MouseNet

MAPPING THE MOUSE BRAIN “CONNECTOME” WITH MULTI-LEVEL ANALYSIS OF STRUCTURAL AND FUNCTIONAL NETWORKS IN NEUROLOGICAL DISEASES


Relevant for Research Area

A - Foundations


Summary

This project aimed at characterizing metabolic, structural and functional network changes associated with neurological diseases. Non-invasive MRI allows studying the longitudinal disease progression in animal models of mesial temporal lobe epilepsy (mTLE) and ischemic stroke as well as the dynamic changes of network activity caused by epileptic seizures. Having set up the methodological framework for MRI, electrophysiological and immunohistochemical analysis, we conducted a longitudinal study identifying biomarkers of epileptogenesis in the mouse model of mTLE. By performing ex vivo measurements on sclerotic human hippocampal tissue we demonstrated the translational  value of  the discovered biomarkers into a clinical setting. In parallel, we performed a longitudinal study including MRI and transcranial direct current stimulation (tDCS) in the rat model of ischemic stroke. Subsequent to the investigation of longitudinal and persistent alterations  during epileptogenesis, we focused on dynamic network changes with  respect  to  evoked epileptiform discharges. Combining MRI, optogenetic stimulation and EEG  recordings,  we were able to monitor the origin and propagation of epileptic seizures. Preliminary results demonstrate a wide-spread and long-lasting activation of distant brain areas upon evoked hippocampal-originating seizures particularly in mice that developed mTLE.  Next,  we  will apply multiple strategies to interfere with and disrupt the epileptic activity.


Publications and Achievements

Peer reviewed publications

Janz P*, Hauser P*, Heining K, Nestel S, Kirsch M, Egert U, Haas CA. Position- and time-dependent Arc expression links neuronal activity to synaptic plasticity during epileptogenesis. Front Cell Neurosci. 2018 Aug 14;12:244. doi: 10.3389/fncel.2018.00244 *equal contribution

Kilias A, Häussler U, Heining K, Froriep UP, Haas CA, Egert U. Theta frequency decreases throughout the hippocampal formation in a focal epilepsy model. Hippocampus. 2018 Jun;28(6):375-391. doi: 10.1002/hipo.22838.

Janz P*, Schwaderlapp N*, Heining K*, Häussler U, Korvink JG, von Elverfeldt D, Hennig J, Egert U, LeVan P*, Haas CA*: Early tissue damage and microstructural reorganization predicts the disease severity in experimental epilepsy. eLIFE,. 2017 Jul 26;6. pii: e25742. doi: 10.7554/eLife.25742 *equal contribution (ground breaking)

Janz P, Savanthrapadian S, Häussler U, Kilias A, Nestel S, Kretz O, Kirsch M, Bartos M, Egert U, Haas CA: Synaptic remodeling of entorhinal input contributes to an aberrant hippocampal network in temporal lobe epilepsy. Cereb Cortex, 2017 Mar 1;27(3):2348-2364. doi: 10.1093/cercor/bhw093

Häussler U, Rinas K, Kilias A, Egert U, Haas CA. Mossy fiber sprouting and pyramidal cell dispersion in the hippocampal CA2 region in a mouse model of temporal lobe epilepsy. Hippocampus. 2016 May;26(5):577-88. doi: 10.1002/hipo.22543.

Egger K, Janz P, Döbrössy M, Bienert T, Reisert M, Obmann M, Glauche V, Haas CA, Harsan L, Urbach H, von Elverfeldt D: Microstructural effects of a neuro-modulating drug evaluated by diffusion tensor imaging Neuroimage, 2016; 127: 1-10. http://dx.doi.org/10.1016/j.neuroimage.2015.10.091

Mechling AE, Arefin T, Lee HL, Bienert T, Reisert M, Ben Hamida S, Darcq E, Ehrlich A, Gaveriaux-Ruff C, Parent MJ, Rosa-Neto P, Hennig J, von Elverfeldt D, Kieffer BL, Harsan LA. Deletion of the mu opioid receptor gene in mice reshapes the reward-aversion connectome. Proc Natl Acad Sci U S A. 2016 Oct 11;113(41):11603- 11608.

Bär S, Weigel M, von Elverfeldt D, Hennig J, Leupold J. Intrinsic diffusion sensitivity of the balanced steady-state free precession (bSSFP) imaging sequence. NMR Biomed, 2015; 28 (11): 1383-1392.

Bedner P, Dupper A, Hüttmann K, Müller J, Herde MK, Dublin P, Deshpande T, Schramm J, Häussler U, Haas CA, Henneberger C, Theis M, Steinhäuser C. Astrocyte uncoupling as a cause of human temporal lobe epilepsy. Brain, 2015, 138: 1208-1222.

Mechling AE, Hübner NS, Lee HL, Hennig J, von Elverfeldt D, Harsan LA. Fine-grained mapping of mouse brain functional connectivity with resting-state fMRI. Neuroimage. 2014 Aug 1;96:203-15.

Harsan LA, David C, Reisert M, Schnell S, Hennig J, von Elverfeldt D, Staiger JF. Mapping remodeling of thalamocortical projections in the living reeler mouse brain by diffusion tractography. Proc Natl Acad Sci U S A, 2013; 110(19):E1797-E1806.

Marx M, Haas CA, Häussler U. Differential vulnerability of interneurons in the epileptic hippocampus. Front Cell Neurosci. 2013 Oct 1;7:167.

 

Other publications

Häussler U, Johnston M, Kilias A, Tulke S, Haas CA. Pathological connectivity of the hippocampal CA2 region in temporal lobe epilepsy. 13th European Congress on Epileptology, Vienna, Austria, August 26 -30, 2018

Janz P, Hauser P, Heining K, Nestel S, Kretz O, Kirsch M, Egert U, Haas CA. Activity-dependent Arc expression is associated with synaptic plasticity of dentate granule cells during epileptogenesis. Annual meeting of the Society for Neuroscience, San Diego, CA, USA, November 3-7. 2018

Kilias A, Tulke S, Barheier N, Heinig K, Egert U, Haas CA, Häussler U. Intergration of dispersed CA2 pyramidal cells in the hippocampal network in a focal epilepsy model. Annual meeting of the Society for Neuroscience, San Diego, CA, USA, November 3-7. 2018

Tulke S, Johnston M, Haas CA, Häussler U. Molecular and structural characterization of inhibitory innervation of the CA2 region in experimental epilepsy. Annual meeting of the Society for Neuroscience, San Diego, CA, USA, November 3-7. 2018

Häussler U, Tulke S, Kilias A, Johnston M, Haas CA. Characterization of mossy fiber synapses in the hippocampal CA2 region in experimental epilepsy. 11th FENS Forum of Neuroscience, Berlin, Germany, July 7 - 11, 2018.

Janz P, Hauser P, Heining K, Nestel S, Kretz O, Kirsch M, Egert U, Haas CA. Position- and time-dependent Arc expression links neuronal activity to synaptic plasticity during epileptogenesis. 11th FENS Forum of Neuroscience, Berlin, Germany, July 7-11, 2018.

Kilias A, Häussler U, Heinig K, Schirmer M, Haas CA, Egert U. Theta rhythm frequency strongly decreases throughout the epileptic hippocampal formation. 11th FENS Forum of Neuroscience, Berlin, Germany, July 7 -11, 2018.

Tulke S, Haas CA, Häussler U. Neuroprotective factors are differentially regulated in CA2 pyramidal cells and dentate granule cells in experimental epilepsy. 11th FENS Forum of Neuroscience, Berlin, Germany, July 7 -11, 2018.

Paschen E, Janz P, Häussler U, Kilias A, Haas CA. Optogenetic stimulation inhibits seizure s generation in a mouse model of temporal lobe epilepsy. 11th FENS Forum of Neuroscience, Berlin, Germany, July 7 -11, 2018.

Häussler U, Johnston M, Kilias A, Janz P, Tulke S, Haas CA. Mossy fiber synapses in the hippocampal CA2 region in temporal lobe epilepsy. 46th annual meeting of the Society for Neuroscience , San Diego, USA, November 12-16, 2016.

Janz P, Hauser P, Heining K, Nestel S, Kretz O, Kirsch M, Egert U, Haas CA. Region-specific activity changes during epileptogenesis determine subcellular Arc mRNA localization and synaptic plasticity of dentate granule cells. 10th FENS Forum of Neuroscience, Copenhagen, Denmark, July 2 -6, 2016.

Janz P, Savanthrapadian S, Häussler U, Kilias A, Nestel S, Kretz O, Kirsch M, Bartos M, Egert U, Haas CA. Structural and functional plasticityof entorhinal input contributes to an epileptic hippocampal circuitry. 45th annual meeting of the Society for Neuroscience, Chicago, USA, October 17-21, 2015.

Janz P, Häussler U, Kilias A, Kretz O, Kirsch M, Egert U, Haas CA. Entorhinal Input Contributes to an Aberrant Hippocampal Circuitry in Mesial Temporal Lobe Epilepsy. 11th meeting of the German Neuro science Society, Göttingen, Germany, March 18-21, 2015.

Schwaderlapp NL, Janz P, Leupol J, Elverfeldt D, Korvink J, Hennig J, Haas C, LeVan P. Imaging of glutamate alterations in a mouse model of temporal lobe epilepsy. Proc. ISMRM, Honolulu, 2017.

Schwaderlapp NL, Janz P, Häussler U, Korvink J, Elverfeldt D, Hennig J, Haas C, LeVan P. MRI monitoring of epileptogenesis with direct histological validation. Proc. ISMRM, Singapore, 2016.

Schwaderlapp NL, Janz P, Leupold J, Häussler U, Lange T, Elverfel dt D, Haas C, Hennig J, Harsan LA, LeVan P: A longitudinal study of MR correlates during epileptogenesis in a mouse model of temporal lobe epilepsy. International Society for Magnetic Resonance in Medicine, Toronto, Canada, May 30 – June 5, 2015.

Häussler U, Marx M, Janz P, Haas CA. Differential vulnerability of interneurons along the septotemporal axis of the hippocampus in experimental epilepsy. 11th European Congress on Epileptology. Stockholm , Sweden, June 29 - July 3, 2014.

Janz P, Häussler U, Kilias A, Egert U, Haas CA. Poster: Structural Plasticity of the Entorhinal Input on Dentate Granule Cells in Mesial Temporal Lobe Epilepsy. 9th FENS Forum of Neuroscience. Milan, Italy. July 5 -9, 2014.