical Assistant

Phone: + 43 662 2420-80836
Tel.: TEM +43 662 2420-80839
Tel.: +43 662 2420-80808

Mail: christina.kreutzer@pmu.ac.at
Publications
Pasquale Romanelli, MSc
Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS)
Institute for Experimental Neuroregeneration

Ph.D.-Student Scient.Med.

Phone: +43 662 2420-80836
Mail: pasquale.romanelli@pmu.ac.at
Publications
Pia Zaunmair, MSc
Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS)
Institute for Experimental Neuroregeneration

Technical Assistant
Core Facility Preclinical Development Unit


Phone: +43 662 2420-80834
Mail: pia.zaunmair@pmu.ac.at
Publications
Ing. Dominika Jakubecova, BSc
Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS)
Institute for Experimental Neuroregeneration

Technical Assistant

Phone: +43 662 2420-80836
Mail: d.jakubecova@pmu.ac.at
Publications
Lisa Maria Jakob, BSc
Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS)
Institute for Experimental Neuroregeneration

Master Student

Phone: +43 662 2420-80836
Mail: lisa.jakob@pmu.ac.at
Publications
Dr. med. univ. Priska Summer
Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS)
Institute for Experimental Neuroregeneration

Ph.D. Student

Phone: +43 662 2420-80836
Mail: priska.summer@pmu.ac.at
Publications