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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    257—Opioids: Neural Mechanisms of Addiction

    Sunday, November 10, 2013, 1:00 pm - 5:00 pm

    257.04: Mapping the brain functional and structural connectivity of mu-opioid receptor knock-out mice

    Location: Halls B-H

    *A. MECHLING1,2,4, T. AREFIN1,4,3, H.-L. LEE1, M. REISERT1, S. BEN HAMIDA4, J. HENNIG1, D. VON ELVERFELDT1, B. KIEFFER4, L.-A. HARSAN1;
    1Med. Physics; Dept. of Radiology, Univ. Med. Ctr. Freiburg, Freiburg, Germany; 2Fac. of Biol., 3Bernstein Ctr., Albert-Ludwigs-Universit‰t Freiburg, Freiburg, Germany; 4Inst. de GÈnÈtique et de Biologie MolÈculaire et Cellulaire, Ctr. Natl. de Recherche Scientifique/Institut Natl. de la SantÈ et de la Recherche MÈdicale/UniversitÈ de Strasbourg, Illkirch-Graffenstaden, France

    Abstract Body: A non-invasive insight into the brain’s intrinsic connectional architecture of functional networks (FN) has only become possible since the development of resting-state functional magnetic resonance imaging (rsfMRI). In humans, the default mode functional networks and their alterations in pathologies are intensively studied. Moreover, when combined with diffusion tensor magnetic resonance imaging (DT-MRI) and fiber tracking investigations [1], recent studies demonstrate the structural connectivity features underlying the FN and their remodeling mapped by rsfMRI [2]. However, the intrinsic connectional architecture of functional and structural networks in the mouse brain remains a significantly underexplored research area. The goal of the present study was to bridge this gap by unifying and adapting the rsfMRI/DT-MRI techniques for studying the functional and structural connectivity pattern in mouse models of brain disorders. We focused our investigation on mapping the brain connectional networks of mu-opioid receptor (MOR) knock-out mice (Oprm1-/-), an extensively used model of drug addiction and reward [3].
    Mouse brain MRI was performed with a 7T small bore animal scanner and a mouse head adapted cryogenic surface coil (Bruker Germany) both allowing for high signal-to-noise ratio and short acquisition times at high resolution. rsfMRI and DT-MRI data was acquired from 8 weeks old wild type (n=14) and Oprm1-/- (n=14) male mice using single shot Gradient Echo Echo Planar Imaging (GE-EPI) and 4 shot DT-EPI sequences. Group Independent Component Analysis (ICA) of rsfMRI data allowed the identification of elementary functional clusters of the Oprm1-/- mouse brain. Their connectional relationship was tested with partial correlation and graph theory providing a comprehensive picture of Oprm1-/- brain functional connectivity. As a step forward, the identified functional clusters were subsequently used as regions of interest in a fiber tracking algorithm, for mapping structural connectivity. We focused our analysis on brain networks involving areas known for their clustered expression of MOR such as striatum, amygdala and thalamus. Our experiment broadens the knowledge about functional and anatomical connectivity in mouse models of brain disorders uncovering also the involvement of the mu opioid receptor in brain networks remodeling. This non-invasive study design forms also the basis for longitudinal investigations, opening a perspective towards testing therapeutic compounds and their influence on the progress of disease patterns.
    [1] Harsan et al, PNAS 2013; [2] van den Heuvel et al, HBM 30, 2009; [3] Kieffer et al, ProgNeurobiol 66, 2002

    Lay Language Summary: Our study provides a unique insight into the functional and structural mouse brain “connectome”, revealing - via non-invasive magnetic resonance imaging (MRI) - significant remodeling of brain connectional networks in mu-opioid receptor (MOR) knock-out mice (Oprm1-/-). MORs are broadly involved in drug addiction and main players in reward processes, attracting increasing attention in psychiatric research with a potential novel role in the development of autism spectrum disorders.
    Combining genetic and brain imaging tools in mice, we establish - for the first time - a clear link between disrupted MOR function and brain connectivity alterations. Particularly interesting are the observed remodeling features of functional networks involving brain areas that control reward processes, with high relevance for drug abuse, eating disorders, social disabilities and autistic spectrum disorders. Therefore, we advance the current knowledge on the etiology and underlying mechanisms of these disorders and form the basis for potential new treatment strategies.
    Our research is highly innovative at brain imaging level. Non-invasive insight into the brain’s intrinsic connectional architecture of functional networks has only become possible since the development of resting-state functional magnetic resonance imaging (rsfMRI). Its combination with diffusion tensor magnetic resonance imaging (DT-MRI) and fiber tracking offers a unique comparative view of whole brain “connectome”. These aspects are currently explored for the human brain, but the mouse intrinsic connectional architecture is a significantly underexplored research area. We bridge this gap between the preclinical and clinical MRI by unifying and adapting the in-vivo rsfMRI/DT-MRI techniques applied at high magnetic field (7T), for studying the functional and structural connectivity in mouse models of brain disorders.
    As a first outcome, we provide the detailed characterization of altered mouse brain connectivity patterns as result of genetic inactivation of MOR. From the rsfMRI data of control and Oprm1-/- mice we identify functional brain nodes, associated with specific anatomical brain areas. The evaluation of their connectional relationship shows a decreased ability of the Oprm1-/- brain to form strong inter-nodal associations. The average connectional strength as a measure of functional connectivity appears to be 31.7% lower than the strength assigned for the control brain nodes. Thus, brain regions in the mutants form weaker connections with multiple other brain areas which reflects remodeling processes in the Oprm1-/- brain due to missing receptors along the animal development and life.
    Additionally, when testing the nodes ability to act as relays or hubs for functional interaction significant differences are obtained between control and Oprm1-/- mice. Important areas of the limbic system, whose key role in reward processes has long been established, show strongly altered connectivity strength in mutant mice. Further, habenula connectivity which raises increasing interest in the field of motivated behaviors and represents the densest site for MOR expression displays remarkably lower importance in mutant mice. These preliminary data together points towards a remarkably altered functional “connectome” associated with known and novel functions of MOR.
    Subsequently, the rsfMRI results were used as regions of interest in a fiber tracking algorithm, for comparative fine-grained mapping of their structural connection pathways. Thus, this study on innate MOR deprived brain highlights a developmental process of functional and structural connectivity remodeling. A fundamental question to be addressed next is the alteration of brain networks after conditional inactivation of MOR in specific brain areas of adult mice. The non-invasive methodological design used here offers the possibility of longitudinal investigations in such models, opening a perspective towards individual follow-up of brain network fluctuations at different stages after inactivation of MOR. Additionally, our imaging framework allows for evaluating possible new therapeutic compounds and their influence on the progress of disease patterns.