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  • 1.
    Bilbao, Ainhoa
    et al.
    Central Institute of Mental Health, Mannheim.
    Rodriguez Parkitna, Jan
    German Cancer Research Center, Heidelberg.
    Engblom, David
    German Cancer Research Center, Heidelberg.
    Perreau-Lenz, Stephanie
    Central Institute of Mental Health, Mannheim.
    Sanchis-Segura, Carles
    Central Institute of Mental Health, Mannheim.
    Schneider, Miriam
    Central Institute of Mental Health, Mannheim.
    Konopka, Witold
    German Cancer Research Center, Heidelberg.
    Westphal, Magdalena
    German Cancer Research Center, Heidelberg.
    Breen, Gerome
    King's College London.
    Desrivieres, Sylvane
    King's College London.
    Klugmann, Matthias
    University of Mainz.
    Guindalini, Camila
    Universidade Federal de São Paulo.
    Vallada, Homero
    Universidade de São Paulo.
    Laranjeira, Ronaldo
    Universidade Federal de São Paulo.
    Rodriguez de Fonseca, Fernando
    Hospital Carlos Haya.
    Schumann, Gunter
    King's College London.
    Schuetz, Guenther
    Central Institute of Mental Health, Mannheim.
    Spanagel, Rainer
    Central Institute of Mental Health, J5, 68159 Mannheim.
    Loss of the Ca2+/calmodulin-dependent protein kinase type IV in dopaminoceptive neurons enhances behavioral effects of cocaine2008In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, no 45, p. 17549-17554Article in journal (Refereed)
    Abstract [en]

    The persistent nature of addiction has been associated with activity-induced plasticity of neurons within the striatum and nucleus accumbens (NAc). To identify the molecular processes leading to these adaptations, we performed Cre/loxP-mediated genetic ablations of two key regulators of gene expression in response to activity, the Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) and its postulated main target, the cAMP-responsive element binding protein (CREB). We found that acute cocaine-induced gene expression in the striatum was largely unaffected by the loss of CaMKIV. On the behavioral level, mice lacking CaMKIV in dopaminoceptive neurons displayed increased sensitivity to cocaine as evidenced by augmented expression of locomotor sensitization and enhanced conditioned place preference and reinstatement after extinction. However, the loss of CREB in the forebrain had no effect on either of these behaviors, even though it robustly blunted acute cocaine-induced transcription. To test the relevance of these observations for addiction in humans, we performed an association study of CAMK4 and CREB promoter polymorphisms with cocaine addiction in a large sample of addicts. We found that a single nucleotide polymorphism in the CAMK4 promoter was significantly associated with cocaine addiction, whereas variations in the CREB promoter regions did not correlate with drug abuse. These findings reveal a critical role for CaMKIV in the development and persistence of cocaine-induced behaviors, through mechanisms dissociated from acute effects on gene expression and CREB-dependent transcription.

  • 2.
    Björk Wilhelms, Daniel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Mirrasekhian, Elahe
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Cyclooxygenase isoform exchange blocks inflammatory symptoms2014Manuscript (preprint) (Other academic)
    Abstract [en]

    Cyclooxygenase‐2 (COX‐2) is the main source of inducible prostaglandin E2 production and mediates inflammatory symptoms including fever, loss of appetite and hyperalgesia. In contrast, COX‐1 is dispensable for most inflammatory symptoms. Global deletion of COX‐2 leads to a blockade of inflammation‐induced fever and appetite loss but also to high rates of fetal mortality. The latter is unfortunate since mice without COX‐2 are powerful tools in the study of inflammation and cardiovascular medicine. The differential functionality of the COX isoforms could be due to differences in regulatory regions of the genes, leading to different expression patterns, or to differences in the coding sequence, leading to distinct functional properties of the proteins. To study this in the context of inflammatory symptoms, we used mice in which the coding sequence of COX‐2 was replaced by the corresponding sequence of COX‐1. In these mice, COX‐1 mRNA was induced by inflammation but COX‐1 protein expression did not fully mimic inflammation‐induced COX‐2 expression. Just like mice globally lacking COX‐2, these mice showed a complete lack of fever and inflammation‐induced anorexia. However, as previously reported, they displayed close to normal survival rates. This shows that the COX activity generated from the hybrid gene was strong enough to allow survival but not strong enough to mediate inflammatory symptoms, making the line an interesting alternative to COX‐2 knockouts for the study of inflammation. Our results also show that the functional differences between COX‐1 and COX‐2 in the context of inflammatory symptoms is not only dependent on the features of the promoter regions. Instead they indicate that there are fundamental differences between the isoforms at translational or posttranslational levels, which make hybrid genes less functional.

  • 3.
    Ek, Monica
    et al.
    Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
    Engblom, David
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Saha, Sipra
    Department of Medical Biochemistry and Biophysics, The Karolinska Institute, Stockholm, Sweden.
    Blomqvist, Anders
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Jakobsson, Per-Johan
    Department of Medical Biochemistry and Biophysics, The Karolinska Institute, Stockholm, Sweden.
    Ericsson-Dahlstrand, Anders
    Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
    Inflammatory response: pathway across the blood–brain barrier2001In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 410, p. 430-431Article in journal (Refereed)
    Abstract [en]

    No abstract available.

  • 4.
    Elander, Louise
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Engström, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Ruud, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Mackerlova, Ludmila
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Jakobsson, Per-Johan
    Karolinska Institute.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Nilsberth, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Inducible Prostaglandin E-2 Synthesis Interacts in a Temporally Supplementary Sequence with Constitutive Prostaglandin-Synthesizing Enzymes in Creating the Hypothalamic-Pituitary-Adrenal Axis Response to Immune Challenge2009In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 29, no 5, p. 1404-1413Article in journal (Refereed)
    Abstract [en]

    Inflammation-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis has been suggested to depend on prostaglandins, but the prostaglandin species and the prostaglandin-synthesizing enzymes that are responsible have not been fully identified. Here, we examined HPA axis activation in mice after genetic deletion or pharmacological inhibition of prostaglandin E-2-synthesizing enzymes, including cyclooxygenase-1 (Cox-1), Cox-2, and microsomal prostaglandin E synthase-1 (mPGES-1). After immune challenge by intraperitoneal injection of lipopolysaccharide, the rapid stress hormone responses were intact after Cox-2 inhibition and unaffected by mPGES-1 deletion, whereas unselective Cox inhibition blunted these responses, implying the involvement of Cox-1. However, mPGES-1-deficient mice showed attenuated transcriptional activation of corticotropin-releasing hormone (CRH) that was followed by attenuated plasma concentrations of adrenocorticotropic hormone and corticosterone. Cox-2 inhibition similarly blunted the delayed corticosterone response and further attenuated corticosterone release in mPGES-1 knock-out mice. The expression of the c-fos gene, an index of synaptic activation, was maintained in the paraventricular hypothalamic nucleus and its brainstem afferents both after unselective and Cox-2 selective inhibition as well as in Cox-1, Cox-2, and mPGES-1 knock-out mice. These findings point to a mechanism by which ( 1) neuronal afferent signaling via brainstem autonomic relay nuclei and downstream Cox-1-dependent prostaglandin release and ( 2) humoral, CRH transcription-dependent signaling through induced Cox-2 and mPGES-1 elicited PGE(2) synthesis, shown to occur in brain vascular cells, play distinct, but temporally supplementary roles for the stress hormone response to inflammation.

  • 5.
    Elander, Louise
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Prostaglandin E2 receptors in IL-1β induced anorexiaManuscript (preprint) (Other academic)
    Abstract [en]

    Anorexia in response to immune challenge by Interleukin-1β (IL-1β) has been shown to be dependent on Prostaglandin E2 (PGE2) produced by the inducible enzyme microsomal prostaglandin E synthase-1 (mPGES-1). However, it is not known which of the four known PGE2 receptors EP1-4, encoded by the genes Ptger 1-4, that mediates the PGE2-induced anorexia. Here we examined food intake in mice deficient in EP1, EP2 and EP3, respectively, during normal conditions and following treatment with IL-1β. Neither of the gene deletions affected baseline food intake, and all the three genotypes displayed anorexia following IL-1β injection, similar to wild type mice. Previous work has demonstrated that the EP3 receptor is critical for the generation of fever, and that EP1 and EP3 receptors mediate inflammationinduced activation of the hypothalamic-pituitary-adrenal (HPA) axis. The present data, showing intact anorexigenic responses in EP1 and EP3 deficient mice, as well as in mice with deletion of the EP2 receptor, hence suggest that PGE2-elicited acute phase responses are mediated by distinct set or sets of PGE2-receptors.

  • 6.
    Engblom, David
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Prostaglandin E2 in immune-to-brain signaling2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Upon immune-challenge, signaling from the immune system to the brain triggers an array of central nervous responses that include fever, anorexia, hyperalgesia and activation of the hypothalamus-pituitary adrenal axis. These symptoms are dependent on cytokines produced at the site of inflammation. However, because cytokines cannot penetrate the blood-brain barrier, the mechanism by which cytokines activate the central nervous system has remained elusive. Among several hypotheses, it has been suggested that prostaglandin E2 (PGE2) synthesized at the blood-brain interface and subsequently binding to PGE2 receptors expressed on deep neural structures may be responsible for the immune-to-brain signaling.

    During inflammatory conditions PGE2 is produced from prostaglandin H2 by the inducible isomerase microsomal prostaglandin E synthase-1 (mPGES-1). By using in situ hybridization, we investigated the expression of this enzyme in the brain of rats subjected to immune challenge induced by intravenous injection of interleukin-1ß. We found that mPGES-1 mRNA had a very restricted and low expression in the brain of naive rats. However, in response to inunune challenge it was rapidly and heavily induced in cells of the cerebral vasculature. Further, we found that the cells expressing mPGES-1 co-expressed cyclooxygenase-2 mRNA and interleukin-1 receptor type 1 mRNA. Thus, circulating interleukin-1 may bind to brain vascular cells and induce the expression of cyclooxygenase-2 and mPGES-1, leading to the production of PGE2 that can diffuse into the brain and trigger central nervous responses. We also showed that the same mechanism may be operating in a model for autoimmune disease. Thus, rats with adjuvant-induced arthritis, a model of rheumatoid arthritis, displayed a similar mPGES-1 and cyclooxygenase-2 induction in interleukin-1 receptor bearing brain endothelial cells.

    To examine the functional role of the central induction of mPGES-1, we studied the febrile response in mice deficient in the gene encoding mPGES-1. These mice showed no fever and no central PGE2 production in response to immune challenge induced by intraperitoneal injection of the bacterial fragment lipopolysaccharide, demonstrating that PGE2 synthesized by mPGES-1 is critical for immune-induced fever.

    We also studied the expression of receptors for PGE2 in the parabrachial nucleus, an autonomic brain stem structure involved in the regulation of food intake, blood pressure and nociceptive processing. We found that neurons in the para brachial nucleus express PGE2 receptors of type EP3 and EP4 and that many of the EP3 and some of the EP4 expressing neurons in this nucleus are activated by immune challenge. The PGE2 receptor expressing neurons also expressed mRNAs for various neuropeptides, such as dynorphin, enkephalin, calcitonin gene related peptide and substance P. Taken together with previous observations, these findings indicate that the PGE2 receptor expressing cells in the parabrachial nucleus are involved in alterations in food intake and in nociceptive processing during immune challenge.

    In summary, these data show the presence of a mechanism, involving cerebrovascular induction of mPGES-1, that conveys an inflammatory message from the blood-stream through the blood-brain barrier to relevant deep neural structures. Further, the findings show that this mechanism is critical for the febrile response and is activated during both acute and prolonged inflammatory conditions. This identifies mPGES-1 as a potential drug target for the alleviation of central nervous symptoms of inflammatory disease, such as fever, pain and anorexia.

    List of papers
    1. Inflammatory response: pathway across the blood–brain barrier
    Open this publication in new window or tab >>Inflammatory response: pathway across the blood–brain barrier
    Show others...
    2001 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 410, p. 430-431Article in journal (Refereed) Published
    Abstract [en]

    No abstract available.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-24947 (URN)10.1038/35068632 (DOI)000167583800030 ()9356 (Local ID)9356 (Archive number)9356 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    2. Induction of microsomal prostaglandin E synthase in the rat brain endothelium and parenchyma in adjuvant-induced arthritis
    Open this publication in new window or tab >>Induction of microsomal prostaglandin E synthase in the rat brain endothelium and parenchyma in adjuvant-induced arthritis
    Show others...
    2002 (English)In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 452, no 3, p. 205-214Article in journal (Refereed) Published
    Abstract [en]

    Although central nervous symptoms such as hyperalgesia, fatigue, malaise, and anorexia constitute major problems in the treatment of patients suffering from chronic inflammatory disease, little has been known about the signaling mechanisms by which the brain is activated during such conditions. Here, in an animal model of rheumatoid arthritis, we show that microsomal prostaglandin E-synthase, the inducible terminal isomerase in the prostaglandin E2-synthesizing pathway, is expressed in endothelial cells along the blood-brain barrier and in the parenchyma of the paraventricular hypothalamic nucleus. The endothelial cells but not the paraventricular hypothalamic cells displayed a concomitant induction of cyclooxygenase-2 and expressed interleukin-1 type 1 receptors, which indicates that the induction is due to peripherally released cytokines. In contrast to cyclooxygenase-2, microsomal prostaglandin E synthase had very sparse constitutive expression, suggesting that it could be a target for developing drugs that will carry fewer side effects than the presently available cyclooxygenase inhibitors. These findings, thus, suggest that immune-to-brain communication during chronic inflammatory conditions involves prostaglandin E2-synthesis both along the blood-brain barrier and in the parenchyma of the hypothalamic paraventricular nucleus and point to novel avenues for the treatment of the brain-elicited disease symptoms during these conditions.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-24943 (URN)10.1002/cne.10380 (DOI)9352 (Local ID)9352 (Archive number)9352 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    3. Microsomal prostaglandin E synthase-1 is the central switch during immune-induced pyresis
    Open this publication in new window or tab >>Microsomal prostaglandin E synthase-1 is the central switch during immune-induced pyresis
    Show others...
    2003 (English)In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 6, no 11, p. 1137-1138Article in journal (Refereed) Published
    Abstract [en]

    We studied the febrile response in mice deficient in microsomal prostaglandin E synthase-1 (mPGES-1), an inducible terminal isomerase expressed in cytokine-sensitive brain endothelial cells. These animals showed no fever and no central prostaglandin (PG) E2 synthesis after peripheral injection of bacterial-wall lipopolysaccharide, but their pyretic capacity in response to centrally administered PGE2 was intact. Our findings identify mPGES-1 as the central switch during immune-induced pyresis and as a target for the treatment of fever and other PGE2-dependent acute phase reactions elicited by the brain.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-24954 (URN)10.1038/nn1137 (DOI)9365 (Local ID)9365 (Archive number)9365 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    4. Distribution of prostaglandin EP3 and EP4 receptor mRNA in the rat parabrachial nucleus
    Open this publication in new window or tab >>Distribution of prostaglandin EP3 and EP4 receptor mRNA in the rat parabrachial nucleus
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    2000 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 281, no 2-3, p. 163-166Article in journal (Refereed) Published
    Abstract [en]

    By using in situ hybridization, the distribution of mRNA for the PGE2 receptors EP3 and EP4 was examined in the rat parabrachial nucleus (PB), a major brain stem relay for autonomic and nociceptive processing. EP3 receptor mRNA was present in most subnuclei, with the densest labeling in the external lateral, dorsal lateral, superior lateral, central lateral and Kölliker–Fuse nuclei. EP4 receptor mRNA expressing cells had a more restricted distribution, largely being confined to the superior lateral and adjacent parts of the dorsal and central lateral nuclei in a pattern complementary to that for EP3 receptor mRNA. These findings suggest that EP3 and EP4 receptors in PB have distinct functional roles that include nociceptive processing, blood pressure regulation and feeding behavior.

    Place, publisher, year, edition, pages
    Elsevier Science B.V., Amsterdam., 2000
    Keywords
    inflammation; pain; in situ hybridization; Kolliker-Fuse nucleus
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-59666 (URN)10.1016/S0304-3940(00)00852-1 (DOI)000085886400023 ()10704768 (PubMedID)
    Available from: 2010-09-23 Created: 2010-09-23 Last updated: 2019-10-14Bibliographically approved
    5. Activation of prostanoid EP3 and EP4 receptor mRNA-expressing neurons in the rat parabrachial nucleus by intravenous injection of bacterial wall lipopolysaccharide
    Open this publication in new window or tab >>Activation of prostanoid EP3 and EP4 receptor mRNA-expressing neurons in the rat parabrachial nucleus by intravenous injection of bacterial wall lipopolysaccharide
    2001 (English)In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 440, no 4, p. 378-386Article in journal (Refereed) Published
    Abstract [en]

    Systemic inflammation activates central autonomic circuits, such as neurons in the pontine parabrachial nucleus. This activation may be the result of afferent signaling through the vagus nerve, but it may also depend on central prostaglandin-mediated mechanisms. Recently, we have shown that neurons in the parts of the parabrachial nucleus that are activated by immune challenge express prostaglandin receptors of the EP3 and EP4 subtypes, but it remains to be determined if the prostaglandin receptor-expressing neurons are identical to those that respond to immune stimuli. In the present study, bacterial wall lipopolysaccharide was injected intravenously in adult male rats and the expression of c-fos mRNA and of EP3 and EP4 receptor mRNA was examined with complementary RNA probes labeled with digoxigenin and radioisotopes, respectively. Large numbers of neurons in the external lateral parabrachial subnucleus, a major target of vagal-solitary tract efferents, expressed c-fos mRNA. Quantitative analysis showed that about 60% (range 40%–79%) of these neurons also expressed EP3 receptor mRNA. Conversely, slightly more than 50% (range 48%–63%) of the EP3 receptor-expressing neurons in the same subnucleus coexpressed c-fos mRNA. In contrast, few EP4 receptor-expressing neurons were c-fos positive, with the exception of a small population located in the superior lateral and dorsal lateral subnuclei. These findings show that immune challenge activates central autonomic neurons that could be the target of centrally produced prostaglandin E2, suggesting that synaptic signaling and paracrine mechanisms may interact on these neurons. J. Comp. Neurol. 440:378–386, 2001. © 2001 Wiley-Liss, Inc.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-24938 (URN)10.1002/cne.1391 (DOI)000172034800004 ()9346 (Local ID)9346 (Archive number)9346 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    6. EP3 and EP4 receptor mRNA expression in peptidergic cell groups of the rat parabrachial nucleus
    Open this publication in new window or tab >>EP3 and EP4 receptor mRNA expression in peptidergic cell groups of the rat parabrachial nucleus
    2004 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 126, no 4, p. 989-999Article in journal (Refereed) Published
    Abstract [en]

    This study examines the distribution of prostaglandin E2 receptors of subtype EP3 and EP4 among brain stem parabrachial neurons that were characterized with respect to their neuropeptide expression. By using a dual-labeling in situ hybridization method, we show that preprodynorphin mRNA expressing neurons in the dorsal and central lateral subnuclei express EP3 receptor mRNA. Such receptors are also expressed in preproenkephalin, calcitonin gene related peptide and preprotachykinin mRNA positive neurons in the external lateral subnucleus, whereas preprodynorphin mRNA expressing neurons in this subnucleus are EP receptor negative. In addition, EP3 receptor expression is seen among some enkephalinergic neurons in the Kölliker-Fuse nucleus. Neurons in the central part of the cholecystokininergic population in the regions of the superior lateral subnucleus express EP4 receptor mRNA, whereas those located more peripherally express EP3 receptors. Taken together with previous findings showing that discrete peptidergic cell groups mediate nociceptive and/or visceral afferent information to distinct brain stem and forebrain regions, the present results suggest that the processing of this information in the parabrachial nucleus is influenced by prostaglandin E2. Recent work has shown that prostaglandin E2 is released into the brain following peripheral immune challenge; hence, the parabrachial nucleus may be a region where humoral signaling of peripheral inflammatory events may interact with neuronal signaling elicited by the same peripheral processes.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-22395 (URN)10.1016/j.neuroscience.2004.03.042 (DOI)1605 (Local ID)1605 (Archive number)1605 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
  • 7.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Reverse genetics in addiction research in EUROPEAN NEUROPSYCHOPHARMACOLOGY, vol 21, issue , pp S210-S2102011In: EUROPEAN NEUROPSYCHOPHARMACOLOGY, Elsevier , 2011, Vol. 21, p. S210-S210Conference paper (Refereed)
    Abstract [en]

    n/a

  • 8.
    Engblom, David
    et al.
    German Cancer Research Center, Heidelberg.
    Bilbao, Ainhoa
    Central Institute of Mental Health, Mannheim.
    Sanchis-Segura, Carles
    Central Institute of Mental Health, Mannheim.
    Dahan, Lionel
    University of Geneva.
    Perreau-Lenz, Stephanie
    Central Institute of Mental Health, Mannheim.
    Balland, Benedicte
    University of Geneva.
    Rodriguez Parkitna, Jan
    German Cancer Research Center, Heidelberg.
    Lujan, Rafael
    University of Castilla La Mancha.
    Halbout, Briac
    Central Institute of Mental Health, Mannheim.
    Mameli, Manuel
    University of Geneva.
    Parlato, Rosanna
    German Cancer Research Center, Heidelberg.
    Sprengel, Rolf
    Max Planck Institute.
    Luescher, Christian
    University of Geneva.
    Schuetz, Guenther
    German Cancer Research Center, Heidelberg.
    Spanagel, Rainer
    Central Institute of Mental Health, Mannheim.
    Glutamate receptors on dopamine neurons control the persistence of cocaine seeking2008In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 59, no 3, p. 497-508Article in journal (Refereed)
    Abstract [en]

    Cocaine strengthens excitatory synapses onto midbrain dopamine neurons through the synaptic delivery of GluR1-containing AMPA receptors. This cocaine-evoked plasticity depends on NMDA receptor activation, but its behavioral significance in the context of addiction remains elusive. Here, we generated mice lacking the GluR1, GluR2, or NR1 receptor subunits selectively in dopamine neurons. We report that in midbrain slices of cocaine-treated mice, synaptic transmission was no longer strengthened when GluR1 or NR1 was abolished, while in the respective mice the drug still induced normal conditioned place preference and locomotor sensitization. In contrast, extinction of drug-seeking behavior was absent in mice lacking GluR1, while in the NR1 mutant mice reinstatement was abolished. In conclusion, cocaine-evoked synaptic plasticity does not mediate concurrent short-term behavioral effects of the drug but may initiate adaptive changes eventually leading to the persistence of drug-seeking behavior.

  • 9.
    Engblom, David
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Ek, Monica
    Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
    Andersson, Ingela
    Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
    Saha, Sipra
    Center for Structural Biochemistry, The Karolinska Institute, Huddinge, Sweden.
    Dahlström, Marie
    Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
    Jakobsson, Per-Johan
    Department of Biochemistry and Biophysics, The Karolinska Institute, Stockholm, Sweden.
    Ericsson-Dahlstrand, Anders
    5 AstraZeneca R&D - Södertälje, Molecular Sciences, Novum, Huddinge, Sweden.
    Blomqvist, Anders
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Induction of microsomal prostaglandin E synthase in the rat brain endothelium and parenchyma in adjuvant-induced arthritis2002In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 452, no 3, p. 205-214Article in journal (Refereed)
    Abstract [en]

    Although central nervous symptoms such as hyperalgesia, fatigue, malaise, and anorexia constitute major problems in the treatment of patients suffering from chronic inflammatory disease, little has been known about the signaling mechanisms by which the brain is activated during such conditions. Here, in an animal model of rheumatoid arthritis, we show that microsomal prostaglandin E-synthase, the inducible terminal isomerase in the prostaglandin E2-synthesizing pathway, is expressed in endothelial cells along the blood-brain barrier and in the parenchyma of the paraventricular hypothalamic nucleus. The endothelial cells but not the paraventricular hypothalamic cells displayed a concomitant induction of cyclooxygenase-2 and expressed interleukin-1 type 1 receptors, which indicates that the induction is due to peripherally released cytokines. In contrast to cyclooxygenase-2, microsomal prostaglandin E synthase had very sparse constitutive expression, suggesting that it could be a target for developing drugs that will carry fewer side effects than the presently available cyclooxygenase inhibitors. These findings, thus, suggest that immune-to-brain communication during chronic inflammatory conditions involves prostaglandin E2-synthesis both along the blood-brain barrier and in the parenchyma of the hypothalamic paraventricular nucleus and point to novel avenues for the treatment of the brain-elicited disease symptoms during these conditions.

  • 10.
    Engblom, David
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Ek, Monica
    Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
    Ericsson-Dahlstrand, Anders
    Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
    Blomqvist, Anders
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Activation of prostanoid EP3 and EP4 receptor mRNA-expressing neurons in the rat parabrachial nucleus by intravenous injection of bacterial wall lipopolysaccharide2001In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 440, no 4, p. 378-386Article in journal (Refereed)
    Abstract [en]

    Systemic inflammation activates central autonomic circuits, such as neurons in the pontine parabrachial nucleus. This activation may be the result of afferent signaling through the vagus nerve, but it may also depend on central prostaglandin-mediated mechanisms. Recently, we have shown that neurons in the parts of the parabrachial nucleus that are activated by immune challenge express prostaglandin receptors of the EP3 and EP4 subtypes, but it remains to be determined if the prostaglandin receptor-expressing neurons are identical to those that respond to immune stimuli. In the present study, bacterial wall lipopolysaccharide was injected intravenously in adult male rats and the expression of c-fos mRNA and of EP3 and EP4 receptor mRNA was examined with complementary RNA probes labeled with digoxigenin and radioisotopes, respectively. Large numbers of neurons in the external lateral parabrachial subnucleus, a major target of vagal-solitary tract efferents, expressed c-fos mRNA. Quantitative analysis showed that about 60% (range 40%–79%) of these neurons also expressed EP3 receptor mRNA. Conversely, slightly more than 50% (range 48%–63%) of the EP3 receptor-expressing neurons in the same subnucleus coexpressed c-fos mRNA. In contrast, few EP4 receptor-expressing neurons were c-fos positive, with the exception of a small population located in the superior lateral and dorsal lateral subnuclei. These findings show that immune challenge activates central autonomic neurons that could be the target of centrally produced prostaglandin E2, suggesting that synaptic signaling and paracrine mechanisms may interact on these neurons. J. Comp. Neurol. 440:378–386, 2001. © 2001 Wiley-Liss, Inc.

  • 11.
    Engblom, David
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Ek, Monica
    Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
    Ericsson-Dahlstrand, Anders
    AstraZeneca R and D–Södertälje, RA CNS and Pain Control, Department of Molecular Sciences, Novum, Huddinge, Sweden.
    Blomqvist, Anders
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    EP3 and EP4 receptor mRNA expression in peptidergic cell groups of the rat parabrachial nucleus2004In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 126, no 4, p. 989-999Article in journal (Refereed)
    Abstract [en]

    This study examines the distribution of prostaglandin E2 receptors of subtype EP3 and EP4 among brain stem parabrachial neurons that were characterized with respect to their neuropeptide expression. By using a dual-labeling in situ hybridization method, we show that preprodynorphin mRNA expressing neurons in the dorsal and central lateral subnuclei express EP3 receptor mRNA. Such receptors are also expressed in preproenkephalin, calcitonin gene related peptide and preprotachykinin mRNA positive neurons in the external lateral subnucleus, whereas preprodynorphin mRNA expressing neurons in this subnucleus are EP receptor negative. In addition, EP3 receptor expression is seen among some enkephalinergic neurons in the Kölliker-Fuse nucleus. Neurons in the central part of the cholecystokininergic population in the regions of the superior lateral subnucleus express EP4 receptor mRNA, whereas those located more peripherally express EP3 receptors. Taken together with previous findings showing that discrete peptidergic cell groups mediate nociceptive and/or visceral afferent information to distinct brain stem and forebrain regions, the present results suggest that the processing of this information in the parabrachial nucleus is influenced by prostaglandin E2. Recent work has shown that prostaglandin E2 is released into the brain following peripheral immune challenge; hence, the parabrachial nucleus may be a region where humoral signaling of peripheral inflammatory events may interact with neuronal signaling elicited by the same peripheral processes.

  • 12.
    Engblom, David
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Ek, Monica
    Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
    Hallbeck, Martin
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Ericsson-Dahlstrand, Anders
    Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Distribution of prostaglandin EP3 and EP4 receptor mRNA in the rat parabrachial nucleus2000In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 281, no 2-3, p. 163-166Article in journal (Refereed)
    Abstract [en]

    By using in situ hybridization, the distribution of mRNA for the PGE2 receptors EP3 and EP4 was examined in the rat parabrachial nucleus (PB), a major brain stem relay for autonomic and nociceptive processing. EP3 receptor mRNA was present in most subnuclei, with the densest labeling in the external lateral, dorsal lateral, superior lateral, central lateral and Kölliker–Fuse nuclei. EP4 receptor mRNA expressing cells had a more restricted distribution, largely being confined to the superior lateral and adjacent parts of the dorsal and central lateral nuclei in a pattern complementary to that for EP3 receptor mRNA. These findings suggest that EP3 and EP4 receptors in PB have distinct functional roles that include nociceptive processing, blood pressure regulation and feeding behavior.

  • 13.
    Engblom, David
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Ek, Monica
    Saha, Sipra
    Ericsson-Dahlstrand, Anders
    Jakobsson, Per-Johan
    Blomqvist, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Prostaglandins as inflammatory messengers across the blood-brain barrier2002In: Journal of Molecular Medicine, ISSN 0946-2716, E-ISSN 1432-1440, Vol. 80, no 1Article in journal (Refereed)
    Abstract [en]

    Upon immune challenge the brain launches a wide range of responses, such as fever, anorexia, and hyperalgesia that serve to maintain homeostasis. While these responses are adaptive during acute infections, they may be destructive during chronic inflammatory conditions. Research performed during the last decade has given us insight into how the brain monitors the presence of a peripheral inflammation and the mechanisms underlying the brain-mediated acute-phase reactions. Here we give a brief review on this subject, with focus on the role of prostaglandin E2 produced in cells associated with the blood-brain barrier in immune-to-brain signaling. The recent advances in this field have not only elucidated the mechanisms behind the anti-pyretic and anti-hyperalgesic effects of cyclooxygenase inhibitors, but have also identified novel and more-selective potential drug targets.

  • 14.
    Engblom, David
    et al.
    German Cancer Research Centre.
    Kornfeld, Jan-Wilhelm
    German Cancer Research Centre.
    Schwake, Lukas
    German Cancer Research Centre.
    Tronche, Francois
    German Cancer Research Centre.
    Reimann, Andreas
    German Cancer Research Centre.
    Beug, Hartmut
    German Cancer Research Centre.
    Hennighausen, Lothar
    German Cancer Research Centre.
    Moriggl, Richard
    German Cancer Research Centre.
    Schuetz, Guenther
    German Cancer Research Centre.
    Direct glucocorticoid receptor-Stat5 interaction in hepatocytes controls body size and maturation-related gene expression2007In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 21, no 10, p. 1157-1162Article in journal (Refereed)
    Abstract [en]

    The glucocorticoid receptor regulates transcription through DNA binding as well as through cross-talk with other transcription factors. In hepatocytes, the glucocorticoid receptor is critical for normal postnatal growth. Using hepatocyte- specific and domain-selective mutations in the mouse we show that Stat5 in hepatocytes is essential for normal postnatal growth and that it mediates the growth- promoting effect of the glucocorticoid receptor through a direct interaction involving the N-terminal tetramerization domain of Stat5b. This interaction mediates a selective and unexpectedly extensive part of the transcriptional actions of these molecules since it controls the expression of gene sets involved in growth and sexual maturation.

  • 15.
    Engblom, David
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Saha, Sipra
    Center for Structural Biochemistry, Karolinska Institute, Huddinge, Sweden.
    Engström, Linda
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Westman, Marie
    Department of Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden..
    Audoly, Laurent
    Inflammation Unit, Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut, USA..
    Jakobsson, Per-Johan
    Department of Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden..
    Blomqvist, Anders
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Microsomal prostaglandin E synthase-1 is the central switch during immune-induced pyresis2003In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 6, no 11, p. 1137-1138Article in journal (Refereed)
    Abstract [en]

    We studied the febrile response in mice deficient in microsomal prostaglandin E synthase-1 (mPGES-1), an inducible terminal isomerase expressed in cytokine-sensitive brain endothelial cells. These animals showed no fever and no central prostaglandin (PG) E2 synthesis after peripheral injection of bacterial-wall lipopolysaccharide, but their pyretic capacity in response to centrally administered PGE2 was intact. Our findings identify mPGES-1 as the central switch during immune-induced pyresis and as a target for the treatment of fever and other PGE2-dependent acute phase reactions elicited by the brain.

  • 16.
    Engström, Linda
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Björk, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Eskilsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Vasilache, Ana-Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Elander, Louise
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Acetaminophen reduces lipopolysaccharide-induced fever by inhibiting cyclooxygenase-22013In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 71, p. 124-129Article in journal (Refereed)
    Abstract [en]

    Acetaminophen is one of the world's most commonly used drugs to treat fever and pain, yet its mechanism of action has remained unclear. Here we tested the hypothesis that acetaminophen blocks fever through inhibition of cyclooxygenase-2 (Cox-2), by monitoring lipopolysaccharide induced fever in mice with genetic manipulations of enzymes in the prostaglandin cascade. We exploited the fact that lowered levels of a specific enzyme make the system more sensitive to any further inhibition of the same enzyme. Mice were immune challenged by an intraperitoneal injection of bacterial wall lipopolysaccharide and their body temperature recorded by telemetry. We found that mice heterozygous for Cox-2, but not for microsomal prostaglandin E synthase-1 (mPGES-1), displayed attenuated fever, indicating a rate limiting role of Cox-2. We then titrated a dose of acetaminophen that did not inhibit the lipopolysaccharide-induced fever in wild-type mice. However, when the same dose of acetaminophen was given to Cox-2 heterozygous mice, the febrile response to lipopolysaccharide was strongly attenuated, resulting in an almost normalized temperature curve, whereas no difference was seen between wild-type and heterozygous mPGES-1 mice. Furthermore, the fever to intracerebrally injected prostaglandin E2 was unaffected by acetaminophen treatment. These findings reveal that acetaminophen, similar to aspirin and other non-steroidal anti-inflammatory drugs, is antipyretic by inhibiting cyclooxygenase-2, and not by inhibiting mPGES-1 or signaling cascades downstream of prostaglandin E2.

  • 17.
    Engström, Linda
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Systemic immune challenge induces preproenkephalin gene transcription in distinct autonomic structures of the rat brain2003In: Journal of Comparative Neurology, ISSN 0021-9967, Vol. 462, no 4, p. 450-461Article in journal (Refereed)
    Abstract [en]

    The involvement of enkephalins in the immune response was investigated in rats injected intravenously with interleukin-1 (2 g/kg). In situ hybridization with a riboprobe complementary to intron A of the preproenkephalin (ppENK) gene showed distinct transcriptional activation within several brain regions known to be activated by immune stimuli, including the nucleus of the solitary tract, the area postrema, the paraventricular hypothalamic nucleus, and the oval nucleus of the bed nucleus of the stria terminalis, and dual labeling confirmed that a large proportion of the intron expressing neurons co-expressed c-fos mRNA. Rats injected with saline (controls) showed little or no heteronuclear transcript in these structures. The induced signal was strongest after 1 hour but was present in some structures 30 minutes after interleukin-1 injection. At 3 hours, transcriptional activity returned to basal levels. High basal expression of the heteronuclear transcript that appeared unchanged by the immune stimulus was seen in regions not primarily involved in the immune response, such as the striatum, the olfactory tubercle, and the islands of Calleja and in the immune activated central nucleus of the amygdala. The heteronuclear transcript colocalized with ppENK mRNA, demonstrating that it occurred in enkephalinergic neurons and was not the result of alternative transcription from the ppENK gene in other cells. These results demonstrated that enkephalin transcription is induced in central autonomic neurons during immune challenge, suggesting that enkephalins are involved in the centrally orchestrated response to such stimuli.

  • 18.
    Engström, Linda
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Örtegren (Kugelberg), Unn
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Mackerlova, Ludmila
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Paues, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Preproenkephalin mRNA expression in rat parabrachial neurons: relation to cells activated by systemic immune challenge2001In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 316, no 3, p. 165-168Article in journal (Refereed)
    Abstract [en]

    By using a dual-labeling immunohistochemical/in situ hybridization technique we examined if enkephalin-expressing neurons in the pontine parabrachial nucleus, a major brain stem relay for ascending visceral and homeostatic information, were activated by systemic immune challenge. While rats subjected to intravenous injection of bacterial wall lipopolysaccharide expressed dense labeling for the immediate-early gene product FOS in parts of the parabrachial nucleus that also demonstrated dense preproenkephalin expression, only a small proportion of the enkephalin-positive neurons were FOS-positive. These data indicate that enkephalins, although implicated in a variety of autonomic responses, are not primarily involved in the transmission of immune-related information from the parabrachial nucleus to its different forebrain and brain stem targets.

  • 19.
    Engström, Linda
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Rosén, Khadijah
    Angel, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology-IKE . Linköping University, Faculty of Health Sciences.
    Fyrberg, Anna
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Mackerlova, Ludmila
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Konsman, Jan Pieter
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Systemic immune challenge activates an intrinsically regulated local inflammatory circuit in the adrenal gland2008In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 149, no 4, p. 1436-1450Article in journal (Refereed)
    Abstract [en]

    There is evidence from in vitro studies that inflammatory messengers influence the release of stress hormone via direct effects on the adrenal gland; however, the mechanisms underlying these effects in the intact organism are unknown. Here we demonstrate that systemic inflammation in rats elicited by iv injection of lipopolysaccharide results in dynamic changes in the adrenal immune cell population, implying a rapid depletion of dendritic cells in the inner cortical layer and the recruitment of immature cells to the outer layers. These changes are accompanied by an induced production of IL-1β and IL-1 receptor type 1 as well as cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in these cells, implying local cytokine-mediated prostaglandin E2 production in the adrenals, which also displayed prostaglandin E2 receptors of subtypes 1 and 3 in the cortex and medulla. The IL-1β expression was also induced by systemically administrated IL-1β and was in both cases attenuated by IL-1 receptor antagonist, consistent with an autocrine signaling loop. IL-1β similarly induced expression of cyclooxygenase-2, but the cyclooxygenase-2 expression was, in contrast, further enhanced by IL-1 receptor antagonist. These data demonstrate a mechanism by which systemic inflammatory agents activate an intrinsically regulated local signaling circuit that may influence the adrenals’ response to immune stress and may help explain the dissociation between plasma levels of ACTH and corticosteroids during chronic immune perturbations.

  • 20.
    Engström, Linda
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Ruud, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Eskilsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Larsson, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Mackerlova, Ludmila
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Kugelberg, Unn
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Qian, Hong
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Vasilache, Ana Maria
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Larsson, Peter
    Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Lipopolysaccharide-Induced Fever Depends on Prostaglandin E2 Production Specifically in Brain Endothelial Cells2012In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 153, no 10, p. 4849-4861Article in journal (Refereed)
    Abstract [en]

    Immune-induced prostaglandin E2 (PGE2) synthesis is critical for fever and other centrally elicited disease symptoms. The production of PGE2 depends on cyclooxygenase-2 and microsomal prostaglandin E synthase-1 (mPGES-1), but the identity of the cells involved has been a matter of controversy. We generated mice expressing mPGES-1 either in cells of hematopoietic or nonhematopoietic origin. Mice lacking mPGES-1 in hematopoietic cells displayed an intact febrile response to lipopolysaccharide, associated with elevated levels of PGE2 in the cerebrospinal fluid. In contrast, mice that expressed mPGES-1 only in hematopoietic cells, although displaying elevated PGE2 levels in plasma but not in the cerebrospinal fluid, showed no febrile response to lipopolysaccharide, thus pointing to the critical role of brain-derived PGE2 for fever. Immunohistochemical stainings showed that induced cyclooxygenase-2 expression in the brain exclusively occurred in endothelial cells, and quantitative PCR analysis on brain cells isolated by flow cytometry demonstrated that mPGES-1 is induced in endothelial cells and not in vascular wall macrophages. Similar analysis on liver cells showed induced expression in macrophages and not in endothelial cells, pointing at the distinct role for brain endothelial cells in PGE2 synthesis. These results identify the brain endothelial cells as the PGE2-producing cells critical for immune-induced fever.

  • 21.
    Eskilsson, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Mirrasekhian, Elahe
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Dufour, Sylvie
    Institute Curie, France.
    Schwaninger, Markus
    Medical University of Lubeck, Germany.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Immune-Induced Fever Is Mediated by IL-6 Receptors on Brain Endothelial Cells Coupled to STAT3-Dependent Induction of Brain Endothelial Prostaglandin Synthesis2014In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, no 48, p. 15957-15961Article in journal (Refereed)
    Abstract [en]

    The cytokine IL-6, which is released upon peripheral immune challenge, is critical for the febrile response, but the mechanism by which IL-6 is pyrogenic has remained obscure. Herewegenerated mice with deletion of themembranebound IL-6 receptor alpha (IL-6R alpha) onneural cells, on peripheral nerves, on fine sensory afferent fibers, and on brain endothelial cells, respectively, and examined its role for the febrile response to peripherally injected lipopolysaccharide. We show that IL-6R alpha on neural cells, peripheral nerves, and fine sensory afferents are dispensable for the lipopolysaccharide-induced fever, whereas IL-6R alpha in the brain endothelium plays an important role. Hence deletion of IL-6R alpha on brain endothelial cells strongly attenuated the febrile response, and also led to reduced induction of the prostaglandin synthesizing enzyme Cox-2 in the hypothalamus, the temperature-regulating center in the brain, as well as reduced expression of SOCS3, suggesting involvement of the STAT signaling pathway. Furthermore, deletion of STAT3 in the brain endothelium also resulted in attenuated fever. These data show that IL-6, when endogenously released during systemic inflammation, is pyrogenic by binding to IL-6R alpha on brain endothelial cells to induce prostaglandin synthesis in these cells, probably in concerted action with other peripherally released cytokines.

  • 22.
    Fieblinger, Tim
    et al.
    Lund University, Sweden .
    Sebastianutto, Irene
    Lund University, Sweden .
    Alcacer, Cristina
    Lund University, Sweden .
    Bimpisidis, Zisis
    Lund University, Sweden .
    Maslava, Natallia
    Lund University, Sweden .
    Sandberg, Sabina
    Lund University, Sweden .
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Cenci, M. Angela
    Lund University, Sweden .
    Mechanisms of Dopamine D1 Receptor-Mediated ERK1/2 Activation in the Parkinsonian Striatum and Their Modulation by Metabotropic Glutamate Receptor Type 52014In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, no 13, p. 4728-4740Article in journal (Refereed)
    Abstract [en]

    In animal models of Parkinsons disease, striatal overactivation of ERK1/2 via dopamine (DA) D1 receptors is the hallmark of a supersensitive molecular response associated with dyskinetic behaviors. Here we investigate the pathways involved in D1 receptor-dependent ERK1/2 activation using acute striatal slices from rodents with unilateral 6-hydroxydopamine (6-OHDA) lesions. Application of the dopamine D1-like receptor agonist SKF38393 induced ERK1/2 phosphorylation and downstream signaling in the DA-denervated but not the intact striatum. This response was mediated through a canonical D1R/PKA/MEK1/2 pathway and independent of ionotropic glutamate receptors but blocked by antagonists of L-type calcium channels. Coapplication of an antagonist of metabotropic glutamate receptor type 5 (mGluR5) or its downstream signaling molecules (PLC, PKC, IP3 receptors) markedly attenuated SKF38393-induced ERK1/2 activation. The role of striatal mGluR5 in D1-dependent ERK1/2 activation was confirmed in vivo in 6-OHDA-lesioned animals treated systemically with SKF38393. In one experiment, local infusion of the mGluR5 antagonistMTEPin the DA-denervated rat striatum attenuated the activation of ERK1/2 signaling by SKF38393. In another experiment, 6-OHDA lesions were applied to transgenic mice with a cell-specific knockdown of mGluR5 in D1 receptor-expressing neurons. These mice showed a blunted striatal ERK1/2 activation in response to SFK38393 treatment. Our results reveal that D1-dependent ERK1/2 activation in the DA-denervated striatum depends on a complex interaction between PKA-and Ca2+ -dependent signaling pathways that is critically modulated by striatal mGluR5.

  • 23.
    Fritz, Michael
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Klawonn, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Jaarola, Maarit
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Engblom, David
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience.
    Interferon-ɣ mediated signaling in the brain endothelium is critical for inflammation-induced aversion2018In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 67, p. 54-58Article in journal (Refereed)
    Abstract [en]

    Systemic inflammation elicits malaise and a negative affective state. The mechanism underpinning the aversive component of inflammation include cerebral prostaglandin synthesis and modulation of dopaminergic reward circuits, but the messengers that mediate the signaling between the peripheral inflammation and the brain have not been sufficiently characterized. Here we investigated the role of interferon-ɣ (IFN-ɣ) in the aversive response to systemic inflammation induced by a low dose (10μg/kg) of lipopolysaccharide (LPS) in mice. LPS induced IFN-ɣ expression in the blood and deletion of IFN-ɣ or its receptor prevented the development of conditioned place aversion to LPS. LPS induced expression of the chemokine Cxcl10 in the striatum of normal mice, but this induction was absent in mice lacking IFN-ɣ receptors or Myd88 in blood brain barrier endothelial cells. Furthermore, inflammation-induced aversion was blocked in mice lacking Cxcl10 or its receptor Cxcr3. Finally, mice with a selective deletion of the IFN-ɣ receptor in brain endothelial cells did not develop inflammation-induced aversion, demonstrating that the brain endothelium is the critical site of IFN-ɣ action. Collectively, these findings show that circulating IFN-ɣ that binds to receptors on brain endothelial cells and induces Cxcl10, is a central link in the signaling chain eliciting inflammation-induced aversion.

  • 24.
    Fritz, Michael
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Klawonn, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Nilsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Kumar Singh, Anand
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Zajdel, Joanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Wilhelms, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Emergency Medicine.
    Lazarus, Michael
    University of Tsukuba, Japan.
    Löfberg, Andreas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Jaarola, Maarit
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Örtegren Kugelberg, Unn
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Billiar, Timothy R.
    University of Pittsburgh, PA USA.
    Hackam, David J.
    Johns Hopkins University, MD USA.
    Sodhi, Chhinder P.
    Johns Hopkins University, MD USA.
    Breyer, Matthew D.
    Lilly Research Labs, IN USA.
    Jakobsson, Johan
    Lund University, Sweden; Lund University, Sweden.
    Schwaninger, Markus
    University of Lubeck, Germany.
    Schuetz, Gunther
    German Cancer Research Centre, Germany.
    Rodriguez Parkitna, Jan
    Polish Academic Science, Poland.
    Saper, Clifford B.
    Beth Israel Deaconess Medical Centre, MA 02215 USA; Harvard University, MA USA.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice2016In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 126, no 2, p. 695-705Article in journal (Refereed)
    Abstract [en]

    Systemic inflammation causes malaise and general feelings of discomfort. This fundamental aspect of the sickness response reduces the quality of life for people suffering from chronic inflammatory diseases and is a nuisance during mild infections like common colds or the flu. To investigate how inflammation is perceived as unpleasant and causes negative affect, we used a behavioral test in which mice avoid an environment that they have learned to associate with inflammation-induced discomfort. Using a combination of cell-type-specific gene deletions, pharmacology, and chemogenetics, we found that systemic inflammation triggered aversion through MyD88-dependent activation of the brain endothelium followed by COX1-mediated cerebral prostaglandin E-2 (PGE(2)) synthesis. Further, we showed that inflammation-induced PGE(2) targeted EP1 receptors on striatal dopamine D1 receptor-expressing neurons and that this signaling sequence induced aversion through GABA-mediated inhibition of dopaminergic cells. Finally, we demonstrated that inflammation-induced aversion was not an indirect consequence of fever or anorexia but that it constituted an independent inflammatory symptom triggered by a unique molecular mechanism. Collectively, these findings demonstrate that PGE(2)-mediated modulation of the dopaminergic motivational circuitry is a key mechanism underlying the negative affect induced by inflammation.

  • 25.
    Hagbom, Marie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Istrate, Claudia
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Karlsson, Thommie
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology.
    Rodriguez-Diaz, Jesus
    University of Valencia.
    Buesa, Javier
    University of Valencia.
    Taylor, John A
    University of Auckland.
    Loitto, Vesa
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Ahlman, Hakan
    University of Gothenburg.
    Lundgren, Ove
    University of Gothenburg.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Rotavirus Stimulates Release of Serotonin (5-HT) from Human Enterochromaffin Cells and Activates Brain Structures Involved in Nausea and Vomiting2011In: PLOS PATHOGENS, ISSN 1553-7366, Vol. 7, no 7Article in journal (Refereed)
    Abstract [en]

    otavirus (RV) is the major cause of severe gastroenteritis in young children. A virus-encoded enterotoxin, NSP4 is proposed to play a major role in causing RV diarrhoea but how RV can induce emesis, a hallmark of the illness, remains unresolved. In this study we have addressed the hypothesis that RV-induced secretion of serotonin (5-hydroxytryptamine, 5-HT) by enterochromaffin (EC) cells plays a key role in the emetic reflex during RV infection resulting in activation of vagal afferent nerves connected to nucleus of the solitary tract (NTS) and area postrema in the brain stem, structures associated with nausea and vomiting. Our experiments revealed that RV can infect and replicate in human EC tumor cells ex vivo and in vitro and are localized to both EC cells and infected enterocytes in the close vicinity of EC cells in the jejunum of infected mice. Purified NSP4, but not purified virus particles, evoked release of 5-HT within 60 minutes and increased the intracellular Ca(2+) concentration in a human midgut carcinoid EC cell line (GOT1) and ex vivo in human primary carcinoid EC cells concomitant with the release of 5-HT. Furthermore, NSP4 stimulated a modest production of inositol 1,4,5-triphosphate (IP(3)), but not of cAMP. RV infection in mice induced Fos expression in the NTS, as seen in animals which vomit after administration of chemotherapeutic drugs. The demonstration that RV can stimulate EC cells leads us to propose that RV disease includes participation of 5-HT, EC cells, the enteric nervous system and activation of vagal afferent nerves to brain structures associated with nausea and vomiting. This hypothesis is supported by treating vomiting in children with acute gastroenteritis with 5-HT(3) receptor antagonists.

  • 26. Jakobsson, Per-Johan
    et al.
    Engblom, David
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Ericsson-Dahlstrand, Anders
    Blomqvist, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Microsomal prostaglandin E synthase: A key enzyme in PGE2 biosynthesis and inflammation2002In: Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents, ISSN 1568-0142, E-ISSN 1875-6131, Vol. 1, p. 167-175Article in journal (Refereed)
  • 27.
    Karlsson, Camilla
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Schank, Jesse R.
    Department of Physiology and Pharmacology, University of Georgia, Athens, GA.
    Rehman, Faazal
    Laboratory of Clinical and Translational Studies, National Institute of Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD, USA.
    Stojakovic, Andrea
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Björk, Karl
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Barbier, Estelle
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Solomon, Matthew
    Laboratory of Clinical and Translational Studies, National Institute of Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD, USA.
    Tapocik, Jenica
    Laboratory of Clinical and Translational Studies, National Institute of Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD, USA.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Thorsell, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Proinflammatory signaling regulates voluntary alcohol intake and stress-induced consumption after exposure to social defeat stress in mice2017In: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 22, no 5, p. 1279-1288Article in journal (Refereed)
    Abstract [en]

    Proinflammatory activity has been postulated to play a role in addictive processes and stress responses, but the underlying mechanisms remain largely unknown. Here, we examined the role of interleukin 1 (IL-1) and tumor necrosis factor-a (TNF-a) in regulation of voluntary alcohol consumption, alcohol reward and stress-induced drinking. Mice with a deletion of the IL-1 receptor I gene (IL-1RI KO) exhibited modestly decreased alcohol consumption. However, IL-1RI deletion affected neither the rewarding properties of alcohol, measured by conditioned place preference (CPP), nor stress-induced drinking induced by social defeat stress. TNF-a signaling can compensate for phenotypic consequences of IL1-RI deletion. We therefore hypothesized that double deletion of both IL-1RI and TNF-1 receptors (TNF-1R) may reveal the role of these pathways in regulation of alcohol intake. Double KOs consumed significantly less alcohol than control mice over a range of alcohol concentrations. The combined deletion of TNF-1R and IL-1RI did not influence alcohol reward, but did prevent increased alcohol consumption resulting from exposure to repeated bouts of social defeat stress. Taken together, these data indicate that IL-1RI and TNF-1R contribute to regulation of stress-induced, negatively reinforced drinking perhaps through overlapping signaling events downstream of these receptors, while leaving rewarding properties of alcohol largely unaffected.

  • 28.
    Klawonn, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Fritz, Michael
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Nilsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Bonaventura, Jordi
    NIDA, MD USA.
    Shionoya, Kiseko
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Mirrasekhian, Elahe
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Karlsson, Urban
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Jaarola, Maarit
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Granseth, Björn
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Michaelides, Michael
    NIDA, MD USA; Johns Hopkins Sch Med, MD USA.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Motivational valence is determined by striatal melanocortin 4 receptors2018In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 128, no 7, p. 3160-3170Article in journal (Refereed)
    Abstract [en]

    It is critical for survival to assign positive or negative valence to salient stimuli in a correct manner. Accordingly, harmful stimuli and internal states characterized by perturbed homeostasis are accompanied by discomfort, unease, and aversion. Aversive signaling causes extensive suffering during chronic diseases, including inflammatory conditions, cancer, and depression. Here, we investigated the role of melanocortin 4 receptors (MC4Rs) in aversive processing using genetically modified mice and a behavioral test in which mice avoid an environment that they have learned to associate with aversive stimuli. In normal mice, robust aversions were induced by systemic inflammation, nausea, pain, and. opioid receptorinduced dysphoria. In sharp contrast, mice lacking MC4Rs displayed preference or indifference toward the aversive stimuli. The unusual flip from aversion to reward in mice lacking MC4Rs was dopamine dependent and associated with a change from decreased to increased activity of the dopamine system. The responses to aversive stimuli were normalized when MC4Rs were reexpressed on dopamine D1 receptor-expressing cells or in the striatum of mice otherwise lacking MC4Rs. Furthermore, activation of arcuate nucleus proopiomelanocortin neurons projecting to the ventral striatum increased the activity of striatal neurons in an MC4R-dependent manner and elicited aversion. Our findings demonstrate that melanocortin signaling through striatal MC4Rs is critical for assigning negative motivational valence to harmful stimuli.

  • 29.
    Lemberger, T.
    et al.
    German Cancer Research Center, Heidelberg, Germany, European Molecular Biology Organization, 69117 Heidelberg, Germany.
    Parkitna, J.R.
    German Cancer Research Center, Heidelberg, Germany.
    Chai, M.
    German Cancer Research Center, Heidelberg, Germany.
    Schutz, G.
    Schütz, G., German Cancer Research Center, Heidelberg, Germany, German Cancer Research Center, 69120 Heidelberg, Germany.
    Engblom, David
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    CREB has a context-dependent role in activity-regulated transcription and maintains neuronal cholesterol homeostasis2008In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 22, no 8, p. 2872-2879Article in journal (Refereed)
    Abstract [en]

    Induction of specific gene expression patterns in response to activity confers functional plasticity to neurons. A principal role in the regulation of these processes has been ascribed to the cAMP responsive element binding protein (CREB). Using genomewide expression profiling in mice lacking CREB in the forebrain, accompanied by deletion of the cAMP responsive element modulator gene (CREM), we here show that the role of these proteins in activity-induced gene expression is surprisingly selective and highly context dependent. Thus, only a very restricted subset of activity-induced genes (i.e., Gadd45b or Nr4a2) requires these proteins for their induction in the hippocampus after kainic acid administration, while they are required for most of the cocaine-induced expression changes in the striatum. Interestingly, in the absence of CREB, CREM is able to rescue activity-regulated transcription, which strengthens the notion of overlapping functions of the two proteins. In addition, we show that cholesterol metabolism is dysregulated in the brains of mutant mice, as reflected coordinated expression changes in genes involved in cholesterol synthesis and neuronal accumulation of cholesterol. These findings provide novel insights into the role of CREB and CREM in stimulus-dependent transcription and neuronal homeostasis. © FASEB.

  • 30.
    Mameli, Manuel
    et al.
    University of Geneva.
    Halbout, Briac
    Central Institute of Mental Health, Mannheim.
    Creton, Cyril
    University of Geneva.
    Engblom, David
    German Cancer Research Center.
    Rodriguez Parkitna, Jan
    German Cancer Research Center.
    Spanagel, Rainer
    Central Institute of Mental Health, Mannheim.
    Luescher, Christian
    University of Geneva.
    Cocaine-evoked synaptic plasticity: persistence in the VTA triggers adaptations in the NAc2009In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 12, no 8, p. 1036-U108Article in journal (Refereed)
    Abstract [en]

    Addictive drugs hijack mechanisms of learning and memory that normally underlie reinforcement of natural rewards and induce synaptic plasticity of glutamatergic transmission in the mesolimbic dopamine (DA) system. In the ventral tegmental area (VTA), a single exposure to cocaine efficiently triggers NMDA receptor-dependent synaptic plasticity in DA neurons, whereas plasticity in the nucleus accumbens (NAc) occurs only after repeated injections. Whether these two forms of plasticity are independent or hierarchically organized remains unknown. We combined ex vivo electrophysiology in acute brain slices with behavioral assays modeling drug relapse in mice and found that the duration of the cocaine-evoked synaptic plasticity in the VTA is gated by mGluR1. Overriding mGluR1 in vivo made the potentiation in the VTA persistent. This led to synaptic plasticity in the NAc, which contributes to cocaine-seeking behavior after protracted withdrawal. Impaired mGluR1 function in vulnerable individuals could represent a first step in the recruitment of the neuronal network that underlies drug addiction.

  • 31.
    Matsuwaki, Takashi
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. University of Tokyo, Japan.
    Shionoya, Kiseko
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Ihnatko, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Eskilsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Kakuta, Shigeru
    University of Tokyo, Japan.
    Dufour, Sylvie
    CNRS, France.
    Schwaninger, Markus
    University of Lubeck, Germany.
    Waisman, Ari
    Johannes Gutenberg University of Mainz, Germany.
    Mueller, Werner
    University of Manchester, England.
    Pinteaux, Emmanuel
    University of Manchester, England.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Involvement of interleukin-1 type 1 receptors in lipopolysaccharide-induced sickness responses2017In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 66, p. 165-176Article in journal (Refereed)
    Abstract [en]

    Sickness responses to lipopolysaccharide (LPS) were examined in mice with deletion of the interleukin (IL)-1 type 1 receptor (IL-1R1). IL-1R1 knockout (1(0) mice displayed intact anorexia and HPA-axis activation to intraperitoneally injected LPS (anorexia: 10 or 120 mu g/kg; HPA-axis: 120 mu g/kg), but showed attenuated but not extinguished fever (120 g/kg). Brain PGE2 synthesis was attenuated, but Cox-2 induction remained intact. Neither the tumor necrosis factor-alpha (TNF alpha) inhibitor etanercept nor the IL -6 receptor antibody tocilizumab abolished the LPS induced fever in IL -1R1 KO mice. Deletion of IL -1R1 specifically in brain endothelial cells attenuated the LPS induced fever, but only during the late, 3rd phase of fever, whereas deletion of IL-1R1 on neural cells or on peripheral nerves had little or no effect on the febrile response. We conclude that while IL-1 signaling is not critical for LPS induced anorexia or stress hormone release, IL-1R1, expressed on brain endothelial cells, contributes to the febrile response to LPS. However, also in the absence of IL-1R1, LPS evokes a febrile response, although this is attenuated. This remaining fever seems not to be mediated by IL-6 receptors or TNFa, but by some yet unidentified pyrogenic factor. 

  • 32.
    Mirrasekhian, Elahe
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Nilsson, Johan L. Å.
    Division of Clinical Chemistry and Pharmacology, Department of Laboratory Medicine, Lund University, Lund, Sweden.
    Shionoya, Kiseko
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Blomgren, Anders
    Division of Clinical Chemistry and Pharmacology, Department of Laboratory Medicine, Lund University, Lund, Sweden.
    Zygmunt, Peter M.
    Division of Clinical Chemistry and Pharmacology, Department of Laboratory Medicine, Lund University, S-221 85 Lund, Sweden.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Högestätt, Edward D.
    Division of Clinical Chemistry and Pharmacology, Department of Laboratory Medicine, Lund University, Lund, Sweden.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    The antipyretic effect of paracetamol occurs independent of transient receptor potential ankyrin 1–mediated hypothermia and is associated with prostaglandin inhibition in the brain2018In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860Article in journal (Refereed)
    Abstract [en]

    The mode of action of paracetamol (acetaminophen), which is widely used for treating pain and fever, has remained obscure, but may involve several distinct mechanisms, including cyclooxygenase inhibition and transient receptor potential ankyrin 1 (TRPA1) channel activation, the latter being recently associated with paracetamol?s propensity to elicit hypothermia at higher doses. Here, we examined whether the antipyretic effect of paracetamol was due to TRPA1 activation or cyclooxygenase inhibition. Treatment of wild-type and TRPA1 knockout mice rendered febrile by immune challenge with LPS with a dose of paracetamol that did not produce hypothermia (150 mg/kg) but is known to be analgetic, abolished fever in both genotypes. Paracetamol completely suppressed the LPS-induced elevation of prostaglandin E2 in the brain and also reduced the levels of several other prostanoids. The hypothermia induced by paracetamol was abolished in mice treated with the electrophile-scavenger N-acetyl cysteine. We conclude that paracetamol?s antipyretic effect in mice is dependent on inhibition of cyclooxygenase activity, including the formation of pyrogenic prostaglandin E2, whereas paracetamol-induced hypothermia likely is mediated by the activation of TRPA1 by electrophilic metabolites of paracetamol, similar to its analgesic effect in some experimental paradigms.?Mirrasekhian, E., Nilsson, J. L. Å., Shionoya, K., Blomgren, A., Zygmunt, P. M., Engblom, D., Högestätt, E. D., Blomqvist, A. The antipyretic effect of paracetamol occurs independent of transient receptor potential ankyrin 1?mediated hypothermia and is associated with prostaglandin inhibition in the brain.

  • 33.
    Mueller, Kristina M
    et al.
    Ludwig Boltzmann Institute for Cancer Research.
    Kornfeld, Jan-Wilhelm
    University of Cologne.
    Friedbichler, Katrin
    Ludwig Boltzmann Institute for Cancer Research.
    Blaas, Leander
    Ludwig Boltzmann Institute for Cancer Research.
    Egger, Gerda
    Medical University of Vienna.
    Esterbauer, Harald
    Medical University of Vienna.
    Hasselblatt, Peter
    Freiburg University Hospital.
    Schlederer, Michaela
    Ludwig Boltzmann Institute for Cancer Research.
    Haindl, Susanne
    Ludwig Boltzmann Institute for Cancer Research.
    Wagner, Kay-Uwe
    University of Nebraska Medical Centre.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Haemmerle, Guenter
    Institute for Molecular Bioscience, Graz.
    Kratky, Dagmar
    Medical University of Graz.
    Sexl, Veronika
    Vet University of Vienna.
    Kenner, Lukas
    Ludwig Boltzmann Institute for Cancer Research.
    Kozlov, Andrey V
    Ludwig Boltzmann Institute for Cancer Research.
    Terracciano, Luigi
    University of Basel Hospital.
    Zechner, Rudolf
    Institute for Molecular Bioscience, Graz.
    Schuetz, Guenther
    German Cancer Research Centre.
    Casanova, Emilio
    Ludwig Boltzmann Institute for Cancer Research.
    Pospisilik, J Andrew
    Max Planck Institute Immunobiology.
    Heim, Markus H
    University of Basel Hospital.
    Moriggl, Richard
    Ludwig Boltzmann Institute for Cancer Research.
    Impairment of Hepatic Growth Hormone and Glucocorticoid Receptor Signaling Causes Steatosis and Hepatocellular Carcinoma in Mice2011In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 54, no 4, p. 1398-1409Article in journal (Refereed)
    Abstract [en]

    Growth hormone (GH)-activated signal transducer and activator of transcription 5 (STAT5) and the glucocorticoid (GC)-responsive glucocorticoid receptor (GR) are important signal integrators in the liver during metabolic and physiologic stress. Their deregulation has been implicated in the development of metabolic liver diseases, such as steatosis and progression to fibrosis. Using liver-specific STAT5 and GR knockout mice, we addressed their role in metabolism and liver cancer onset. STAT5 single and STAT5/GR double mutants developed steatosis, but only double-mutant mice progressed to liver cancer. Mechanistically, STAT5 deficiency led to the up-regulation of prolipogenic sterol regulatory element binding protein 1 (SREBP-1) and peroxisome proliferator activated receptor gamma (PPAR-gamma) signaling. Combined loss of STAT5/GR resulted in GH resistance and hypercortisolism. The combination of both induced expression of adipose tissue lipases, adipose tissue lipid mobilization, and lipid flux to the liver, thereby aggravating STAT5-dependent steatosis. The metabolic dysfunctions in STAT5/GR compound knockout animals led to the development of hepatic dysplasia at 9 months of age. At 12 months, 35% of STAT5/GR-deficient livers harbored dysplastic nodules and similar to 60% hepatocellular carcinomas (HCCs). HCC development was associated with GH and insulin resistance, enhanced tumor necrosis factor alpha (TNF-alpha) expression, high reactive oxygen species levels, and augmented liver and DNA damage parameters. Moreover, activation of the c-Jun N-terminal kinase 1 (JNK1) and STAT3 was prominent. Conclusion: Hepatic STAT5/GR signaling is crucial for the maintenance of systemic lipid homeostasis. Impairment of both signaling cascades causes severe metabolic liver disease and promotes spontaneous hepatic tumorigenesis.

  • 34.
    Nilsson, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Elander, Louise
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Örtegren (Kugelberg), Unn
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    The involvement of prostaglandin E2 in interleukin-1β evoked anorexia is strain dependent2017In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 60, p. 27-31Article in journal (Refereed)
    Abstract [en]

    From experiments in mice in which the prostaglandin E2 (PGE2) synthesizing enzyme mPGES-1 was genetically deleted, as well as from experiments in which PGE2 was injected directly into the brain, PGE2 has been implicated as a mediator of inflammatory induced anorexia. Here we aimed at examining which PGE2 receptor (EP1–4) that was critical for the anorexic response to peripherally injected interleukin-1β (IL-1β). However, deletion of neither EP receptor in mice, either globally (for EP1, EP2, and EP3) or selectively in the nervous system (EP4), had any effect on the IL-1β induced anorexia. Because these mice were all on a C57BL/6 background, whereas previous observations demonstrating a role for induced PGE2 in IL-1β evoked anorexia had been carried out on mice on a DBA/1 background, we examined the anorexic response to IL-1β in mice with deletion of mPGES-1 on a C57BL/6 background and a DBA/1 background, respectively. We confirmed previous findings that mPGES-1 knock-out mice on a DBA/1 background displayed attenuated anorexia to IL-1β; however, mice on a C57BL/6 background showed the same profound anorexia as wild type mice when carrying deletion of mPGES-1, while displaying almost normal food intake after pretreatment with a cyclooxygenase-2 inhibitor. We conclude that the involvement of induced PGE2 in IL-1β evoked anorexia is strain dependent and we suggest that different routes that probably involve distinct prostanoids exist by which inflammatory stimuli may evoke an anorexic response and that these routes may be of different importance in different strains of mice.

  • 35.
    Nilsson, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Wilhelms, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Emergency Medicine.
    Mirrasekhian, Elahe
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Jaarola, Maarit
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Inflammation-induced anorexia and fever are elicited by distinct prostaglandin dependent mechanisms, whereas conditioned taste aversion is prostaglandin independent.2017In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 61, p. 236-243, article id S0889-1591(16)30549-9Article in journal (Refereed)
    Abstract [en]

    Systemic inflammation evokes an array of brain-mediated responses including fever, anorexia and taste aversion. Both fever and anorexia are prostaglandin dependent but it has been unclear if the cell-type that synthesizes the critical prostaglandins is the same. Here we show that pharmacological inhibition or genetic deletion of cyclooxygenase (COX)-2, but not of COX-1, attenuates inflammation-induced anorexia. Mice with deletions of COX-2 selectively in brain endothelial cells displayed attenuated fever, as demonstrated previously, but intact anorexia in response to peripherally injected lipopolysaccharide (10μg/kg). Whereas intracerebroventricular injection of a cyclooxygenase inhibitor markedly reduced anorexia, deletion of COX-2 selectively in neural cells, in myeloid cells or in both brain endothelial and neural cells had no effect on LPS-induced anorexia. In addition, COX-2 in myeloid and neural cells was dispensable for the fever response. Inflammation-induced conditioned taste aversion did not involve prostaglandin signaling at all. These findings collectively show that anorexia, fever and taste aversion are triggered by distinct routes of immune-to-brain signaling.

  • 36.
    Nilsson, Staffan
    et al.
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in the East of Östergötland, East County Primary Health Care.
    Scheike, Morten
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Karlsson, Lars-Göran
    Mölstad, Sigvard
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    Åkerlind, Ingemar
    Linköping University, Department of Medicine and Health Sciences, Health and Society. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in the West of Östergötland, Unit of Research and Development in Local Health Care, County of Östergötland.
    Örtoft, Kjell
    Nylander, Eva
    Linköping University, Department of Medicine and Health Sciences, Clinical Physiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Clinical Physiology.
    Chest pain and ischaemic heart disease in primary care2003In: British Journal of General Practice, ISSN 0960-1643, Vol. 53, no 490, p. 378-382Article in journal (Refereed)
    Abstract [en]

    Background: Chest pain is the main symptom of first presentation with ischaemic heart disease (IHD). Little is known about the incidence of IHD among patients consulting the general practitioner (GP) for chest pain.

    Aims: To estimate the occurrence of IHD among patients consulting for chest pain, to study the results of the bicycle exercise test, and to estimate the incidence of IHD in the population.

    Design of study: Prospective descriptive study.

    Setting: Three primary health centres in south-eastern Sweden

    Method: All patients without a current IHD diagnosis, aged 20 to 79 years, and consulting for a new episode of chest pain, were included consecutively. The outcome was classified as IHD, possible IHD or not IHD, according to the results of a postal questionnaire, an exercise test or hospital care. Data from the hospital registry on patients with a diagnosis of IHD were analysed retrospectively.

    Results: Out of 38 075 GP consultations, 577 (1.5%) were for chest pain. IHD was diagnosed in 41 (8%) of the chest pain patients, in 41 (83%) the diagnosis was excluded, and in 50 (9%) the diagnosis was judged as being uncertain. Even though the diagnostic criteria were strict, the exercise tests led to a diagnostic conclusion in 77% of the cases, most frequently a normal test result. Combining data from primary and hospital care, the yearly incidence of IHD was 6.5 diagnosed per 1000 inhabitants (aged 20 to 79 years old).

    Conclusion: The incidence of a new episode of chest pain bringing the patient to the GP was low. Eight per cent of the patients received an IHD diagnosis, and in 9% further investigation or clinical assessment is needed.

  • 37.
    Novak, Martin
    et al.
    German Cancer Research Centre.
    Halbout, Briac
    Central Institute for Mental Health, Mannheim.
    O'Connor, Eoin C
    University of Sussex.
    Rodriguez Parkitna, Jan
    German Cancer Research Centre.
    Su, Tian
    German Cancer Research Centre.
    Chai, Minqiang
    German Cancer Research Centre.
    Crombag, Hans S
    University of Sussex.
    Bilbao, Ainhoa
    Central Institute for Mental Health, Mannheim.
    Spanagel, Rainer
    Central Institute for Mental Health, Mannheim.
    Stephens, David N
    University of Sussex.
    Schutz, Gunther
    German Cancer Research Centre.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Incentive Learning Underlying Cocaine-Seeking Requires mGluR5 Receptors Located on Dopamine D1 Receptor-Expressing Neurons2010In: JOURNAL OF NEUROSCIENCE, ISSN 0270-6474, Vol. 30, no 36, p. 11973-11982Article in journal (Refereed)
    Abstract [en]

    Understanding the psychobiological basis of relapse remains a challenge in developing therapies for drug addiction. Relapse in cocaine addiction often occurs following exposure to environmental stimuli previously associated with drug taking. The metabotropic glutamate receptor, mGluR5, is potentially important in this respect; it plays a central role in several forms of striatal synaptic plasticity proposed to underpin associative learning and memory processes that enable drug-paired stimuli to acquire incentive motivational properties and trigger relapse. Using cell type-specific RNA interference, we have generated a novel mouse line with a selective knock-down of mGluR5 in dopamine D1 receptor-expressing neurons. Although mutant mice self-administer cocaine, we show that reinstatement of cocaine-seeking induced by a cocaine-paired stimulus is impaired. By examining different aspects of associative learning in the mutant mice, we identify deficits in specific incentive learning processes that enable a reward-paired stimulus to directly reinforce behavior and to become attractive, thus eliciting approach toward it. Our findings show that glutamate signaling through mGluR5 located on dopamine D1 receptor-expressing neurons is necessary for incentive learning processes that contribute to cue-induced reinstatement of cocaine-seeking and which may underpin relapse in drug addiction.

  • 38.
    Paues, Jakob
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Mackerlova, Ludmila
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Ericsson-Dahlstrand, Anders
    Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Feeding-related immune responsive brain stem neurons: association with CGRP2001In: Neuroreport, ISSN 0959-4965, Vol. 12, no 11, p. 2399-2403Article in journal (Refereed)
    Abstract [en]

    Using dual-labeling in situ hybridization histochemistry, the neurotransmitter expression of immune-responsive neurons in the pontine parabrachial nucleus, a major relay for interoceptive information, was investigated. Intravenous injection of bacterial wall lipopolysaccharide resulted in dense c-fos mRNA expression in the external lateral parabrachial nucleus, and a majority of the c-fos expressing cells also expressed calcitonin gene-related peptide (CGRP) mRNA. In contrast CGRP-posi- tive cells in the adjoining external medial subnucleus were c-fos negative. Taken together with previous hodological and behavioral studies, these data suggest that CGRPergic parabrachial neurons may mediate lipopolysaccharide-induced anorexia by means of their projection to central nucleus of the amygdala.

  • 39.
    Refojo, Damian
    et al.
    Max Planck Inst Psychiat, Munich, Germany.
    Schweizer, Martin
    Max Planck Inst Psychiat, Munich, Germany.
    Kuehne, Claudia
    Max Planck Inst Psychiat, Munich, Germany.
    Ehrenberg, Stefanie
    Max Planck Inst Psychiat, Munich, Germany.
    Thoeringer, Christoph
    Max Planck Inst Psychiat, Munich, Germany.
    Vogl, Annette M
    Max Planck Inst Psychiat, Munich, Germany.
    Dedic, Nina
    Max Planck Inst Psychiat, Munich, Germany.
    Schumacher, Marion
    Max Planck Inst Psychiat, Munich, Germany.
    von Wolff, Gregor
    Max Planck Inst Psychiat, Munich, Germany.
    Avrabos, Charilaos
    Max Planck Inst Psychiat, Munich, Germany.
    Touma, Chadi
    Max Planck Inst Psychiat, Munich, Germany.
    Engblom, David
    German Canc Res Ctr, Heidelberg, Germany.
    Schuetz, Guenther
    German Canc Res Ctr, Heidelberg, Germany.
    Nave, Klaus-Armin
    Max Planck Inst Expt Med, Gottingen, Germany.
    Eder, Matthias
    Max Planck Inst Psychiat, Munich, Germany.
    Wotjak, Carsten T
    Max Planck Inst Psychiat, Munich, Germany.
    Sillaber, Inge
    Max Planck Inst Psychiat, Munich, Germany.
    Holsboer, Florian
    Max Planck Inst Psychiat, Munich, Germany.
    Wurst, Wolfgang
    Max Planck Inst Psychiat, Munich, Germany.
    Deussing, Jan M
    Max Planck Inst Psychiat, Munich, Germany.
    Glutamatergic and Dopaminergic Neurons Mediate Anxiogenic and Anxiolytic Effects of CRHR12011In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 333, no 6051, p. 1903-1907Article in journal (Refereed)
    Abstract [en]

     The corticotropin-releasing hormone receptor 1 (CRHR1) critically controls behavioral adaptation to stress and is causally linked to emotional disorders. Using neurochemical and genetic tools, we determined that CRHR1 is expressed in forebrain glutamatergic and gamma-aminobutyric acid-containing (GABAergic) neurons as well as in midbrain dopaminergic neurons. Via specific CRHR1 deletions in glutamatergic, GABAergic, dopaminergic, and serotonergic cells, we found that the lack of CRHR1 in forebrain glutamatergic circuits reduces anxiety and impairs neurotransmission in the amygdala and hippocampus. Selective deletion of CRHR1 in midbrain dopaminergic neurons increases anxiety-like behavior and reduces dopamine release in the prefrontal cortex. These results define a bidirectional model for the role of CRHR1 in anxiety and suggest that an imbalance between CRHR1-controlled anxiogenic glutamatergic and anxiolytic dopaminergic systems might lead to emotional disorders.

  • 40.
    Richard, Sabine
    et al.
    Station de Recherches Avicoles, Institut National de la Recherche Agronomique, Nouzilly, France.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Paues, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Mackerlova, Ludmila
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Activation of the parabrachio-amygdaloid pathway by immune challenge or spinal nociceptive input: a quantitative study in the rat using Fos immunohistochemistry and retrograde tract tracing2005In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 481, no 2, p. 210-219Article in journal (Refereed)
    Abstract [en]

    Peripheral nociceptive stimulation results in activation of neurons in the pontine parabrachial nucleus (PB) of rats. Electrophysiological studies have suggested that noxiously activated PB neurons project to the amygdala, constituting a potential pathway for emotional aspects of pain. In the present study we examined this hypothesis by combining retrograde tract tracing with Fos immunohistochemistry. Cholera toxin subunit B was injected into the amygdala of rats. After a minimum of 48 hours the rats were given a subcutaneous injection of 100 l of 5% formalin into one hindpaw and killed 60-90 minutes later. A dense aggregation of retrogradely labeled neurons was seen in the external lateral PB. Fos-expressing neurons were present preferentially in the central, dorsal, and superior lateral subnuclei as well as in the lateral crescent area, as described previously. There was little overlap between the retrogradely labeled and Fos-expressing populations and double-labeled neurons were rare. In contrast, systemic immune challenge by intravenous injection of bacterial wall lipopolysaccharide resulted in a Fos expression that overlapped the retrograde labeling in the external lateral PB, and many double-labeled neurons were seen. While these data provide direct functional anatomical evidence that nociceptive information from the hindlimb is relayed to the amygdala via the parabrachial nucleus, the number of parabrachio-amygdaloid neurons involved is small. Considering the widespread activation of parabrachio-amygdaloid neurons by a variety of visceral and humoral stimuli, the parabrachio-amygdaloid pathway thus appears to be more involved in the mediation of information related to viscerally and humorally elicited activity than in transmission of spinal nociceptive inputs.

  • 41.
    Rieker, Claus
    et al.
    University of Heidelberg.
    Engblom, David
    University of Heidelberg.
    Kreiner, Grzegorz
    University of Heidelberg.
    Domanskyi, Andrii
    University of Heidelberg.
    Schober, Andreas
    University of Heidelberg.
    Stotz, Stefanie
    University of Heidelberg.
    Neumann, Manuela
    Universitätsspital Zürich, Switzerland .
    (Yuan, Xuejun
    University of Heidelberg.
    Grummt, Ingrid
    University of Heidelberg.
    Schuetz, Guenther
    University of Heidelberg.
    Parlato, Rosanna
    University of Heidelberg.
    Nucleolar Disruption in Dopaminergic Neurons Leads to Oxidative Damage and Parkinsonism through Repression of Mammalian Target of Rapamycin Signaling2011In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 31, no 2, p. 453-460Article in journal (Refereed)
    Abstract [en]

    The nucleolus represents an essential stress sensor for the cell. However, the molecular consequences of nucleolar damage and their possible link with neurodegenerative diseases remain to be elucidated. Here, we show that nucleolar damage is present in both genders in Parkinson's disease (PD) and in the pharmacological PD model induced by the neurotoxin 1,2,3,6-tetrahydro-1-methyl-4-phenylpyridine hydrochloride (MPTP). Mouse mutants with nucleolar disruption restricted to dopaminergic (DA) neurons show phenotypic alterations that resemble PD, such as progressive and differential loss of DA neurons and locomotor abnormalities. At the molecular level, nucleolar disruption results in increased p53 levels and downregulation of mammalian target of rapamycin (mTOR) activity, leading to mitochondrial dysfunction and increased oxidative stress, similar to PD. In turn, increased oxidative stress induced by MPTP causes mTOR and ribosomal RNA synthesis inhibition. Collectively, these observations suggest that the interplay between nucleolar dysfunction and increased oxidative stress, involving p53 and mTOR signaling, may constitute a destructive axis in experimental and sporadic PD.

  • 42.
    Rodriguez Parkitna, J
    et al.
    German Cancer Research Center, Heidelberg, Germany.
    Bilbao, A
    Central Institute of Mental Health,.
    Rieker, C
    German Cancer Research Center, Heidelberg, Germany.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Piechota, M
    Institute of Pharmacology of the Polish Academy of Sciences, Cracow, Poland.
    Nordheim, A
    Tübingen University, Tübingen, Germany.
    Spanagel, R
    Central Institute of Mental Health,.
    Schütz, G
    German Cancer Research Center, Heidelberg, Germany.
    Loss of the serum response factor in the dopaminesystem leads to hyperactivity2010In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 24, p. 2427-2435Article in journal (Refereed)
    Abstract [en]

    The serum response factor (SRF) is a key regulator of neural development and cellular plasticity, which enables it to act as a regulator of long-term adaptations in neurons. Here we performed a comprehensive analysis of SRF function in the murine dopamine system. We found that loss of SRF in dopaminoceptive, but not dopaminergic, neurons is responsible for the development of a hyperactivity syndrome, characterized by reduced body weight into adulthood, enhanced motor activity, and deficits in habituation processes. Most important, the hyperactivity also develops when the ablation of SRF is induced in adult animals. On the molecular level, the loss of SRF in dopaminoceptive cells is associated with altered expression of neuronal plasticity-related genes, in particular transcripts involved in calcium ion binding, formation of the cytoskeleton, and transcripts encoding neuropeptide precursors. Furthermore, abrogation of SRF causes specific deficits in activity-dependent transcription, especially a complete lack of psychostimulant-induced expression of the Egr   genes. We inferred that alterations in SRFdependent  gene expression underlie the observed hyperactive behavior. Thus, SRF depletion in dopaminoceptive neurons might trigger molecular mechanisms responsible for development of psychopathological conditions involving hyperactivity.

  • 43.
    Rodriguez Parkitna, Jan
    et al.
    Polish Academy of Science.
    Bilbao, Ainhoa
    Central Institute of Mental Health, Mannheim, Germany .
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Solecki, Wojciech
    Polish Academy of Science.
    Sprengel, Rolf
    Max Planck Institute Med Research.
    Spanagel, Rainer
    Central Institute of Mental Health, Mannheim, Germany .
    Schuetz, Guenther
    German Cancer Research Centre.
    Przewlocki, Ryszard
    Polish Academy of Science.
    Changes in glutamate-catecholamine interactions underlie persistence of drug-conditioned behaviors in PHARMACOLOGICAL REPORTS, vol 62, issue , pp 9-102010In: PHARMACOLOGICAL REPORTS, Institute of Pharmcology Polish Academy of Sciences / Inst. of Pharmacology, Polish Acad. of Sciences , 2010, Vol. 62, p. 9-10Conference paper (Refereed)
    Abstract [en]

    n/a

  • 44.
    Rodriguez Parkitna, Jan
    et al.
    Polish Academic Science, Poland .
    Sikora, Magdalena
    Polish Academic Science, Poland .
    Golda, Slawomir
    Polish Academic Science, Poland .
    Golembiowska, Krystyna
    Polish Academic Science, Poland .
    Bystrowska, Beata
    Jagiellonian University, Poland .
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Bilbao, Ainhoa
    Heidelberg University, Germany .
    Przewlocki, Ryszard
    Polish Academic Science, Poland .
    Novelty-Seeking Behaviors and the Escalation of Alcohol Drinking After Abstinence in Mice Are Controlled by Metabotropic Glutamate Receptor 5 on Neurons Expressing Dopamine D1 Receptors2013In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 73, no 3, p. 263-270Article in journal (Refereed)
    Abstract [en]

    Background: Novel experiences activate the brains reward system in a manner similar to drugs of abuse, and high levels of novelty-seeking and sensation-seeking behavior have been associated with increased susceptibility to alcohol and drug abuse. Here, we show that metabotropic glutamate receptor 5 (mGluR5) signaling on dopaminoceptive neurons is necessary for both novelty-seeking behavior and the abstinence-induced escalation of alcohol drinking. less thanbrgreater than less thanbrgreater thanMethods: Mice harboring a transgene expressing microRNA hairpins against mGluR5 messenger RNA under the control of the D1 dopamine receptor gene promoter (mGluR5KD-D1) were tested in a battery of behavioral tests measuring learning abilities, anxiety levels, reactions to novelty, operant sensation seeking, and alcohol sensitivity. In addition, we have developed a method to assess long-term patterns of alcohol drinking in mice housed in groups using the IntelliCage system. less thanbrgreater than less thanbrgreater thanResults: mGluR5KD-D1 mice showed no behavioral deficits and exhibited normal anxiety-like behaviors and learning abilities. However, mGluR5KD-D1 animals showed reduced locomotor activity when placed in a novel environment, and exhibited decreased interaction with a novel object. Moreover, unlike control animals, mutant mice did not perform instrumental responses under the operant sensation-seeking paradigm, although they learned to respond for food normally. When mGluR5KD-D1 mice were provided access to alcohol, they showed similar patterns of consumption as wild-type animals. However, mutant mice did not escalate their alcohol consumption after a period of forced abstinence, but control mice almost doubled their intake. less thanbrgreater than less thanbrgreater thanConclusions: These data identify mGluR5 receptors on D1-expressing neurons as a common molecular substrate of novelty-seeking behaviors and behaviors associated with alcohol abuse.

  • 45.
    Ruud, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Backhed, Fredrik
    University of Gothenburg.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Deletion of the gene encoding MyD88 protects from anorexia in a mouse tumor model2010In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 24, no 4, p. 554-557Article in journal (Refereed)
    Abstract [en]

    The anorexia-cachexia syndrome, characterized by a rise in energy expenditure and loss of body weight that paradoxically are associated with loss of appetite and decreased food intake, contributes significantly to the morbidity and mortality in cancer. While the pathophysiology of cancer anorexia-cachexia is poorly understood, evidence indicates that pro-inflammatory cytokines are key mediators of this response. Although inflammation hence is recognized as an important component of cancer anorexia-cachexia, the molecular pathways involved are largely unknown. We addressed this issue in mice carrying a deletion of the gene encoding MyD88, the key intracellular adaptor molecule in Toll-like and interleukin-1 family receptor signaling. Wild-type and MyD88-deficient mice were transplanted subcutaneously with a syngenic methylcholanthrene-induced tumor (MCG 101) and daily food intake and body weight were recorded. Wild-type mice showed progressively reduced food intake from about 5 days after tumor transplantation and displayed a slight body weight loss after 10 days when the experiment was terminated. In contrast, MyD88-deficient mice did not develop anorexia, and displayed a positive body weight development during the observation period. While the MyD88-deficient mice on average developed somewhat smaller tumors than wild-type mice, this did not explain the absence of anorexia, because anorexia was seen in wild-type mice with similar tumor mass as non-anorexic knock-out mice. These data suggest that MyD88-dependent mechanisms are involved in the metabolic derangement during cancer anorexia-cachexia and that innate immune signaling is important for the development of this syndrome.

  • 46.
    Ruud, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Björk, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Nilsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Eskilsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Tang, Yan-juan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Stroehle, Peter
    University of Cologne, Germany Max Planck Institute Neurol Research, Germany .
    Caesar, Robert
    University of Gothenburg, Sweden .
    Schwaninger, Markus
    Medical University of Lubeck, Germany .
    Wunderlich, Thomas
    University of Cologne, Germany Max Planck Institute Neurol Research, Germany .
    Backhed, Fredrik
    University of Gothenburg, Sweden .
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Inflammation- and tumor-induced anorexia and weight loss require MyD88 in hematopoietic/myeloid cells but not in brain endothelial or neural cells2013In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 27, no 5, p. 1973-1980Article in journal (Refereed)
    Abstract [en]

    Loss of appetite is a hallmark of inflammatory diseases. The underlying mechanisms remain undefined, but it is known that myeloid differentiation primary response gene 88 (MyD88), an adaptor protein critical for Toll-like and IL-1 receptor family signaling, is involved. Here we addressed the question of determining in which cells the MyD88 signaling that results in anorexia development occurs by using chimeric mice and animals with cell-specific deletions. We found that MyD88-knockout mice, which are resistant to bacterial lipopolysaccharide (LPS)-induced anorexia, displayed anorexia when transplanted with wild-type bone marrow cells. Furthermore, mice with a targeted deletion of MyD88 in hematopoietic or myeloid cells were largely protected against LPS-induced anorexia and displayed attenuated weight loss, whereas mice with MyD88 deletion in hepatocytes or in neural cells or the cerebrovascular endothelium developed anorexia and weight loss of similar magnitude as wild-type mice. Furthermore, in a model for cancer-induced anorexia-cachexia, deletion of MyD88 in hematopoietic cells attenuated the anorexia and protected against body weight loss. These findings demonstrate that MyD88-dependent signaling within the brain is not required for eliciting inflammation-induced anorexia. Instead, we identify MyD88 signaling in hematopoietic/myeloid cells as a critical component for acute inflammatory-driven anorexia, as well as for chronic anorexia and weight loss associated with malignant disease.

  • 47.
    Ruud, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Björk Wilhelms, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Nilsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Eskilsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Yan-Juan, Tang
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Bäckhed, Fredrik
    Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Lundholm, Kent
    Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    MyD88 in hematopoietic cells, but not in cerebrovascular endothelial cells or neural cells, is critical for inflammation- and cancer-induced loss of appetiteManuscript (preprint) (Other academic)
    Abstract [en]

    Loss of appetite concomitant with reduced food intake is a hallmark of both acute and chronic inflammatory diseases. Yet, despite extensive investigations, the underlying mechanisms remain undefined. Here we addressed this issue using mice lacking MyD88, critical for Tolllike and IL-1 receptor family signaling, generally or in specific cell types. Ubiquitous null deletions conferred complete resistance to bacterial lipopolysaccharide (LPS) induced anorexia, but this resistance was lost when knock-out mice subjected to whole-body irradiation to delete hematopoietic cells were transplanted with wild-type bone-marrow. In line with this observation, mice lacking MyD88 in hematopoietic cells were largely protected against LPS-induced anorexia, whereas mice with abrogated MyD88 signaling in neural cells, being leaner and smaller, developed anorexia of similar magnitude as wild-type littermates. The effect of hematopoietic MyD88-deletion on feeding seemed however partially dissociated from the effect on body weight, since LPS triggered weight loss, although attenuated, in these mutants. Furthermore, MyD88 deficiency in the cerebrovascular endothelium affected neither LPS-induced anorexia nor weight loss. In a model for the cancer anorexia-cachexia syndrome, inactivation of MyD88 in hematopoietic cells strongly impaired the anorexia development and protected against body weight loss. These findings identify hematopoietic cells as a critical nexus for acute inflammatory driven anorexia as well as for chronic anorexia associated with malignant disease.

  • 48.
    Ruud, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Nilsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Engström, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Wang, Wenhua
    Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Nilsberth, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Iresjö, Britt-Marie
    Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Lundholm, Kent
    Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    A putative role for Cox-1 in the initiation of cancer anorexia independent of mPGES-1, PGE2 and neuronal EP4 receptorsManuscript (preprint) (Other academic)
    Abstract [en]

    It is well-established that prostaglandins (PGs) affect tumorigenesis, and evidence indicates that PGs also are important for the reduced food intake and body weight loss, the so called anorexia-cachexia syndrome, in malignant cancer. However, the identity of the PG and the cyclooxygenase (Cox) species responsible for cancer anorexia-cachexia is unknown. Here, we addressed this issue by transplanting mice with a tumor that elicits anorexia. Meal pattern analysis revealed that the reduced food intake in the tumor-bearing animals was due to decreased meal frequency. Treatment with a nonselective Cox inhibitor attenuated the anorexia, and also tumor growth. However, when given at manifest anorexia, the nonselective Cox inhibitors restored appetite and prevented body weight loss without affecting tumor size. Despite the pronounced effect of nonselective Cox-inhibitors, a selective Cox-2 inhibitor had no effect on the anorexia, whereas Cox-1 inhibition delayed its onset. Tumor growth was associated with robust increase of PGE2 levels in plasma - a response blocked by nonselective Cox-inhibition - but not in the cerebrospinal fluid, and there was no rise in body temperature. Neutralization of PGE2 with specific antibodies did not ameliorate the anorexia, and genetic deletion of microsomal PGE synthase-1 (mPGES-1), the inducible terminal isomerase for PGE2 synthesis, affected neither anorexia nor tumor growth. Furthermore, tumor-bearing mice lacking EP4 receptors selectively in the nervous system developed anorexia. These observations suggest that Cox-enzymes, most likely Cox-1, are involved in cancer-elicited anorexia and weight loss, but that these phenomena occur independently of host mPGES-1, PGE2 and neuronal EP4 signaling.

  • 49.
    Ruud, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Nilsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Engström Ruud, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Wang, Wenhua
    Sahlgrens University Hospital, Sweden .
    Nilsberth, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Iresjo, Britt-Marie
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Lundholm, Kent
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Cancer-induced anorexia in tumor-bearing mice is dependent on cyclooxygenase-12013In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 29, p. 124-135Article in journal (Refereed)
    Abstract [en]

    It is well-established that prostaglandins (PGs) affect tumorigenesis, and evidence indicates that PGs also are important for the reduced food intake and body weight loss, the anorexia–cachexia syndrome, in malignant cancer. However, the identity of the PGs and the PG producing cyclooxygenase (COX) species responsible for cancer anorexia–cachexia is unknown. Here, we addressed this issue by transplanting mice with a tumor that elicits anorexia. Meal pattern analysis revealed that the anorexia in the tumor-bearing mice was due to decreased meal frequency. Treatment with a non-selective COX inhibitor attenuated the anorexia, and also tumor growth. When given at manifest anorexia, non-selective COX-inhibitors restored appetite and prevented body weight loss without affecting tumor size. Despite COX-2 induction in the cerebral blood vessels of tumor-bearing mice, a selective COX-2 inhibitor had no effect on the anorexia, whereas selective COX-1 inhibition delayed its onset. Tumor growth was associated with robust increase of PGE2 levels in plasma – a response blocked both by non-selective COX-inhibition and by selective COX-1 inhibition, but not by COX-2 inhibition. However, there was no increase in PGE2-levels in the cerebrospinal fluid. Neutralization of plasma PGE2 with specific antibodies did not ameliorate the anorexia, and genetic deletion of microsomal PGE synthase-1 (mPGES-1) affected neither anorexia nor tumor growth. Furthermore, tumor-bearing mice lacking EP4 receptors selectively in the nervous system developed anorexia. These observations suggest that COX-enzymes, most likely COX-1, are involved in cancer-elicited anorexia and weight loss, but that these phenomena occur independently of host mPGES-1, PGE2 and neuronal EP4 signaling.

  • 50.
    Sikora, M.
    et al.
    Polish Academy of Science.
    Solecki, W.
    Polish Academy of Science.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Rodriguez Parkitna, J.
    Polish Academy of Science.
    Selective ablation of mGluR5 receptors on dopamine D1-expressing neurons abolishes novelty-seeking behaviours in EUROPEAN NEUROPSYCHOPHARMACOLOGY, vol 21, issue , pp S300-S3012011In: EUROPEAN NEUROPSYCHOPHARMACOLOGY, Elsevier , 2011, Vol. 21, p. S300-S301Conference paper (Refereed)
    Abstract [en]

    n/a

12 1 - 50 of 55
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