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1. Brain network remodelling reflects tau-related pathology prior to memory deficits in Thy-Tau22 mice

Author

Julien Lamy, Frédéric Blanc, Jean-Paul Armspach, Marion Sourty, Meltem Karatas, Emilie Faivre, Vincent Noblet, Luc Buée, Laetitia Degiorgis, Anne-Laurence Boutillier, Thomas Bienert, Laura-Adela Harsan, David Blum, Dominik von Elverfeldt, Marco Reisert, Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Imagerie Multimodale Intégrative en Santé [Strasbourg] (IMIS), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA)-Université de Strasbourg (UNISTRA), University of Freiburg [Freiburg], Institut des Neurosciences Cellulaires et Intégratives (INCI), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), The University of Sydney, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de neurosciences cognitives et adaptatives (LNCA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, Anne Laurence, Boutillier, Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC))

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Hippocampus, Mice, Transgenic, tau Proteins, Context (language use), Biology, Amygdala, Mice, 03 medical and health sciences, 0302 clinical medicine, Connectome, Image Processing, Computer-Assisted, medicine, Animals, Humans, Cognitive Dysfunction, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], tau, Gliosis, Dynamic functional connectivity, Memory Disorders, Resting state fMRI, medicine.diagnostic_test, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Brain, medicine.disease, Magnetic Resonance Imaging, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Tauopathies, Astrocytes, Disease Progression, functional MRI, resting state connectivity, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Tauopathy, Nerve Net, Functional magnetic resonance imaging, Alzheimer’s disease, [SDV.NEU.SC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, 030217 neurology & neurosurgery, dementia
Abstract

In Alzheimer’s disease, the tauopathy is known as a major mechanism responsible for the development of cognitive deficits. Early biomarkers of such affectations for diagnosis/stratification are crucial in Alzheimer’s disease research, and brain connectome studies increasingly show their potential establishing pathology fingerprints at the network level. In this context, we conducted an in vivo multimodal MRI study on young Thy-Tau22 transgenic mice expressing tauopathy, performing resting state functional MRI and structural brain imaging to identify early connectome signatures of the pathology, relating with histological and behavioural investigations. In the prodromal phase of tauopathy, before the emergence of cognitive impairments, Thy-Tau22 mice displayed selective modifications of brain functional connectivity involving three main centres: hippocampus (HIP), amygdala (AMG) and the isocortical areas, notably the somatosensory (SS) cortex. Each of these regions showed differential histopathological profiles. Disrupted ventral HIP-AMG functional pathway and altered dynamic functional connectivity were consistent with high pathological tau deposition and astrogliosis in both hippocampus and amygdala, and significant microglial reactivity in amygdalar nuclei. These patterns were concurrent with widespread functional hyperconnectivity of memory-related circuits of dorsal hippocampus—encompassing dorsal HIP-SS communication—in the absence of significant cortical histopathological markers. These findings suggest the coexistence of two intermingled mechanisms of response at the functional connectome level in the early phases of pathology: a maladaptive and a likely compensatory response. Captured in the connectivity patterns, such first responses to pathology could further be used in translational investigations as a lead towards an early biomarker of tauopathy as well as new targets for future treatments.

Published
2020

2. Mapping the living mouse brain neural architecture: strain-specific patterns of brain structural and functional connectivity

Author

Taufiq Nasseef, Dominik von Elverfeldt, Marco Reisert, Jürgen Hennig, Ipek Yalcin, Thomas Bienert, Brigitte L. Kieffer, Meltem Karatas, Laura-Adela Harsan, Vincent Noblet, Institut des Neurosciences Cellulaires et Intégratives (INCI), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Neuropsychologie Cognitive et Physiopathologie de la Schizophrénie (NCPS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Civil de Strasbourg, Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), and Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Histology, [SDV]Life Sciences [q-bio], Splenium, Brain Structure and Function, Biology, Corpus callosum, 050105 experimental psychology, 03 medical and health sciences, Mice, 0302 clinical medicine, Neurochemical, Reward, Neural Pathways, Connectome, Animals, 0501 psychology and cognitive sciences, Default mode network, ComputingMilieux_MISCELLANEOUS, Basal forebrain, Brain Mapping, General Neuroscience, 05 social sciences, Brain, Magnetic Resonance Imaging, Diffusion Magnetic Resonance Imaging, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], Anatomy, Nerve Net, Neuroscience, 030217 neurology & neurosurgery, Diffusion MRI
Abstract

Mapping brain structural and functional connectivity (FC) became an essential approach in neuroscience as network properties can underlie behavioral phenotypes. In mouse models, revealing strain-related patterns of brain wiring is crucial, since these animals are used to answer questions related to neurological or neuropsychiatric disorders. C57BL/6 and BALB/cJ strains are two of the primary "genetic backgrounds" for modeling brain disease and testing therapeutic approaches. However, extensive literature describes basal differences in the behavioral, neuroanatomical and neurochemical profiles of the two strains, which raises questions on whether the observed effects are pathology specific or depend on the genetic background of each strain. Here, we performed a systematic comparative exploration of brain structure and function of C57BL/6 and BALB/cJ mice using Magnetic Resonance Imaging (MRI). We combined deformation-based morphometry (DBM), diffusion MRI and high-resolution fiber mapping (hrFM) along with resting-state functional MRI (rs-fMRI) and demonstrated brain-wide differences in the morphology and "connectome" features of the two strains. Essential inter-strain differences were depicted regarding the size and the fiber density (FD) within frontal cortices, along cortico-striatal, thalamic and midbrain pathways as well as genu and splenium of corpus callosum. Structural dissimilarities were accompanied by specific FC patterns, emphasizing strain differences in frontal and basal forebrain functional networks as well as hubness characteristics. Rs-fMRI data further indicated differences of reward-aversion circuitry and default mode network (DMN) patterns. The inter-hemispherical FC showed flexibility and strain-specific adjustment of their patterns in agreement with the structural characteristics.

Published
2021

3. Common functional networks in the mouse brain revealed by multi-centre resting-state fMRI analysis

Author

Andreas Meyer-Lindenberg, Nachiket A. Nadkarni, Katja Sauer, Alexander Sartorius, Nicole Wenderoth, Joanes Grandjean, Ichio Aoki, Gulebru Ayranci, Georgios A. Keliris, Disha Shah, Cynthia Anckaerts, Andreas Hess, Alessandro Gozzi, Wolfgang Weber-Fahr, Isabel Wank, Neele S. Hübner, M. Mallar Chakravarty, Francesca Mandino, Hideyuki Okano, Sandra Strobelt, Carola Canella, Jason P. Lerch, Ling Yun Yeow, Noriaki Yahata, Wei-Tang Chang, Laura-Adela Harsan, Natalia Gass, Yohan Yee, Clément M. Garin, Markus Rudin, Yuji Komaki, Marleen Verhoye, Marc Dhenain, David Buehlmann, Tianzi Jiang, Anna E. Mechling, Meltem Karatas, Norio Takata, Thomas Bienert, Valerio Zerbi, Salma Bougacha, Silke Kreitz, Chika Sato, Tong Wu, Dominik von Elverfeldt, Annemie Van der Linden, Ludovico Coletta, Daniel Gallino, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Rodent, Computer science, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13], Mice, Functional connectivity, 0302 clinical medicine, Image Processing, Computer-Assisted, MOTOR CORTEX, Default mode network, 11 Medical and Health Sciences, biology, medicine.diagnostic_test, 05 social sciences, Radiology, Nuclear Medicine & Medical Imaging, ANESTHESIA PROTOCOLS, Brain, FLUCTUATIONS, Magnetic Resonance Imaging, Seed-based, 17 Psychology and Cognitive Sciences, Neurology, Default-mode network, Connectome, Female, Life Sciences & Biomedicine, MRI, CONNECTOMICS, Cognitive Neuroscience, Image processing, Neuroimaging, CONNECTIVITY NETWORKS, 050105 experimental psychology, Article, lcsh:RC321-571, Functional networks, 03 medical and health sciences, biology.animal, medicine, Animals, 0501 psychology and cognitive sciences, MICRODELETION, ICA, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Computer. Automation, Neurology & Neurosurgery, Science & Technology, Resting state fMRI, Neurosciences, Reproducibility of Results, GENE, Mice, Inbred C57BL, MICE, Human medicine, Neurosciences & Neurology, Nerve Net, Functional magnetic resonance imaging, Neuroscience, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 219632.pdf (Publisher’s version ) (Open Access) Preclinical applications of resting-state functional magnetic resonance imaging (rsfMRI) offer the possibility to non-invasively probe whole-brain network dynamics and to investigate the determinants of altered network signatures observed in human studies. Mouse rsfMRI has been increasingly adopted by numerous laboratories worldwide. Here we describe a multi-centre comparison of 17 mouse rsfMRI datasets via a common image processing and analysis pipeline. Despite prominent cross-laboratory differences in equipment and imaging procedures, we report the reproducible identification of several large-scale resting-state networks (RSN), including a mouse default-mode network, in the majority of datasets. A combination of factors was associated with enhanced reproducibility in functional connectivity parameter estimation, including animal handling procedures and equipment performance. RSN spatial specificity was enhanced in datasets acquired at higher field strength, with cryoprobes, in ventilated animals, and under medetomidine-isoflurane combination sedation. Our work describes a set of representative RSNs in the mouse brain and highlights key experimental parameters that can critically guide the design and analysis of future rodent rsfMRI investigations.

Published
2020

4. The connectomics of brain demyelination: Functional and structural patterns in the cuprizone mouse model

Author

Jürgen Hennig, Thomas Bienert, Neele S. Hübner, Laura-Adela Harsan, Anna E. Mechling, Dominik von Elverfeldt, Marco Reisert, and Hsu-Lei Lee

Subjects
0301 basic medicine, Connectomics, Cognitive Neuroscience, Central nervous system, Cuprizone, 03 medical and health sciences, Myelin, 0302 clinical medicine, Neural Pathways, Connectome, medicine, Animals, Default mode network, Resting state fMRI, Brain, Magnetic Resonance Imaging, Oligodendrocyte, Mice, Inbred C57BL, Disease Models, Animal, Diffusion Tensor Imaging, 030104 developmental biology, medicine.anatomical_structure, Neurology, Female, Psychology, Neuroscience, 030217 neurology & neurosurgery, Demyelinating Diseases, Diffusion MRI
Abstract

Connectomics of brain disorders seeks to reveal how altered brain function emerges from the architecture of cerebral networks; however the causal impact of targeted cellular damage on the whole brain functional and structural connectivity remains unknown. In the central nervous system, demyelination is typically the consequence of an insult targeted at the oligodendrocytes, the cells forming and maintaining the myelin. This triggered perturbation generates cascades of pathological events that most likely alter the brain connectome. Here we induced oligodendrocyte death and subsequent demyelinating pathology via cuprizone treatment in mice and combining mouse brain resting state functional Magnetic Resonance Imaging and diffusion tractography we established functional and structural pathology-to-network signatures. We demonstrated that demyelinated brain fundamentally reorganizes its intrinsic functional connectivity paralleled by widespread damage of the structural scaffolding. We evidenced default mode-like network as core target of demyelination-induced connectivity modulations and hippocampus as the area with strongest connectional perturbations.

Published
2017

5. Atlas registration for edema-corrected MRI lesion volume in mouse stroke models

Author

Stefan Koch, Susanne Mueller, Marco Foddis, Dominik von Elverfeldt, Thomas Bienert, André Rex, Monika Dopatka, Tracy D. Farr, Ulrich Dirnagl, René Bernard, Philipp Boehm-Sturm, Felix Knab, and Christoph Harms

Subjects
0301 basic medicine, Male, medicine.medical_specialty, neuroanatomy, Image registration, diagnostic imaging [Brain Edema], Lesion, 03 medical and health sciences, Mice, 0302 clinical medicine, Atlas (anatomy), etiology [Brain Edema], Edema, diagnostic imaging [Stroke], Medicine, Animals, complications [Stroke], ddc:610, Stroke, brain edema, medicine.diagnostic_test, business.industry, diagnostic imaging [Blood-Brain Barrier], Brain atlas, Magnetic resonance imaging, Original Articles, medicine.disease, Magnetic Resonance Imaging, animal models, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Neurology, Blood-Brain Barrier, Neurology (clinical), Radiology, medicine.symptom, Cardiology and Cardiovascular Medicine, business, 030217 neurology & neurosurgery, Neuroanatomy
Abstract

Lesion volume measurements with magnetic resonance imaging are widely used to assess outcome in rodent models of stroke. In this study, we improved a mathematical framework to correct lesion size for edema which is based on manual delineation of the lesion and hemispheres. Furthermore, a novel MATLAB toolbox to register mouse brain MR images to the Allen brain atlas is presented. Its capability to calculate edema-corrected lesion size was compared to the manual approach. Automated image registration performed equally well in in a mouse middle cerebral artery occlusion model (Pearson r = 0.976, p = 2.265e-11). Information encapsulated in the registration was used to generate maps of edema induced tissue volume changes. These showed discrepancies to simplified tissue models underlying the manual approach. The presented techniques provide biologically more meaningful, voxel-wise biomarkers of vasogenic edema after stroke.

Published
2019

6. Common functional networks in the mouse brain revealed by multi-centre resting-state fMRI analysis

Author

Salma Bougacha, Disha Shah, Gulebru Ayranci, Silke Kreitz, Francesca Mandino, Nicole Wenderoth, David Buehlmann, Georgios A. Keliris, Chika Sato, Tong Wu, M. Mallar Chakravarty, Dominik von Elverfeldt, Nachiket A. Nadkarni, Ludovico Coletta, Alessandro Gozzi, Thomas Bienert, Natalia Gass, Carola Canella, Wei-Tang Chang, Cynthia Anckaerts, Ichio Aoki, Valerio Zerbi, Marleen Verhoye, Marc Dhenain, Wolfgang Weber-Fahr, Alexander Sartorius, Daniel Gallino, Clément M. Garin, Tianzi Jiang, Sandra Strobelt, Katja Sauer, Isabel Wank, Yuji Komaki, Annemie Van der Linden, Andreas Hess, Markus Rudin, Laura-Adela Harsan, Norio Takata, Noriaki Yahata, Meltem Karatas, Neele S. Hübner, Anna E. Mechling, Jason P. Lerch, Yohan Yee, Hideyuki Okano, Ling Yun Yeow, and Joanes Grandjean

Subjects
Rodent, Computer science, Bioinformatics, Cognitive Neuroscience, Functional magnetic resonance imaging, Image processing, Network dynamics, Functional networks, 03 medical and health sciences, 0302 clinical medicine, biology.animal, Cognitive psychology, medicine, Psychology, Multi centre, Biology, 030304 developmental biology, 0303 health sciences, biology, Resting state fMRI, medicine.diagnostic_test, Imaging Procedures, Functional connectivity, Neurology, Default mode network, Human medicine, Neuroscience, 030217 neurology & neurosurgery
Abstract

Preclinical applications of resting-state functional magnetic resonance imaging (rsfMRI) offer the possibility to non-invasively probe whole-brain network dynamics and to investigate the determinants of altered network signatures observed in human studies. Mouse rsfMRI has been increasingly adopted by numerous laboratories worldwide. Here we describe a multi-centre comparison of 17 mouse rsfMRI datasets via a common image processing and analysis pipeline. Despite prominent cross-laboratory differences in equipment and imaging procedures, we report the reproducible identification of several large-scale resting-state networks (RSN), including a mouse default-mode network, in the majority of datasets. A combination of factors was associated with enhanced reproducibility in functional connectivity parameter estimation, including animal handling procedures and equipment performance. RSN spatial specificity was enhanced in datasets acquired at higher field strength, with cryoprobes, in ventilated animals, and under medetomidine-isoflurane combination sedation. Our work describes a set of representative RSNs in the mouse brain and highlights key experimental parameters that can critically guide the design and analysis of future rodent rsfMRI investigations.

Published
2019

7. Microstructural effects of a neuro-modulating drug evaluated by diffusion tensor imaging

Author

Horst Urbach, Carola A. Haas, Laura Harsan, Philipp Janz, Máté D. Döbrössy, Markus M. Obmann, Thomas Bienert, Karl Egger, D. von Elverfeldt, Marco Reisert, and Volkmar Glauche

Subjects
Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Doublecortin Protein, Cognitive Neuroscience, Morris water navigation task, Hippocampus, Hippocampal formation, Corpus callosum, White matter, Mice, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Fractional anisotropy, Image Processing, Computer-Assisted, medicine, Animals, Longitudinal Studies, Maze Learning, Erythropoietin, Cell Proliferation, business.industry, Dentate gyrus, Subiculum, Brain, Immunohistochemistry, Mice, Inbred C57BL, Diffusion Tensor Imaging, 030104 developmental biology, medicine.anatomical_structure, nervous system, Neurology, business, Neuroscience, 030217 neurology & neurosurgery
Abstract

In a longitudinal mouse study we evaluated whether diffusion tensor imaging (DTI) can monitor microstructural changes after administration of the neuromodulating drug EPO and whether erythropoietin (EPO) has an effect on cognitive performance. Twelve mice (2 groups with 6 mice each) were scanned in a 7T Bruker Biospin animal scanner with a highly resolved DTI sequence before and 16 days after intraperitoneal injections of EPO or saline. All mice underwent behavioral testing (Morris water maze) and histologic evaluation of hippocampal and corpus callosum cell proliferation and oligodendrogenesis. Whole brain DTI analysis showed significant Trace, RD and AD decrease within the dentate gyrus, subiculum, primary motor, somatosensory, and supplementary somatosensory areas and FA increase in the hippocampus, corpus callosum, and fimbria fornix in EPO treated mice only. ROI-based DTI analysis showed significant Trace and RD decrease and FA increase only in the corpus callosum of EPO treated mice, whereas in the dentate gyrus significant Trace, RD, and AD decrease occurred in both, EPO- and control-group. Behavioral tests showed that EPO treated mice performed better and learned faster than controls. Histologically, the number of BrdU-positive nuclei and optical density of DCX-labeled juvenile neurons significantly increased within the dentate gyrus, corpus callosum and fimbria fornix and the number of NG2-positive oligodendrocyte progenitors in corpus callosum and fimbria fornix, respectively. In conclusion we were able to monitor microstructural changes with DTI and showed EPO treatment-related alterations correlating with enhanced dentate gyrus and corpus callosum cell proliferation and better learning capabilities.

Published
2016

8. Remodeling of Sensorimotor Brain Connectivity in Gpr88-Deficient Mice

Author

Thomas Bienert, Laura-Adela Harsan, Daniel Roquet, Hsu-Lei Lee, Anna E. Mechling, Neele S. Hübner, Brigitte L. Kieffer, Aliza T. Ehrlich, Sami Ben Hamida, A. C. Meirsman, Jürgen Hennig, Dominik von Elverfeldt, Tanzil Mahmud Arefin, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Neuropsychologie Cognitive et Physiopathologie de la Schizophrénie (NCPS), and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Civil de Strasbourg

Subjects
0301 basic medicine, Male, Biology, Hippocampus, Receptors, G-Protein-Coupled, 03 medical and health sciences, default mode network, Mice, 0302 clinical medicine, Deficient mouse, Connectome, Image Processing, Computer-Assisted, Animals, Gene activity, Default mode network, mouse brain functional connectivity, Mice, Knockout, Brain Mapping, Behavior, Animal, General Neuroscience, Motor Cortex, Brain, Somatosensory Cortex, Original Articles, Gpr88, Amygdala, Magnetic Resonance Imaging, 030104 developmental biology, Diffusion Tensor Imaging, Expression (architecture), [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroscience, 030217 neurology & neurosurgery
Abstract

Recent studies have demonstrated that orchestrated gene activity and expression support synchronous activity of brain networks. However, there is a paucity of information on the consequences of single gene function on overall brain functional organization and connectivity and how this translates at the behavioral level. In this study, we combined mouse mutagenesis with functional and structural magnetic resonance imaging (MRI) to determine whether targeted inactivation of a single gene would modify whole-brain connectivity in live animals. The targeted gene encodes GPR88 (G protein-coupled receptor 88), an orphan G protein-coupled receptor enriched in the striatum and previously linked to behavioral traits relevant to neuropsychiatric disorders. Connectivity analysis of Gpr88-deficient mice revealed extensive remodeling of intracortical and cortico-subcortical networks. Most prominent modifications were observed at the level of retrosplenial cortex connectivity, central to the default mode network (DMN) whose alteration is considered a hallmark of many psychiatric conditions. Next, somatosensory and motor cortical networks were most affected. These modifications directly relate to sensorimotor gating deficiency reported in mutant animals and also likely underlie their hyperactivity phenotype. Finally, we identified alterations within hippocampal and dorsal striatum functional connectivity, most relevant to a specific learning deficit that we previously reported in Gpr88-/- animals. In addition, amygdala connectivity with cortex and striatum was weakened, perhaps underlying the risk-taking behavior of these animals. This is the first evidence demonstrating that GPR88 activity shapes the mouse brain functional and structural connectome. The concordance between connectivity alterations and behavior deficits observed in Gpr88-deficient mice suggests a role for GPR88 in brain communication.

Published
2017

9. Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food

Author

Veronica A. Alvarez, Ian Kitchen, Laura-Adela Harsan, Thomas Bienert, Anna E. Mechling, Elena Martín-García, Sami Ben Hamida, Alexis Bailey, Claire Gaveriaux-Ruff, Brigitte L. Kieffer, Alain Gratton, Anne Robé, Patricia Robledo, Helen L. Keyworth, Aya Matsui, Katia Befort, Jürgen Hennig, Dominik von Elverfeldt, Luc Moquin, Olivier Gardon, Emmanuel Darcq, Rafael Maldonado, Pauline Charbogne, Audrey Matifas, Taufiq Nasseef, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Alexis Vautrin (CAV), Douglas Mental Health University Institute [Montréal], McGill University = Université McGill [Montréal, Canada], Cell Biology of Addiction in Neurology, Ernest Gallo Clinic and Research Center, Neuropharmacology Laboratory [Barcelone, Espagne], Universitat Pompeu Fabra [Barcelona] (UPF), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de neurosciences cognitives et adaptatives (LNCA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), and Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Male, Narcotics, [SDV]Life Sciences [q-bio], Dopamine, Conditioning, Classical, Receptors, Opioid, mu, Physical dependence, Striatum, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Prosencephalon, Opiate, Conditional gene knockout, Neural Pathways, mental disorders, medicine, Animals, GABAergic Neurons, ComputingMilieux_MISCELLANEOUS, Biological Psychiatry, Mice, Knockout, Motivation, Morphine, Ventral Tegmental Area, Feeding Behavior, Corpus Striatum, 3. Good health, Mu opioid receptor, Ventral tegmental area, Heroin, 030104 developmental biology, medicine.anatomical_structure, Inhibitory Postsynaptic Potentials, nervous system, Disinhibition, Forebrain, Female, μ-opioid receptor, medicine.symptom, Psychology, Neuroscience, 030217 neurology & neurosurgery, medicine.drug
Abstract

BACKGROUND: Mu opioid receptors (MORs) are central to pain control, drug reward, and addictive behaviors, but underlying circuit mechanisms have been poorly explored by genetic approaches. Here we investigate the contribution of MORs expressed in gamma-aminobutyric acidergic forebrain neurons to major biological effects of opiates, and also challenge the canonical disinhibition model of opiate reward. METHODS: We used Dlx5/6-mediated recombination to create conditional Oprm1 mice in gamma-aminobutyric acidergic forebrain neurons. We characterized the genetic deletion by histology, electrophysiology, and microdialysis; probed neuronal activation by c-Fos immunohistochemistry and resting-state functional magnetic resonance imaging; and investigated main behavioral responses to opiates, including motivation to obtain heroin and palatable food. RESULTS: Mutant mice showed MOR transcript deletion mainly in the striatum. In the ventral tegmental area, local MOR activity was intact, and reduced activity was only observed at the level of striatonigral afferents. Heroin-induced neuronal activation was modified at both sites, and whole-brain functional networks were altered in live animals. Morphine analgesia was not altered, and neither was physical dependence to chronic morphine. In contrast, locomotor effects of heroin were abolished, and heroin-induced catalepsy was increased. Place preference to heroin was not modified, but remarkably, motivation to obtain heroin and palatable food was enhanced in operant self-administration procedures. CONCLUSIONS: Our study reveals dissociable MOR functions across mesocorticolimbic networks. Thus, beyond a well-established role in reward processing, operating at the level of local ventral tegmental area neurons, MORs also moderate motivation for appetitive stimuli within forebrain circuits that drive motivated behaviors. This work was supported by the Centre National de la Recherche Scientifique (BLK), Institut National de la Santé et de la Recherche Médicale (BK), Université de Strasbourg (BLK), Medical Research Council/Economic and Social Research Council interdisciplinary studentship (to HLK), the British Pharmacological Society (IK), the European Commission (Genaddict Grant No. LSHMCT2004-005166 to BLK), the U.S. National Institutes of Health (National Institute of Drug Addiction, Grant No. 05010 to BLK and National Institute on Alcohol Abuse and Alcoholism, Grant No. 16658 to BLK), the Canada Fund for Innovation, and the Canada Research Chairs (to BLK). Electrophysiological experiments were funded by the Intramural Programs of National Institute on Alcohol Abuse and Alcoholism and National Institute of Neurological Disorders and Stroke (Grant No. ZIA-AA000421 to VAA) and Japan Society for Promotion of Science (to AMats). Self-administration studies were supported by the Intramural Programs of National Institute on Alcohol Abuse and Alcoholism and National Institute of Neurological Disorders and Stroke (Grant No. ZIA-AA000421 to RM), the Directorate-General for Research of the European Commission Framework Programme 7 (Grant No. HEALTH-2013-602891 to RM), the Spanish Redes Temáticas de Investigación Cooperativa en Salud-Instituto de Salud Carlos III (Grant No. RD12/0028/0023 to RM), the Spanish Ministerio de Economia y Competitividad (Grant No. SAF-2014-59648P to RM), the Plan Nacional Sobre Drogas (Grant No. PNSD-2013-5068 to RM), and the Catalan Government Agència de Gestió d'Ajuts Universitaris i de Recerca (Grant No. 2014-SGR-1547 to RM) and Institució Catalana de Recerca i Estudis Avançats-Acadèmia (Grant No. 2015 to RM). Part of the work was supported by German Research Foundation Excellence Cluster EXC-1086 BrainLinks-BrainTools (to JH).

Published
2017

10. Qualitative and quantitative evaluation of in vivo SD-OCT measurement of rat brain

Author

Dominik von Elverfeldt, Laura-Adela Harsan, Thomas Bienert, Robert D. Kirch, Ulrich G. Hofmann, and Yijing Xie

Subjects
Pathology, medicine.medical_specialty, Correlation coefficient, genetic structures, Computer science, Image registration, 01 natural sciences, Article, 010309 optics, Correlation, 03 medical and health sciences, Cresyl violet, chemistry.chemical_compound, 0302 clinical medicine, In vivo, 0103 physical sciences, medicine, medicine.diagnostic_test, Magnetic resonance imaging, Mutual information, Atomic and Molecular Physics, and Optics, chemistry, sense organs, 030217 neurology & neurosurgery, Preclinical imaging, Biotechnology, Biomedical engineering
Abstract

OCT has been demonstrated as an efficient imaging modality in various biomedical and clinical applications. However, there is a missing link with respect to the source of contrast between OCT and other modern imaging modalities, no quantitative comparison has been demonstrated between them, yet. We evaluated, to our knowledge, for the first time in vivo OCT measurement of rat brain with our previously proposed forward imaging method by both qualitatively and quantitatively correlating OCT with the corresponding T1-weighted and T2-weighted magnetic resonance images, fiber density map (FDM), and two types of histology staining (cresyl violet and acetylcholinesterase AchE), respectively. Brain anatomical structures were identified and compared across OCT, MRI and histology imaging modalities. Noticeable resemblances corresponding to certain anatomical structures were found between OCT and other image profiles. Correlation was quantitatively assessed by estimating correlation coefficient (R) and mutual information (MI). Results show that the 1-D OCT measurements in regards to the intensity profile and estimated attenuation factor, do not have profound linear correlation with the other image modalities suggested from correlation coefficient estimation. However, findings in mutual information analysis demonstrate that there are markedly high MI values in OCT-MRI signals.

Published
2017

11. Deletion of the mu opioid receptor gene in mice reshapes the reward–aversion connectome

Author

Brigitte L. Kieffer, Sami Ben Hamida, Aliza T. Ehrlich, Pedro Rosa-Neto, Thomas Bienert, Juergen Hennig, Hsu-Lei Lee, Anna E. Mechling, Maxime Parent, Dominik von Elverfeldt, Marco Reisert, Laura-Adela Harsan, Tanzil Mahmud Arefin, Emmanuel Darcq, Claire Gaveriaux-Ruff, University of Freiburg [Freiburg], Universitäts Klinikum Freiburg = University Medical Center Freiburg (Uniklinik), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), McGill University = Université McGill [Montréal, Canada], Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, and univOAK, Archive ouverte

Subjects
Male, 0301 basic medicine, resting-state functional MRI, Genotype, reward/aversion network, Models, Neurological, Receptors, Opioid, mu, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, mu opioid receptor, Mice, 03 medical and health sciences, 0302 clinical medicine, Reward, Connectome, Animals, Diffusion Tractography, Receptor, Gene, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Brain Mapping, Multidisciplinary, Functional connectivity, Brain, Biological Sciences, diffusion tensor imaging, Magnetic Resonance Imaging, 030104 developmental biology, Habenula, μ-opioid receptor, Psychology, Neuroscience, Gene Deletion, 030217 neurology & neurosurgery, mouse brain connectivity, Diffusion MRI
Abstract

Significance Mice manipulated by targeted deletion of a specific brain gene show diverse pathological phenotypes, apparent, for example, in behavioral experiments. To explain observed findings, connectome genetics attempts to uncover how brain functional connectivity is affected by genetics. However the causal impact of a single gene on whole-brain networks is still unclear. Here the sole targeted deletion of the mu opioid receptor gene ( Oprm 1), the main target for morphine, induced widespread remodeling of brain functional connectome in mice. The strongest perturbations occurred within the so-called reward/aversion-circuitry, predominantly influencing the negative affect centers. We present a hypothesis-free analysis of combined structural and functional connectivity data obtained via MRI of the living mouse brain, and identify a specific Oprm 1 gene-to-network signature.

Published
2016

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