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  • 1.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Nordenankar, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Arvidsson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Birgner, Carolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Mahmoudi, Souha
    Halbout, Briac
    Smith, Casey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Fortin, Guillaume M.
    Olson, Lars
    Descarries, Laurent
    Trudeau, Louis-Eric
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Levesque, Daniel
    Wallén-Mackenzie, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Enhanced Sucrose and Cocaine Self-Administration and Cue-Induced Drug Seeking after Loss of VGLUT2 in Midbrain Dopamine Neurons in Mice2011In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 31, no 35, p. 12593-12603Article in journal (Refereed)
    Abstract [en]

    The mesostriatal dopamine (DA) system contributes to several aspects of responses to rewarding substances and is implicated in conditions such as drug addiction and eating disorders. A subset of DA neurons has been shown to express the type 2 Vesicular glutamate transporter (Vglut2) and may therefore corelease glutamate. In the present study, we analyzed mice with a conditional deletion of Vglut2 in DA neurons (Vglut2(f/f;DAT-Cre)) to address the functional significance of the glutamate-DA cophenotype for responses to cocaine and food reinforcement. Biochemical parameters of striatal DA function were also examined by using DA receptor autoradiography, immediate-early gene quantitative in situ hybridization after cocaine challenge, and DA-selective in vivo chronoamperometry. Mice in which Vglut2 expression had been abrogated in DA neurons displayed enhanced operant self-administration of both high-sucrose food and intravenous cocaine. Furthermore, cocaine seeking maintained by drug-paired cues was increased by 76%, showing that reward-dependent plasticity is perturbed in these mice. In addition, several lines of evidence suggest that adaptive changes occurred in both the ventral and dorsal striatum in the absence of VGLUT2: DA receptor binding was increased, and basal mRNA levels of the DA-induced early genes Nur77 and c-fos were elevated as after cocaine induction. Furthermore, in vivo challenge of the DA system by potassium-evoked depolarization revealed less DA release in both striatal areas. This study demonstrates that absence of VGLUT2 in DA neurons leads to perturbations of reward consumption as well as reward-associated memory, features of particular relevance for addictive-like behavior.

  • 2. Andersson, Lisa S.
    et al.
    Larhammar, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Memic, Fatima
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Wootz, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Schwochow, Doreen
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Patra, Kalicharan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Arnason, Thorvaldur
    Wellbring, Lisbeth
    Hjälm, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Imsland, Freyja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Petersen, Jessica L.
    McCue, Molly E.
    Mickelson, James R.
    Cothran, Gus
    Ahituv, Nadav
    Roepstorff, Lars
    Mikko, Sofia
    Vallstedt, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Lindgren, Gabriella
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Mutations in DMRT3 affect locomotion in horses and spinal circuit function in mice2012In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 488, no 7413, p. 642-646Article in journal (Refereed)
    Abstract [en]

    Locomotion in mammals relies on a central pattern-generating circuitry of spinal interneurons established during development that coordinates limb movement(1). These networks produce left-right alternation of limbs as well as coordinated activation of flexor and extensor muscles(2). Here we show that a premature stop codon in the DMRT3 gene has a major effect on the pattern of locomotion in horses. The mutation is permissive for the ability to perform alternate gaits and has a favourable effect on harness racing performance. Examination of wild-type and Dmrt3-null mice demonstrates that Dmrt3 is expressed in the dI6 subdivision of spinal cord neurons, takes part in neuronal specification within this subdivision, and is critical for the normal development of a coordinated locomotor network controlling limb movements. Our discovery positions Dmrt3 in a pivotal role for configuring the spinal circuits controlling stride in vertebrates. The DMRT3 mutation has had a major effect on the diversification of the domestic horse, as the altered gait characteristics of a number of breeds apparently require this mutation.

  • 3.
    Aresh, Bejan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Functional Aspects of Peripheral and Spinal Cord Neurons Involved in Itch and Pain2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    We have investigated the role of the metabotropic glutamate receptor 7 (mGluR7) and the gastrin releasing peptide receptor (Grpr) population that are involved at different levels of itch transmission. We found that mGuR7 deficient mice displayed an anaphylaxis-like behavior when provoked with histamine. Analysis of blood revealed elevated plasma levels of histamine and mouse mast cell protease-1 (mMCP1), two indicators of anaphylaxis, in mGluR7 deficient mice compared with control mice. Inhibition of the neurokinin 1 receptor, by preventing binding of the corresponding ligand substance P (SP), prior to provocation with histamine prevented the development of anaphylaxis in mGluR7 deficient animals. However, blocking GRPR (gastrin releasing peptide receptor) only resulted in decreased itch levels in mGluR7 deficient mice but did not prevent the systemic anaphylaxis-like behavior. Our findings indicate that mGluR7 normally functions as a brake on histaminergic itch that is mediated through GRPR as well as anaphylaxis through Substance P.

    Grpr has previously been shown to mediate both histaminergic and non-histaminergic itch but little is known about the GRPR neuronal population. We used a BAC cloning strategy to construct a Grpr-Cre line, which we crossed with the reporter lines tdTomato and Viaat-egfp as well as with Vglut2-lox. We could conclude that Grpr-Cre neurons are mainly excitatory interneurons located in lamina II-IV, that convey itch using VGLUT2-mediated glutamatergic transmission to the next, currently unknown, step in the labeled line of chemical itch.

    To eventually deduce the function of the endogenous opioids dynorphin and enkephalin, which are hypothesized to be involved in gating pain and itch in the spinal cord, we constructed two Cre lines using BAC cloning that targeted the precursor proteins preprodynorphin and preproenkephalin, respectively. Preprodynorphin-Cre neurons were mainly located in lamina II-IV and overlapped to 47% with Vglut2 mRNA, while the co-expression with the inhibitory markers Viaat-egfp and PAX2 was 13% and 28% respectively in the spinal cord. Preproenkephalin neurons were more localized to lamina III in the dorsal horn, furthermore single cell analysis showed that they overlapped to 94% with Vglut2 mRNA while 7% and 13% expressed Viaat-egfp and PAX2 respectively.

    List of papers
    1. Identification of a Neuronal Receptor Controlling Anaphylaxis
    Open this publication in new window or tab >>Identification of a Neuronal Receptor Controlling Anaphylaxis
    Show others...
    2016 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 14, no 2, p. 370-379Article in journal (Refereed) Published
    Abstract [en]

    Allergic reactions can in severe cases induce a state of circulatory shock referred to as anaphylaxis. Histamine, the primary mediator of this condition, is released from immune cells, and, therefore, anaphylaxis has so far been considered an immune system disorder. However, we here show that the glutamatergic receptor mGluR7, expressed on a subpopulation of both peripheral and spinal cord neurons, controls histamine-induced communication through calcium-dependent autoinhibition with implications for anaphylaxis. Genetic ablation of mGluR7, and thus altered regulation of histamine-sensing neurons, caused an anaphylaxis-like state in mGluR7(-/-) mice, which could be reversed by antagonizing signaling between neurons and mast cells but not by antagonizing a central itch pathway. Our findings demonstrate the vital role of nervous system control by mGluR7 in anaphylaxis and open up possibilities for preventive strategies for this life-threatening condition.

    National Category
    Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-272637 (URN)10.1016/j.celrep.2015.12.033 (DOI)000368101600019 ()26748715 (PubMedID)
    Funder
    Swedish Research CouncilRagnar Söderbergs stiftelseKnut and Alice Wallenberg FoundationÅke Wiberg FoundationMagnus Bergvall FoundationThe Royal Swedish Academy of Sciences
    Available from: 2016-01-15 Created: 2016-01-15 Last updated: 2018-01-10Bibliographically approved
    2. Spinal Cord Interneurons Expressing the Gastrin-Releasing Peptide Receptor Convey Itch Through VGLUT2-Mediated Signaling
    Open this publication in new window or tab >>Spinal Cord Interneurons Expressing the Gastrin-Releasing Peptide Receptor Convey Itch Through VGLUT2-Mediated Signaling
    Show others...
    2017 (English)In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 158, no 5, p. 945-961Article in journal (Refereed) Published
    Abstract [en]

    Itch is a sensation that promotes the desire to scratch, which can be evoked by mechanical and chemical stimuli. In the spinal cord, neurons expressing the gastrin-releasing peptide receptor (GRPR) have been identified as specific mediators of itch. However, our understanding of the GRPR population in the spinal cord, and thus how these neurons exercise their functions, is limited. For this purpose, we constructed a Cre line designed to target the GRPR population of neurons (Grpr-Cre). Our analysis revealed that Grpr-Cre cells in the spinal cord are predominantly excitatory interneurons that are found in the dorsal lamina, especially in laminae II-IV. Application of the specific agonist gastrin-releasing peptide induced spike responses in 43.3% of the patched Grpr-Cre neurons, where the majority of the cells displayed a tonic firing property. Additionally, our analysis showed that the Grpr-Cre population expresses Vglut2 mRNA, and mice ablated of Vglut2 in Grpr-Cre cells (Vglut2-lox; Grpr-Cre mice) displayed less spontaneous itch and attenuated responses to both histaminergic and nonhistaminergic agents. We could also show that application of the itch-inducing peptide, natriuretic polypeptide B, induces calcium influx in a subpopulation of Grpr-Cre neurons. To summarize, our data indicate that the Grpr-Cre spinal cord neural population is composed of interneurons that use VGLUT2-mediated signaling for transmitting chemical and spontaneous itch stimuli to the next, currently unknown, neurons in the labeled line of itch.

    Keywords
    Itch, Gastrin-releasing peptide receptor population, Natriuretic polypeptide B, Spinal cord, Vesicular glutamate transporter 2, Neuronal networks, Labeled line of itch, Electrophysiology, Conditional knockout analysis, Tracing, Calcium imaging, Grpr, VGLUT2
    National Category
    Medical and Health Sciences
    Research subject
    Medical Science
    Identifiers
    urn:nbn:se:uu:diva-284058 (URN)10.1097/j.pain.0000000000000861 (DOI)000402430600021 ()28157737 (PubMedID)
    Funder
    Swedish Research CouncilThe Swedish Brain FoundationThe Royal Swedish Academy of SciencesRagnar Söderbergs stiftelseMagnus Bergvall FoundationGunvor och Josef Anérs stiftelse
    Note

    Title in thesis list of papers: Spinal Cord Interneurons Expressing the Gastrin Releasing Peptide Receptor Convey Itch through VGLUT2-mediated Signaling

    Available from: 2016-04-14 Created: 2016-04-14 Last updated: 2017-07-10Bibliographically approved
    3. Characterization of preprodynorphin-expressing cells in the mouse nervous system
    Open this publication in new window or tab >>Characterization of preprodynorphin-expressing cells in the mouse nervous system
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Dynorphin is an endogenous opioid that has been implicated in maintaining chronic pain and gating of both itch and acute mechanical pain through acting on both opioid and non-opioid receptors. To improve our understanding of the complex and multifunctional population that expresses dynorphin, we have constructed a preprodynorphin Cre line (Pdyn-Cre) using BAC cloning. Single cell analysis of tdTomato;Pdyn-Cre cells revealed that 43% of the population expressed Pdyn mRNA, and no analyzed tdTomato;Pdyn-Cre negative cell expressed Pdyn mRNA, thus confirming that Cre had been inserted under the control of the Pdyn promoter. The Pdyn-Cre expressing population was found in the dorsal spinal cord, mainly in lamina II-IV and overlapped to 47% with Vglut2 mRNA, while co-expression with the inhibitory markers Viaat-egfp and Pax2 was 13% and 28%, respectively. The expression of Pdyn-Cre in the brain was extensive, marking virtually all cortical structures, including somatosensory and motor cortex. Furthermore, Pdyn-Cre was densely expressed in the striatum, amygdala and parts of the hippocampus, and expression was also observed in several pain and itch processing areas, including amygdala, lateral parabrachial nucleus, claustrum, insular cortex and raphe magnus nucleus. Our analysis indicates that the transgenic Pdyn-Cre line includes PDYN cells in the nervous system and will thus be useful as a transgenic tool for studies of the role and connectivity of the PDYN population.

    Keywords
    Preprodynorphin, characterization
    National Category
    Medical and Health Sciences
    Research subject
    Medical Science
    Identifiers
    urn:nbn:se:uu:diva-284066 (URN)
    Available from: 2016-04-14 Created: 2016-04-14 Last updated: 2016-06-01Bibliographically approved
    4. Characterization of preproenkephalin expressing neurons in the nervous system using a transgenic line
    Open this publication in new window or tab >>Characterization of preproenkephalin expressing neurons in the nervous system using a transgenic line
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Here we have constructed a Cre line to target preproenkephalin expressing cells (Penk-Cre) using a BAC cloning strategy. By crossing our Penk-Cre line with the tdTomato reporter, tdTomato;Penk-Cre expressing cells could be visualized. Penk-Cre was expressed throughout the dorsal spinal cord, where approximately 50% of the neurons were residing within lamina III. Furthermore, single-cell analysis of spinal Penk-Cre expressing cells showed that 41% was positive for Penk mRNA and that a majority (94%) of the population expressed Vglut2 mRNA. Immunohistochemical analysis showed that only 7% and 13% expressed the inhibitory markers Viaat-egfp and Pax2, respectively, hence identifying spinal Penk-Cre expressing neurons as mainly excitatory. The expression of Penk-Cre in the brain was extensive, including dense expression in the striatum, nucleus accumbens and several amygdaloid nuclei. Furthermore, Penk-Cre expression was also shown in insular cortex, cingulated cortex, primary and secondary somatosensory cortices and the trigeminal nuclei. The Penk-Cre line represents a useful genetic tool for future analysis of PENK expressing neurons in the nervous system.

     

    Keywords
    characterization, Cre, preproenkephalin, Penk
    National Category
    Medical and Health Sciences
    Research subject
    Medical Science
    Identifiers
    urn:nbn:se:uu:diva-284068 (URN)
    Available from: 2016-04-14 Created: 2016-04-14 Last updated: 2016-06-01Bibliographically approved
  • 4.
    Aresh, Bejan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Freitag, Fabio B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Perry, Sharn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Blümel, Edda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Lau, Joey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Franck, Marina C.M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Lagerström, Malin C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Spinal Cord Interneurons Expressing the Gastrin-Releasing Peptide Receptor Convey Itch Through VGLUT2-Mediated Signaling2017In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 158, no 5, p. 945-961Article in journal (Refereed)
    Abstract [en]

    Itch is a sensation that promotes the desire to scratch, which can be evoked by mechanical and chemical stimuli. In the spinal cord, neurons expressing the gastrin-releasing peptide receptor (GRPR) have been identified as specific mediators of itch. However, our understanding of the GRPR population in the spinal cord, and thus how these neurons exercise their functions, is limited. For this purpose, we constructed a Cre line designed to target the GRPR population of neurons (Grpr-Cre). Our analysis revealed that Grpr-Cre cells in the spinal cord are predominantly excitatory interneurons that are found in the dorsal lamina, especially in laminae II-IV. Application of the specific agonist gastrin-releasing peptide induced spike responses in 43.3% of the patched Grpr-Cre neurons, where the majority of the cells displayed a tonic firing property. Additionally, our analysis showed that the Grpr-Cre population expresses Vglut2 mRNA, and mice ablated of Vglut2 in Grpr-Cre cells (Vglut2-lox; Grpr-Cre mice) displayed less spontaneous itch and attenuated responses to both histaminergic and nonhistaminergic agents. We could also show that application of the itch-inducing peptide, natriuretic polypeptide B, induces calcium influx in a subpopulation of Grpr-Cre neurons. To summarize, our data indicate that the Grpr-Cre spinal cord neural population is composed of interneurons that use VGLUT2-mediated signaling for transmitting chemical and spontaneous itch stimuli to the next, currently unknown, neurons in the labeled line of itch.

  • 5.
    Aresh, Bejan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Moelijker, Nynke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Blümel, Edda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Lagerström, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Characterization of preproenkephalin expressing neurons in the nervous system using a transgenic lineManuscript (preprint) (Other academic)
    Abstract [en]

    Here we have constructed a Cre line to target preproenkephalin expressing cells (Penk-Cre) using a BAC cloning strategy. By crossing our Penk-Cre line with the tdTomato reporter, tdTomato;Penk-Cre expressing cells could be visualized. Penk-Cre was expressed throughout the dorsal spinal cord, where approximately 50% of the neurons were residing within lamina III. Furthermore, single-cell analysis of spinal Penk-Cre expressing cells showed that 41% was positive for Penk mRNA and that a majority (94%) of the population expressed Vglut2 mRNA. Immunohistochemical analysis showed that only 7% and 13% expressed the inhibitory markers Viaat-egfp and Pax2, respectively, hence identifying spinal Penk-Cre expressing neurons as mainly excitatory. The expression of Penk-Cre in the brain was extensive, including dense expression in the striatum, nucleus accumbens and several amygdaloid nuclei. Furthermore, Penk-Cre expression was also shown in insular cortex, cingulated cortex, primary and secondary somatosensory cortices and the trigeminal nuclei. The Penk-Cre line represents a useful genetic tool for future analysis of PENK expressing neurons in the nervous system.

     

  • 6.
    Aresh, Bejan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Peuckert, Christiane
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Dissection and Culture of Mouse Embryonic Kidney2017In: Journal of Visualized Experiments, ISSN 1940-087X, E-ISSN 1940-087X, no 123, article id e55715Article in journal (Refereed)
    Abstract [en]

    The goal of this protocol is to describe a method for the dissection, isolation, and culture of mouse metanephric rudiments. During mammalian kidney development, the two progenitor tissues, the ureteric bud and the metanephric mesenchyme, communicate and reciprocally induce cellular mechanisms to eventually form the collecting system and the nephrons of the kidney. As mammalian embryos grow intrauterine and therefore are inaccessible to the observer, an organ culture has been developed. With this method, it is possible to study epithelial-mesenchymal interactions and cellular behavior during kidney organogenesis. Furthermore, the origin of congenital kidney and urogenital tract malformations can be investigated. After careful dissection, the metanephric rudiments are transferred onto a filter that floats on culture medium and can be kept in a cell culture incubator for several days. However, one must be aware that the conditions are artificial and could influence the metabolism in the tissue. Also, the penetration of test substances could be limited due to the extracellular matrix and basal membrane present in the explant. One main advantage of organ culture is that the experimenter can gain direct access to the organ. This technology is cheap, simple, and allows a large number of modifications, such as the addition of biologically active substances, the study of genetic variants, and the application of advanced imaging techniques.

  • 7.
    Aresh, Bejan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Stjärne, Ludvig
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Blümel, Edda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Maturi, Naga Prathyusha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Lagerström, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Characterization of preprodynorphin-expressing cells in the mouse nervous systemManuscript (preprint) (Other academic)
    Abstract [en]

    Dynorphin is an endogenous opioid that has been implicated in maintaining chronic pain and gating of both itch and acute mechanical pain through acting on both opioid and non-opioid receptors. To improve our understanding of the complex and multifunctional population that expresses dynorphin, we have constructed a preprodynorphin Cre line (Pdyn-Cre) using BAC cloning. Single cell analysis of tdTomato;Pdyn-Cre cells revealed that 43% of the population expressed Pdyn mRNA, and no analyzed tdTomato;Pdyn-Cre negative cell expressed Pdyn mRNA, thus confirming that Cre had been inserted under the control of the Pdyn promoter. The Pdyn-Cre expressing population was found in the dorsal spinal cord, mainly in lamina II-IV and overlapped to 47% with Vglut2 mRNA, while co-expression with the inhibitory markers Viaat-egfp and Pax2 was 13% and 28%, respectively. The expression of Pdyn-Cre in the brain was extensive, marking virtually all cortical structures, including somatosensory and motor cortex. Furthermore, Pdyn-Cre was densely expressed in the striatum, amygdala and parts of the hippocampus, and expression was also observed in several pain and itch processing areas, including amygdala, lateral parabrachial nucleus, claustrum, insular cortex and raphe magnus nucleus. Our analysis indicates that the transgenic Pdyn-Cre line includes PDYN cells in the nervous system and will thus be useful as a transgenic tool for studies of the role and connectivity of the PDYN population.

  • 8.
    Arvidsson, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Schweizer, Nadine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Lévesque, Daniel
    Faculty of Pharmacy, Université de Montréal, Montréal, QC, Canada..
    Wallén, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Selective targeting within the subthalamic nucleus alters responsiveness to sugar and regulates accumbal dopamine levelsManuscript (preprint) (Other academic)
  • 9.
    Arvidsson, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Viereckel, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Mikulovic, Sanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Wallén-Mackenzie, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Age- and Sex-Dependence of Dopamine Release and Capacity for Recovery Identified in the Dorsal Striatum ofC57/Bl6J Mice2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 6, p. e99592-Article in journal (Refereed)
    Abstract [en]

    The dorsal striatum is the main input structure of the basal ganglia and the major target area of dopaminergic projections originating in the substantia nigra pars compacta. Heavily involved in the regulation of voluntary movement and habit formation, this structure is of strong importance in Parkinson's disease, obsessive-compulsive disorder, Tourette's syndrome and addiction. The C57/Bl6J mouse strain, the most commonly used strain in preclinical research today, is frequently used as a model organism for analysis of dopaminergic parameters implicated in human pathophysiology. Several components of the dopamine system have been shown to vary with age and sex, however knowledge of the contribution of these factors for dopamine release kinetics in the C57/Bl6J mouse strain is lacking. In the present study, we used an intracranial KCl-stimulation challenge paradigm to provoke release from dopaminergic terminals in the dorsal striatum of anaesthetized C57/Bl6J mice. By high-speed in vivo chronoamperometric recordings, we analyzed DA release parameters in male and female mice of two different ages. Our experiments demonstrate elevated DA amplitudes in adult compared to young mice of both sexes and higher DA amplitudes in females compared to males at both ages. Adult mice exhibited higher recovery capabilities after repeated stimulation than did young mice and also showed a lower variability in the kinetic parameters trise and t80 between stimulations. These results identified age- and sex- dimorphisms in DA release parameters and point to the importance of taking these dimorphisms into account when utilizing the C57/Bl6J mouse strain as model for neurological and neuropsychiatric disorders.

  • 10.
    Babateen, Omar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Korol, Sergiy V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bhandage, Amol K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Ahemaiti, Aikeremu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Liraglutide modulates GABAergic signaling in rat hippocampal CA3 pyramidal neurons predominantly by presynaptic mechanism2017In: BMC Pharmacology & Toxicology, E-ISSN 2050-6511, Vol. 18, article id 83Article in journal (Refereed)
    Abstract [en]

    Background

    γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain where it regulates activity of neuronal networks. The receptor for glucagon-like peptide-1 (GLP-1) is expressed in the hippocampus, which is the center for memory and learning. In this study we examined effects of liraglutide, a GLP-1 analog, on GABA signaling in CA3 hippocampal pyramidal neurons.

    Methods

    We used patch-clamp electrophysiology to record synaptic and tonic GABA-activated currents in CA3 pyramidal neurons in rat hippocampal brain slices.

    Results

    We examined the effects of liraglutide on the neurons at concentrations ranging from one nM to one μM. Significant changes of the spontaneous inhibitory postsynaptic currents (sIPSCs) were only recorded with 100 nM liraglutide and then in just ≈50% of the neurons tested at this concentration. In neurons affected by liraglutide both the sIPSC frequency and the most probable amplitudes increased. When the action potential firing was inhibited by tetrodotoxin (TTX) the frequency and amplitude of IPSCs in TTX and in TTX plus 100 nM liraglutide were similar.

    Conclusions

    The results demonstrate that liraglutide regulation of GABA signaling of CA3 pyramidal neurons is predominantly presynaptic and more limited than has been observed for GLP-1 and exendin-4 in hippocampal neurons.

  • 11.
    Bauer, Pavol
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computational Science.
    Engblom, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computational Science.
    Mikulovic, Sanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Senek, Aleksandar
    Multiscale modelling via split-step methods in neural firing2018In: Mathematical and Computer Modelling of Dynamical Systems, ISSN 1387-3954, E-ISSN 1744-5051, Vol. 24, p. 426-445Article in journal (Refereed)
  • 12.
    Bengtsson, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Epifantseva, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Åbrink, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kylberg, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Ebendal, Ted
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Usoskin, Dmitry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Generation and characterization of a Gdf1 conditional null allele2008In: Genesis, ISSN 1526-954X, E-ISSN 1526-968X, Vol. 46, no 7, p. 368-372Article in journal (Refereed)
    Abstract [en]

    Growth differentiation factor-1 (GDF1), a TGF-beta superfamily member, participates in early embryo patterning. Later functions are implied by the Gdf1 expression in the peripheral and central nervous system. Such roles of the gene have been difficult to study, because Gdf1 null mice die during late embryogenesis. Here, we report the production of a mouse carrying a conditional Gdf1 allele, with exon 2 flanked by loxP sites. Crossing these mice with CaMKIIalpha-Cre mice resulted in Gdf1 ablation in the forebrain postnatally. Such mice displayed no behavioral changes or altered expression levels in a set of hippocampal genes examined. However, excision of the floxed Gdf1 exon caused increased expression of the remaining part of the bicistronic Uog1-Gdf1 transcript in the hippocampus. This indicates that the transcript level is regulated by a negative feedback-loop, sensing presence of either the protein or the mRNA region encoded by Gdf1 exon 2.

  • 13.
    Benlloch, Jose M.
    et al.
    Univ Politecn Valencia, CSIC, Inst Instrumentat Mol Imaging M I3, Valencia, Spain.
    Gonzalez, Antonio J.
    Univ Politecn Valencia, CSIC, Inst Instrumentat Mol Imaging M I3, Valencia, Spain.
    Pani, Roberto
    Sapienza Univ Rome, Dept Mol Med, Rome, Italy.
    Preziosi, Enrico
    Sapienza Univ Rome, Dept Mol Med, Rome, Italy.
    Jackson, Carl
    SensL Technol, Cork, Ireland.
    Murphy, John
    SensL Technol, Cork, Ireland.
    Barbera, Julio
    Oncovision, Valencia, Spain.
    Correcher, Carlos
    Oncovision, Valencia, Spain.
    Aussenhofer, Sebastian
    NORAS MRI Prod GmbH, Hochberg, Germany.
    Gareis, Daniel
    NORAS MRI Prod GmbH, Hochberg, Germany.
    Visvikis, Dimitris
    Univ Bretagne Occidentale, INSERM, UMR1101, LaTIM, Brest, France.
    Bert, Julien
    Univ Bretagne Occidentale, INSERM, UMR1101, LaTIM, Brest, France.
    Langstrom, Bengt
    BENCAR, Uppsala, Sweden.
    Farde, Lars
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden;Stockholm Cty Council, Stockholm, Sweden;Karolinska Inst, PET Sci Ctr, AstraZeneca, Precis Med & Genom, Stockholm, Sweden.
    Toth, Miklos
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden;Stockholm Cty Council, Stockholm, Sweden.
    Haggkvist, Jenny
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden;Stockholm Cty Council, Stockholm, Sweden.
    Caixeta, Fabio Viegas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Somlai-Schweiger, Ian
    Tech Univ Munich, Dept Nucl Med, Munich, Germany.
    Schwaiger, Markus
    Tech Univ Munich, Dept Nucl Med, Munich, Germany.
    The MINDVIEW project: First results2018In: European psychiatry, ISSN 0924-9338, E-ISSN 1778-3585, Vol. 50, p. 21-27Article in journal (Refereed)
    Abstract [en]

    We present the first results of the MINDVIEW project. An innovative imaging system for the human brain examination, allowing simultaneous acquisition of PET/MRI images, has been designed and constructed. It consists of a high sensitivity and high resolution PET scanner integrated in a novel, head-dedicated, radio frequency coil for a 3T MRI scanner. Preliminary measurements from the PET scanner show sensitivity 3 times higher than state-of-the-art PET systems that will allow safe repeated studies on the same patient. The achieved spatial resolution, close to 1 mm, will enable differentiation of relevant brain structures for schizophrenia. A cost-effective and simple method of radiopharmaceutical production from 11C-carbon monoxide and a mini-clean room has been demonstrated. It has been shown that 11C-raclopride has higher binding potential in a new VAAT null mutant mouse model of schizophrenia compared to wild type control animals. A significant reduction in TSPO binding has been found in gray matter in a small sample of drug-naïve, first episode psychosis patients, suggesting a reduced number or an altered function of immune cells in brain at early stage schizophrenia.

  • 14. Berg, Alexander
    et al.
    Zelano, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Stephan, Alexander
    Thams, Sebastian
    Barres, Ben A.
    Pekny, Milos
    Pekna, Marcela
    Cullheim, Staffan
    Reduced removal of synaptic terminals from axotomized spinal motoneurons in the absence of complement C32012In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 237, no 1, p. 8-17Article in journal (Refereed)
    Abstract [en]

    Complement proteins C1q and C3 play a critical role in synaptic elimination during development. Axotomy of spinal motoneurons triggers removal of synaptic terminals from the cell surface of motoneurons by largely unknown mechanisms. We therefore hypothesized that the complement system is involved also in synaptic stripping of injured motoneurons. In the sciatic motor pool of wild type (WT) mice, the immunoreactivity (IR) for both C1q and C3 was increased after sciatic nerve transection (SNT). Mice deficient in C3 (C3(-/-)) showed a reduced loss of synaptic terminals from injured motoneurons at one week after SNT, as assessed by immunoreactivity for synaptic markers and electron microscopy. In particular, the removal of putative inhibitory terminals, immunopositive for vesicular inhibitory amino acid transporter (VIAAT) and ultrastructurally identified as type F synapses, was reduced in C3(-/-) mice. In contrast, lesion-induced removal of nerve terminals in C1q(-/-) mice appeared similar to WT mice. Growth associated protein (GAP)-43 mRNA expression in lesioned motoneurons increased much more in C3(-/-) compared to WT mice after SNT. After sciatic nerve crush (SNC), the C3(-/-) mice showed a faster functional recovery, assessed as grip strength, compared to WT mice. No differences were detected regarding nerve inflammation at the site of injury or pattern of muscle reinnervation. These data indicate that a non-classical pathway of complement activation is involved in axotomy-induced adult synapse removal, and that its inhibition promotes functional recovery.

  • 15. Berg, Alexander
    et al.
    Zelano, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Thams, Sebastian
    Cullheim, Staffan
    The Extent of Synaptic Stripping of Motoneurons after Axotomy Is Not Correlated to Activation of Surrounding Glia or Downregulation of Postsynaptic Adhesion Molecules2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 3, p. e59647-Article in journal (Refereed)
    Abstract [en]

    Synapse elimination in the adult central nervous system can be modelled by axotomy of spinal motoneurons which triggers removal of synapses from the cell surface of lesioned motoneurons by processes that remain elusive. Proposed candidate mechanisms are removal of synapses by reactive microglia and astrocytes, based on the remarkable activation of these cell types in the vicinity of motoneurons following axon lesion, and/or decreased expression of synaptic adhesion molecules in lesioned motoneurons. In the present study, we investigated glia activation and adhesion molecule expression in motoneurons in two mouse strains with deviant patterns of synapse elimination following axotomy. Mice deficient in complement protein C3 display a markedly reduced loss of synapses from axotomized motoneurons, whereas mice with impaired function of major histocompatibility complex (MHC) class Ia display an augmented degree of stripping after axotomy. Activation of microglia and astrocytes was assessed by semiquantative immunohistochemistry for Iba 1 (microglia) and GFAP (astrocytes), while expression of synaptic adhesion molecules was determined by in situ hybridization. In spite of the fact that the two mouse strains display very different degrees of synapse elimination, no differences in terms of glial activation or in the downregulation of the studied adhesion molecules (SynCAM1, neuroligin-2,-3 and netrin G-2 ligand) could be detected. We conclude that neither glia activation nor downregulation of synaptic adhesion molecules are correlated to the different extent of the synaptic stripping in the two studied strains. Instead the magnitude of the stripping event is most likely a consequence of a precise molecular signaling, which at least in part is mediated by immune molecules.

  • 16.
    Bernhardt, Nadine Rabe
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Memic, Fatima
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Genetic analysis of left-right coordination of locomotion2013In: Frontiers in Bioscience, ISSN 1093-9946, E-ISSN 1093-4715, Vol. 18, p. 20-35Article in journal (Refereed)
    Abstract [en]

    While there is a rather large amount of data from pharmacological and anatomical studies of the murine locomotor CPG network, comprehensive information regarding the cellular and functional properties of the neuronal populations is lacking. Here, we describe concepts arising from genetic studies of the locomotor network with a focus on commissural interneurons regulating left-right coordination. In particular, this involves several families of axon guidance molecules relevant for midline crossing. We also describe recent advances within the field of neural circuit analysis, including imaging, genetic inactivation and optogenetic strategies, which are applicable to locomotor circuits. Such efforts, for example by using available genetic markers, should substantially increase our possibilities to decipher the functionality of spinal cord neuronal networks.

  • 17. Berube-Carriere, Noemie
    et al.
    Guay, Ginette
    Fortin, Guillaume M.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Olson, Lars
    Wallén-Mackenzie, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Trudeau, Louis-Eric
    Descarries, Laurent
    Ultrastructural characterization of the mesostriatal dopamine innervation in mice, including two mouse lines of conditional VGLUT2 knockout in dopamine neurons2012In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 35, no 4, p. 527-538Article in journal (Refereed)
    Abstract [en]

    Despite the increasing use of genetically modified mice to investigate the dopamine (DA) system, little is known about the ultrastructural features of the striatal DA innervation in the mouse. This issue is particularly relevant in view of recent evidence for expression of the vesicular glutamate transporter 2 (VGLUT2) by a subset of mesencephalic DA neurons in mouse as well as rat. We used immuno-electron microscopy to characterize tyrosine hydroxylase (TH)-labeled terminals in the core and shell of nucleus accumbens and the neostriatum of two mouse lines in which the Vglut2 gene was selectively disrupted in DA neurons (cKO), their control littermates, and C57BL/6/J wild-type mice, aged P15 or adult. The three regions were also examined in cKO mice and their controls of both ages after dual THVGLUT2 immunolabeling. Irrespective of the region, age and genotype, the TH-immunoreactive varicosities appeared similar in size, vesicular content, percentage with mitochondria, and exceedingly low frequency of synaptic membrane specialization. No dually labeled axon terminals were found at either age in control or in cKO mice. Unless TH and VGLUT2 are segregated in different axon terminals of the same neurons, these results favor the view that the glutamatergic cophenotype of mesencephalic DA neurons is more important during the early development of these neurons than for the establishment of their scarce synaptic connectivity. They also suggest that, in mouse even more than rat, the mesostriatal DA system operates mainly through non-targeted release of DA, diffuse transmission and the maintenance of an ambient DA level.

  • 18.
    Birgner, Carolina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Nordenankar, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Lundblad, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Mendez, José Alfredo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Smith, Casey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    le Grevés, Madeleine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Galter, Dagmar
    Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Olson, Lars
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, Ulleråker, University Hospital.
    Trudeau, Louis-Eric
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Wallén-Mackenzie, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    VGLUT2 in dopamine neurons is required for psychostimulant-induced behavioural activation2010In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, no 1, p. 389-394Article in journal (Refereed)
    Abstract [en]

    The “One neuron-one neurotransmitter” concept has been challenged frequently during the last three decades, and the coexistence of neurotransmitters in individual neurons is now regarded as a common phenomenon. The functional significance of neurotransmitter coexistence is, however, less well understood. Several studies have shown that a subpopulation of dopamine (DA) neurons in the ventral tegmental area (VTA) expresses the vesicular glutamate transporter 2 (VGLUT2) and has been suggested to use glutamate as a cotransmitter. The VTA dopamine neurons project to limbic structures including the nucleus accumbens, and are involved in mediating the motivational and locomotor activating effects of psychostimulants. To determine the functional role of glutamate cotransmission by these neurons, we deleted VGLUT2 in DA neurons by using a conditional gene-targeting approach in mice. A DAT-Cre/Vglut2Lox mouse line (Vglut2f/f;DAT-Cre mice) was produced and analyzed by in vivo amperometry as well as by several behavioral paradigms. Although basal motor function was normal in the Vglut2f/f;DAT-Cre mice, their risk-taking behavior was altered. Interestingly, in both home-cage and novel environments, the gene targeted mice showed a greatly blunted locomotor response to the psychostimulant amphetamine, which acts via the midbrain DA system. Our results show that VGLUT2 expression in DA neurons is required for normal emotional reactivity as well as for psychostimulant-mediated behavioral activation.

  • 19.
    Boije, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Kullander, Klas
    Origin and circuitry of spinal locomotor interneurons generating different speeds.2018In: Current Opinion in Neurobiology, ISSN 0959-4388, E-ISSN 1873-6882, Vol. 53, p. 16-21, article id S0959-4388(18)30075-8Article in journal (Refereed)
    Abstract [en]

    The spinal circuitry governing the undulatory movements of swimming vertebrates consist of excitatory and commissural inhibitory interneurons and motor neurons. This locomotor network generates the rhythmic output, coordinate left/right alternation, and permit communication across segments. Through evolution, more complex movement patterns have emerged, made possible by sub-specialization of neural populations within the spinal cord. Walking tetrapods use a similar basic circuitry, but have added layers of complexity for the coordination of intralimbic flexor and extensor muscles as well as interlimbic coordination between the body halves and fore/hindlimbs. Although the basics of these circuits are known there is a gap in our knowledge regarding how different speeds and gaits are coordinated. Analysing subpopulations among described neuronal populations may bring insight into how changes in locomotor output are orchestrated by a hard-wired network.

  • 20.
    Boije, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics. Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3DY, England..
    Rulands, Steffen
    Univ Cambridge, Dept Phys, Cambridge CB3 0HE, England..
    Dudczig, Stefanie
    Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3DY, England..
    Simons, Benjamin D.
    Univ Cambridge, Dept Phys, Cambridge CB3 0HE, England..
    Harris, William A.
    Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3DY, England..
    The Independent Probabilistic Firing of Transcription Factors: A Paradigm for Clonal Variability in the Zebrafish Retina2015In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 34, no 5, p. 532-543Article in journal (Refereed)
    Abstract [en]

    Early retinal progenitor cells (RPCs) in vertebrates produce lineages that vary greatly both in terms of cell number and fate composition, yet how this variability is achieved remains unknown. One possibility is that these RPCs are individually distinct and that each gives rise to a unique lineage. Another is that stochastic mechanisms play upon the determinative machinery of equipotent early RPCs to drive clonal variability. Here we show that a simple model, based on the independent firing of key fate-influencing transcription factors, can quantitatively account for the intrinsic clonal variance in the zebrafish retina and predict the distributions of neuronal cell types in clones where one or more of these fates are made unavailable.

  • 21.
    Brunell, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Ridefelt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Zelano, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Differential diagnostic yield of lumbar puncture in investigation of suspected subarachnoid haemorrhage: a retrospective study2013In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 260, no 6, p. 1631-1636Article in journal (Refereed)
    Abstract [en]

    The diagnostic algorithm of computerized tomography (CT) and lumbar puncture (LP) for suspected subarachnoid haemorrhage (SAH) has lately been challenged by the advancement of radiological techniques, such as higher resolution offered by newer generation CT-scanners and increased availability of CT-angiography. A purely radiological workup of suspected SAH offers great advantages for both patients and the health care system, but the risks of abandoning LP in this setting are not well investigated. We have characterized the differential diagnostic yield of LP in the investigation of suspected SAH by a retrospective study. From the hospital laboratory database, we analyzed the medical records of all patients who had undergone CSF-analysis in search of subarachnoid bleeding during 2009-2011. A total of 453 patients were included. In 14 patients (3 %) the LP resulted in an alternative diagnosis, the most common being aseptic meningitis. Two patients (0.5 %) received treatment for herpes meningitis. Five patients (1 %) with subarachnoid haemorrhages were identified. Among these, the four patients presenting with thunderclap headache had non-aneurysmal bleedings and did not require surgical intervention. We conclude that the differential diagnostic yield of LP in investigation of suspected SAH is low, which indicates that alternative diagnoses is not a reason to keep LP in the workup when a purely radiological strategy has been validated. However, algorithms should be developed to increase the recognition of aseptic meningitis. One hundred and fifty-three patients (34 %) were admitted to undergo LP, which estimates the number of hospital beds that might be made available by a radiological diagnostic algorithm.

  • 22.
    Caruso, Vanni
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lagerström, Malin C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Olszewski, Pawel K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Synaptic changes induced by melanocortin signalling2014In: Nature Reviews Neuroscience, ISSN 1471-003X, E-ISSN 1471-0048, Vol. 15, no 2, p. 98-110Article, review/survey (Refereed)
    Abstract [en]

    The melanocortin system has a well-established role in the regulation of energy homeostasis, but there is growing evidence of its involvement in memory, nociception, mood disorders and addiction. In this Review, we focus on the role of the melanocortin 4 receptor and provide an integrative view of the molecular mechanisms that lead to melanocortin-induced changes in synaptic plasticity within these diverse physiological systems. We also highlight the importance of melanocortin peptides and receptors in chronic pain syndromes, memory impairments, depression and drug abuse, and the possibility of targeting them for therapeutic purposes.

  • 23.
    Comasco, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Hallman, Jarmila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Wallen-Mackenzie, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Haplotype-tag single nucleotide polymorphism analysis of the Vesicular Glutamate Transporter (VGLUT) genes in severely alcoholic women2014In: Psychiatry Research, ISSN 0165-1781, E-ISSN 1872-7123, Vol. 219, no 2, p. 403-405Article in journal (Refereed)
  • 24.
    Comasco, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Hallman, Jarmila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Wallen-Mackenzie, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Haplotype tag single-nucleotide polymorphism analysis of the vesicular glutamate transporter 2 gene in severe alcoholism among women2012In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 22, no S2, p. S397-S397Article in journal (Other academic)
  • 25.
    Corell, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Neuron-glial Interaction in the Developing Peripheral Nervous System2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The nervous system, including the brain, is the most sophisticated organ in the mammalian body. In such a complex network, neuron-glial interaction is essential and controls most developmental processes, such as stem cell fate determination, migration, differentiation, synapse formation, ensheathment and myelination. Many of these events are critical for the developmental process and small errors can lead to growth retardation, malformation or disease. The understanding of the normal progress of nervous system development is fundamental and will help the discovery of new treatments for disease.

    This thesis discusses three types of neuron-glia interactions at different developmental stages; neural stem/progenitor cell (NSPC) differentiation, building and maintaining the structure of the sciatic nerve, and myelin formation.

    In Paper I we show that NSPCs, based upon their morphology and expression of specific protein markers, have the capacity to differentiate into cells of either the peripheral nervous system (PNS) or enteric nervous system (ENS) when grown with PNS or ENS primary cell cultures, or fed with conditioned medium from these. This indicates that soluble factors secreted from the PNS or ENS cultures are important for stem cell differentiation and fate determination.

    The adhesion protein neuronal cadherin (N-cadherin) is implicated in migration, differentiation and nerve outgrowth in the developing PNS. In Paper II N-cadherin was exclusively found in ensheathing glia (nonmyelinating Schwann cells, satellite cells and enteric glia) in contact with each other or with axons. Functional blocking of N-cadherin in dissociated fetal dorsal root ganglia (DRG) cultures led to a decrease in attachment between Schwann cells. N-cadherin-mediated adhesion of nonmyelinating Schwann cells may be important in encapsulating thin calibre axons and provide support to myelinating Schwann cells.

    In Paper III the inhibitory gamma aminobutyric acid (GABA) and GABAB receptors were studied in the Schwann cell of the adult sciatic nerve and DRG cultures. GABAB receptors were primarily expressed in nonmyelinating Schwann cells and protein levels decreased during development and myelination. Blocking the GABAB receptor in long-term DRG cultures led to decreased levels of mRNA markers for myelin. These results indicate that the GABA and GABAB receptors may be involved in Schwann cell myelination.

    List of papers
    1. Environmental cues from CNS, PNS, and ENS cells regulate CNS progenitor differentiation
    Open this publication in new window or tab >>Environmental cues from CNS, PNS, and ENS cells regulate CNS progenitor differentiation
    2008 (English)In: NeuroReport, ISSN 0959-4965, E-ISSN 1473-558X, Vol. 19, no 13, p. 1283-9Article in journal (Refereed) Published
    Abstract [en]

    Cellular origin and environmental cues regulate stem cell fate determination. Neuroepithelial stem cells form the central nervous system (CNS), whereas neural crest stem cells generate the peripheral (PNS) and enteric nervous system (ENS). CNS neural stem/progenitor cell (NSPC) fate determination was investigated in combination with dissociated cultures or conditioned media from CNS, PNS, or ENS. Cells or media from ENS or PNS cultures efficiently promoted NSPC differentiation into neurons, glia, and smooth muscle cells with a similar morphology as the feeder culture. Together with CNS cells or its conditioned medium, NSPC differentiation was partly inhibited and cells remained immature. Here, we demonstrate that secreted factors from the environment can influence CNS progenitor cells to choose a PNS-like cell fate.

    Keywords
    cerebellum, coculture, dorsal root ganglion, multipotency, neural stem/progenitor cells, intestine
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-98176 (URN)10.1097/WNR.0b013e32830bfba4 (DOI)000258767700007 ()18695508 (PubMedID)
    Available from: 2009-02-16 Created: 2009-02-16 Last updated: 2017-12-13Bibliographically approved
    2. Spatiotemporal Distribution and Function of N-Cadherin in Postnatal Schwann Cells: A Matter of Adhesion?
    Open this publication in new window or tab >>Spatiotemporal Distribution and Function of N-Cadherin in Postnatal Schwann Cells: A Matter of Adhesion?
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    2010 (English)In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 88, no 11, p. 2338-2349Article in journal (Refereed) Published
    Abstract [en]

    During embryonic development of the peripheral nervous system (PNS), the adhesion molecule neuronal cadherin (N-cadherin) is expressed by Schwann cell precursors and associated with axonal growth cones. N-cadherin expression levels decrease as precursors differentiate into Schwann cells. In this study, we investigated the distribution of N-cadherin in the developing postnatal and adult rat peripheral nervous system. N-cadherin was found primarily in ensheathing glia throughout development, concentrated at neuron glial or glial glial contacts of the sciatic nerve, dorsal root ganglia (DRG), and myenteric plexi. In the sciatic nerve, N-cadherin decreases with age and progress of myelination. In adult animals, N-cadherin was found exclusively in nonmyelinating Schwann cells. The distribution of N-cadherin in developing E17 DRG primary cultures is similar to what was observed in vivo. Functional studies of N-cadherin in these cultures, using the antagonist peptide INPISGQ, show a disruption of the attachment between Schwann cells, but no interference in the initial or long-term contact between Schwann cells and axons. We suggest that N-cadherin acts primarily in the adhesion between glial cells during postnatal development. It may form adherents/junctions between nonmyelinating glia, which contribute to the stable tubular structure encapsulating thin caliber axons and thus stabilize the nerve structure as a whole.

    Keywords
    PNS development, nonmyelinating Schwann cells, myelination, enteric glia, satellite cells
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-135742 (URN)10.1002/jnr.22398 (DOI)000280436600004 ()20623533 (PubMedID)
    Available from: 2010-12-08 Created: 2010-12-08 Last updated: 2017-12-11Bibliographically approved
    3. The function of GABA and its B-receptor in Schwann cell development
    Open this publication in new window or tab >>The function of GABA and its B-receptor in Schwann cell development
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Keywords
    GABA, GABA(B) receptor, GAD, Schwann cell, nonmyelinating Schwann cell, satellite cell, baclofen, CGP55485
    National Category
    Neurosciences
    Research subject
    Neuroscience
    Identifiers
    urn:nbn:se:uu:diva-157967 (URN)
    Available from: 2011-08-28 Created: 2011-08-28 Last updated: 2018-01-12
  • 26.
    Corell, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Wicher, Grzegorz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Katarzyna J., Radomska
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Trier Kjær, Marcel
    Syddansk Universitet, IMM-Neurobiology Reseach, Denmark .
    Dağlıkoca, E. Duygu
    Bogazici University, Deptartment of Molecular Biology and Genetics, Turkey .
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fex Svenningsen, Åsa
    Syddansk Universitet, IMM-Neurobiology Reseach, Denmark .
    The function of GABA and its B-receptor in Schwann cell developmentManuscript (preprint) (Other academic)
  • 27.
    Corell, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Wicher, Grzegorz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Limbach, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Molecular Cell Biology.
    Kilimann, Manfred W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Molecular Cell Biology.
    Colman, David R.
    Svenningsen, Åsa Fex
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Spatiotemporal Distribution and Function of N-Cadherin in Postnatal Schwann Cells: A Matter of Adhesion?2010In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 88, no 11, p. 2338-2349Article in journal (Refereed)
    Abstract [en]

    During embryonic development of the peripheral nervous system (PNS), the adhesion molecule neuronal cadherin (N-cadherin) is expressed by Schwann cell precursors and associated with axonal growth cones. N-cadherin expression levels decrease as precursors differentiate into Schwann cells. In this study, we investigated the distribution of N-cadherin in the developing postnatal and adult rat peripheral nervous system. N-cadherin was found primarily in ensheathing glia throughout development, concentrated at neuron glial or glial glial contacts of the sciatic nerve, dorsal root ganglia (DRG), and myenteric plexi. In the sciatic nerve, N-cadherin decreases with age and progress of myelination. In adult animals, N-cadherin was found exclusively in nonmyelinating Schwann cells. The distribution of N-cadherin in developing E17 DRG primary cultures is similar to what was observed in vivo. Functional studies of N-cadherin in these cultures, using the antagonist peptide INPISGQ, show a disruption of the attachment between Schwann cells, but no interference in the initial or long-term contact between Schwann cells and axons. We suggest that N-cadherin acts primarily in the adhesion between glial cells during postnatal development. It may form adherents/junctions between nonmyelinating glia, which contribute to the stable tubular structure encapsulating thin caliber axons and thus stabilize the nerve structure as a whole.

  • 28. Defourny, Jean
    et al.
    Poirrier, Anne-Lise
    Lallemend, Francois
    Sanchez, Susana Mateo
    Neef, Jakob
    Vanderhaeghen, Pierre
    Soriano, Eduardo
    Peuckert, Christiane
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Fritzsch, Bernd
    Nguyen, Laurent
    Moonen, Gustave
    Moser, Tobias
    Malgrange, Brigitte
    Ephrin-A5/EphA4 signalling controls specific afferent targeting to cochlear hair cells2013In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 4, p. 1438-Article in journal (Refereed)
    Abstract [en]

    Hearing requires an optimal afferent innervation of sensory hair cells by spiral ganglion neurons in the cochlea. Here we report that complementary expression of ephrin-A5 in hair cells and EphA4 receptor among spiral ganglion neuron populations controls the targeting of type I and type II afferent fibres to inner and outer hair cells, respectively. In the absence of ephrin-A5 or EphA4 forward signalling, a subset of type I projections aberrantly overshoot the inner hair cell layer and invade the outer hair cell area. Lack of type I afferent synapses impairs neurotransmission from inner hair cells to the auditory nerve. By contrast, radial shift of type I projections coincides with a gain of presynaptic ribbons that could enhance the afferent signalling from outer hair cells. Ephexin-1, cofilin and myosin light chain kinase act downstream of EphA4 to induce type I spiral ganglion neuron growth cone collapse. Our findings constitute the first identification of an Eph/ephrin-mediated mutual repulsion mechanism responsible for specific sorting of auditory projections in the cochlea.

  • 29. Dufour, Audrey
    et al.
    Egea, Joaquim
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Klein, Rüdiger
    Vanderhaeghen, Pierre
    Genetic analysis of EphA-dependent signaling mechanisms controlling topographic mapping in vivo2006In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 133, no 22, p. 4415-4420Article in journal (Refereed)
    Abstract [en]

    Ephrin/Eph ligands and receptors are best known for their prominent role in topographic mapping of neural connectivity. Despite the large amount of work centered on ephrin/Eph-dependent signaling pathways in various cellular contexts, the molecular mechanisms of action of Eph receptors in neural mapping, requiring dynamic interactions between complementary gradients of ephrins and Eph receptors, remain largely unknown. Here, we investigated in vivo the signaling mechanisms of neural mapping mediated by the EphA4 receptor, previously shown to control topographic specificity of thalamocortical axons in the mouse somatosensory system. Using axon tracing analyses of knock-in mouse lines displaying selective mutations for the Epha4 gene, we determined for the first time which intracellular domains of an Eph receptor are required for topographic mapping. We provide direct in vivo evidence that the tyrosine kinase domain of EphA4, as well as a tight regulation of its activity, are required for topographic mapping of thalamocortical axons, whereas non-catalytic functional modules, such as the PDZ-binding motif (PBM) and the Sterile-alpha motif (SAM) domain, are dispensable. These data provide a novel insight into the molecular mechanisms of topographic mapping, and constitute a physiological framework for the dissection of the downstream signaling cascades involved.

  • 30. Egea, J
    et al.
    Nissen, UV
    Dufour, A
    Sahin, M
    Greer, P
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Mrsic-Flogel, TD
    Greenberg, ME
    Kiehn, O
    Vanderhaeghen, P
    Klein, R
    Regulation of EphA 4 kinase activity is required for a subset of axon guidance decisions suggesting a key role for receptor clustering in Eph function2005In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 47, no 4, p. 515-528Article in journal (Refereed)
    Abstract [en]

    Signaling by receptor tyrosine kinases (RTKs) is mediated by their intrinsic kinase activity. Typically, kinase-activating mutations result in ligand-independent signaling and gain-of-function phenotypes. Like other RTKs, Ephs require kinase activity to signal, but signaling by Ephs in vitro also requires clustering by their membrane bound ephrin ligands. The relative importance of Eph kinase activity and clustering for in vivo functions is unknown. We find that knockin mice expressing a mutant form of EphA4 (EphA4(EE)), whose kinase is constitutively activated in the absence of ephrinB ligands, are deficient in the development of thalamocortical projections and some aspects of central pattern generator rhythmicity. Surprisingly, other functions of EphA4 were regulated normally by EphA4(EE), including midline axon guidance, hindlimb locomotion, in vitro growth cone collapse, and phosphorylation of ephexin1. These results suggest that signaling of Eph RTKs follows a multistep process of induced kinase activity and higher-order clustering different from RTKs responding to soluble ligands.

  • 31. El Mestikawy, Salah
    et al.
    Wallén-Mackenzie, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Fortin, Guillaume M.
    Descarries, Laurent
    Trudeau, Louis-Eric
    From glutamate co-release to vesicular synergy: vesicular glutamate transporters2011In: Nature Reviews Neuroscience, ISSN 1471-003X, E-ISSN 1471-0048, Vol. 12, no 4, p. 204-216Article, review/survey (Refereed)
    Abstract [en]

    Recent data indicate that 'classical' neurotransmitters can also act as co-transmitters. This notion has been strengthened by the demonstration that three vesicular glutamate transporters (vesicular glutamate transporter 1 (VGLUT1), VGLUT2 and VGLUT3) are present in central monoamine, acetylcholine and GABA neurons, as well as in primarily glutamatergic neurons. Thus, intriguing questions are raised about the morphological and functional organization of neuronal systems endowed with such a dual signalling capacity. In addition to glutamate co-release, vesicular synergy - a process leading to enhanced packaging of the 'primary' transmitter - is increasingly recognized as a major property of the glutamatergic co-phenotype. The behavioural relevance of this co-phenotype is presently the focus of considerable interest.

  • 32.
    Enjin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Neural Control of Movement: Motor Neuron Subtypes, Proprioception and Recurrent Inhibition2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Movement is central for life, and all animals depend on accurate regulation of movement for purposeful behavior. There is great diversity of movements, ranging between simple and vital breathing movements to minute and subtle movements of the face used to communicate emotions. Consequently, motor neurons, which are the only route of central nervous system output, are essential for all motor behaviors. To control the many motor behaviors expressed by an animal, motor neurons are exposed to a large number and variety of modulating synaptic inputs and have evolved into subtypes with specific functions. In this thesis, motor neuron subtypes and the synaptic input to motor neurons from Renshaw cells and Ia afferents have been studied. Novel molecular markers that identify subtypes of motor neurons are described. Three markers, Chodl, Calca and ERRβ, have been used to study the degeneration of subtypes of motor neurons in a mouse model of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Another marker, 5-ht1d, has been used to record the electrophysiological character of gamma motor neurons. In mice that lack 5-ht1d, motor neurons develop with reduced proprioceptive input. Remarkably, these mice had fewer foot faults than control animals when challenged to cross a narrow beam suggesting that the amplitude of monosynaptic proprioceptive input to motor neurons is not essential for motor coordination. In a final set of experiments, genetic removal of vesicular transport of neurotransmitter from Renshaw cells suggest that Renshaw cells are not integral for motor circuit function or motor behaviors. However, they are involved in the development of motor circuits in the spinal cord. Together, this thesis provides novel molecular tools for studies of motor neuron subtypes and novel data regarding the development and function of spinal motor circuits.

     

    List of papers
    1. Identification of novel spinal cholinergic genetic subtypes disclose Chodl and Pitx2 as markers for fast motor neurons and partition cells
    Open this publication in new window or tab >>Identification of novel spinal cholinergic genetic subtypes disclose Chodl and Pitx2 as markers for fast motor neurons and partition cells
    Show others...
    2010 (English)In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 518, no 12, p. 2284-2304Article in journal (Refereed) Published
    Abstract [en]

    Spinal cholinergic neurons are critical for motor function in both the autonomic and somatic nervous systems and are affected in spinal cord injury and in diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy. Using two screening approaches and in situ hybridization, we identified 159 genes expressed in typical cholinergic patterns in the spinal cord. These include two general cholinergic neuron markers, one gene exclusively expressed in motor neurons and nine genes expressed in unknown subtypes of somatic motor neurons. Further, we present evidence that Chondrolectin (Chodl) is a novel genetic marker for putative fast motor neurons and that estrogen-related receptor b (ERRb) is a candidate genetic marker for slow motor neurons. In addition, we suggest paired-like homeodomain transcription factor 2 (Pitx2) as a marker for cholinergic partition cells.

    Keywords
    mouse genetics, neuronal network, interneuron, motor neuron, spinal cord, genetic screen
    National Category
    Medical and Health Sciences
    Research subject
    Developmental Neurosciences; Genetics
    Identifiers
    urn:nbn:se:uu:diva-109916 (URN)10.1002/cne.22332 (DOI)000277580600007 ()20437528 (PubMedID)
    Available from: 2009-10-30 Created: 2009-10-29 Last updated: 2017-12-12Bibliographically approved