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  • 51.
    Brown, Russell
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Physiology.
    Thorén, Peter
    Skott, Ole
    Fredholm, Bertil
    Persson, A Erik G
    The Influence of the Adenosine A1-receptor on Blood Pressure Regulation and Renin ReleaseManuscript (Other academic)
  • 52. Cadeddu, Marta
    et al.
    Vargiu, Laura
    Rodriguez-Tome, Patricia
    Sperber, Göran O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Virology.
    Tramontano, Enzo
    Identification and analysis of HML2 sequences in human genome assembly GRCh37/hg192013In: Retrovirology, ISSN 1742-4690, E-ISSN 1742-4690, Vol. 10, no S1, p. P9-Article in journal (Other academic)
    Download full text (pdf)
    fulltext
  • 53.
    Cai, Yixiao
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Edin, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Alexsson, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Gudjonsson, Olafur
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Karlsson, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Li, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Strategy towards independent electrical stimulation from cochlear implants: Guided auditory neuron growth on topographically modified nanocrystalline diamond2016In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 31, p. 211-220Article in journal (Refereed)
    Abstract [en]

    Cochlear implants (CI) have been used for several decades to treat patients with profound hearing loss. Nevertheless, results vary between individuals, and fine hearing is generally poor due to the lack of discrete neural stimulation from the individual receptor hair cells. A major problem is the deliverance of independent stimulation signals to individual auditory neurons. Fine hearing requires significantly more stimulation contacts with intimate neuron/electrode interphases from ordered axonal re-growth, something current CI technology cannot provide.

    Here, we demonstrate the potential application of micro-textured nanocrystalline diamond (NCD) surfaces on CI electrode arrays. Such textured NCD surfaces consist of micrometer-sized nail-head-shaped pillars (size 5 5 lm2) made with sequences of micro/nano-fabrication processes, including sputtering, photolithography and plasma etching.

    The results show that human and murine inner-ear ganglion neurites and, potentially, neural progenitor cells can attach to patterned NCD surfaces without an extracellular matrix coating. Microscopic methods revealed adhesion and neural growth, specifically along the nail-head-shaped NCD pillars in an ordered manner, rather than in non-textured areas. This pattern was established when the inter-NCD pillar distance varied between 4 and 9 lm.

    The findings demonstrate that regenerating auditory neurons show a strong affinity to the NCD pillars, and the technique could be used for neural guidance and the creation of new neural networks. Together with the NCD’s unique anti-bacterial and electrical properties, patterned NCD surfaces could provide designed neural/electrode interfaces to create independent electrical stimulation signals in CI electrode arrays for the neural population.

  • 54.
    Cedernaes, Jonathan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Olszewski, Pawel K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Sällman Almén, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Stephansson, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Levine, Allen S.
    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.
    Nylander, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Comprehensive analysis of localization of 78 solute carrier genes throughout the subsections of the rat gastrointestinal tract2011In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 411, no 4, p. 702-707Article in journal (Refereed)
    Abstract [en]

    Solute carriers (SLCs), the second largest super-family of membrane proteins in the human genome, transport amino acids, sugars, fatty acids, inorganic ions, essential metals and drugs over membranes. To date no study has provided a comprehensive analysis of SLC localization along the entire GI tract. The aim of the present study was to provide a comprehensive, segment-specific description of the localization of SLC genes along the rat Cl tract by employing bioinformatics and molecular biology methods. The Unigene database was screened for rat SLC entries in the intestinal tissue. Using qPCR we measured expression of the annotated genes in the Cl tract divided into the following segments: the esophagus, the corpus and the antrum of the stomach, the proximal and distal parts of the duodenum, ileum, jejunum and colon, and the cecum. Our Unigene-derived gene pool was expanded with data from in-house tissue panels and a literature search. We found 44 out of 78 (56%) of gut SLC transcripts to be expressed in all Cl tract segments, whereas the majority of remaining SLCs were detected in more than five segments. SLCs are predominantly expressed in gut regions with absorptive functions although expression was also found in segments unrelated to absorption. The proximal jejunum had the highest number of differentially expressed SLCs. In conclusion, SLCs are a crucial molecular component of the Cl tract, with many of them expressed along the entire GI tract. This work presents the first overall road map of localization of transporter genes in the Cl tract.

  • 55.
    Clark, Timothy D.
    et al.
    Univ Tasmania, Hobart, Tas, Australia.;CSIRO Agr & Food, Hobart, Tas, Australia..
    Binning, Sandra A.
    Univ Neuchatel, Inst Biol, Neuchatel, Switzerland..
    Raby, Graham D.
    Univ Windsor, Great Lakes Inst Environm Res, Windsor, ON N9B 3P4, Canada..
    Speers-Roesch, Ben
    Univ New Brunswick, Dept Biol, St John, NB, Canada..
    Sundin, Josefin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jutfelt, Fredrik
    Norwegian Univ Sci & Technol, Dept Biol, Trondheim, Norway..
    Roche, Dominique G.
    Univ Neuchatel, Inst Biol, Neuchatel, Switzerland..
    Scientific Misconduct: The Elephant in the Lab. A Response to Parker et al2016In: Trends in Ecology & Evolution, ISSN 0169-5347, E-ISSN 1872-8383, Vol. 31, no 12, p. 899-900Article in journal (Refereed)
  • 56.
    Clark, Timothy D.
    et al.
    Deakin Univ, Sch Life & Environm Sci, Geelong, Vic, Australia.
    Raby, Graham D.
    Univ Windsor, Great Lakes Inst Environm Res, Windsor, ON, Canada.
    Roche, Dominique G.
    Carleton Univ, Dept Biol, Ottawa, ON, Canada;Univ Neuchatel, Inst Biol, Ecoethol, Neuchatel, Switzerland;Univ Montreal, Dept Sci Biol, Montreal, PQ, Canada.
    Binning, Sandra A.
    Univ Neuchatel, Inst Biol, Ecoethol, Neuchatel, Switzerland;Univ Montreal, Dept Sci Biol, Montreal, PQ, Canada.
    Speers-Roesch, Ben
    Univ New Brunswick, Dept Biol Sci, St John, NB, Canada.
    Jutfelt, Fredrik
    Norwegian Univ Sci & Technol, Dept Biol, Trondheim, Norway.
    Sundin, Josefin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology. Norwegian Univ Sci & Technol, Dept Biol, Trondheim, Norway;Swedish Univ Agr Sci, Dept Aquat Resources, Drottningholm, Sweden.
    Ocean acidification does not impair the behaviour of coral reef fishes2020In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 577, no 7790, p. 370-+Article in journal (Refereed)
    Abstract [en]

    The partial pressure of CO2 in the oceans has increased rapidly over the past century, driving ocean acidification and raising concern for the stability of marine ecosystems(1-3). Coral reef fishes are predicted to be especially susceptible to end-of-century ocean acidification on the basis of several high-profile papers(4,5) that have reported profound behavioural and sensory impairments-for example, complete attraction to the chemical cues of predators under conditions of ocean acidification. Here, we comprehensively and transparently show that-in contrast to previous studies-end-of-century ocean acidification levels have negligible effects on important behaviours of coral reef fishes, such as the avoidance of chemical cues from predators, fish activity levels and behavioural lateralization (left-right turning preference). Using data simulations, we additionally show that the large effect sizes and small within-group variances that have been reported in several previous studies are highly improbable. Together, our findings indicate that the reported effects of ocean acidification on the behaviour of coral reef fishes are not reproducible, suggesting that behavioural perturbations will not be a major consequence for coral reef fishes in high CO2 oceans.

  • 57.
    Clark, Timothy D.
    et al.
    Univ Tasmania, Inst Marine & Antarctic Studies, Hobart, Tas 7000, Australia.;CSIRO Agr & Food, Hobart, Tas 7000, Australia..
    Roche, Dominique G.
    Univ Neuchatel, Inst Biol, CH-2000 Neuchatel, Switzerland..
    Binning, Sandra A.
    Univ Neuchatel, Inst Biol, CH-2000 Neuchatel, Switzerland..
    Speers-Roesch, Ben
    Sundin, Josefin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Maximum thermal limits of coral reef damselfishes are size dependent and resilient to near-future ocean acidification2017In: Journal of Experimental Biology, ISSN 0022-0949, E-ISSN 1477-9145, Vol. 220, no 19, p. 3519-3526Article in journal (Refereed)
    Abstract [en]

    Theoretical models predict that ocean acidification, caused by increased dissolved CO2, will reduce the maximum thermal limits of fishes, thereby increasing their vulnerability to rising ocean temperatures and transient heatwaves. Here, we tested this prediction in three species of damselfishes on the Great Barrier Reef, Australia. Maximum thermal limits were quantified using critical thermal maxima (CTmax) tests following acclimation to either presentday or end-of-century levels of CO2 for coral reef environments (similar to 500 or similar to 1000 mu atm, respectively). While species differed significantly in their thermal limits, whereby Dischistodus perspicillatus exhibited greater CTmax (37.88 +/- 0.03 degrees C; N=47) than Dascyllus aruanus (37.68 +/- 0.02 degrees C; N=85) and Acanthochromis polyacanthus (36.58 +/- 0.02 degrees C; N=63), end-of-century CO2 had no effect (D. aruanus) or a slightly positive effect (increase in CTmax of 0.16 degrees C in D. perspicillatus and 0.21 degrees C in A. polyacanthus) on CTmax. Contrary to expectations, early-stage juveniles were equally as resilient to CO2 as larger conspecifics, and CTmax was higher at smaller body sizes in two species. These findings suggest that ocean acidification will not impair the maximum thermal limits of reef fishes, and they highlight the critical role of experimental biology in testing predictions of theoretical models forecasting the consequences of environmental change.

  • 58.
    Cocco, Arianna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    The γ-aminobutyric acid and proton signaling systems in the zebrafish brain: Characterization and effect of stress2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The central nervous system of vertebrates is continuously processing sensory information relayed from the periphery, integrating it and producing outputs transmitted to efferents. In the brain, neurons employ an array of messenger molecules to filter afferent information and finely regulate synaptic transmission. The γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the adult vertebrate central nervous system, synthesized from α, L-glutamate by the glutamate decarboxylases (GADs). GABA promotes fast hyperpolarization of target cells mediated by the ionotropic, chloride-conducting type A GABA (GABAA) receptors. Those channels are homo- or heteropentamers and, in the zebrafish, at least twenty-three genes encode for putative GABAA receptor subunits.

    The present PhD thesis presents the expression levels of the almost complete panel of the GABA signaling machinery in the adult zebrafish brain and retinas. The results point toward GABA signaling modalities in zebrafish strikingly similar to those observed in mammals. The most common GABAA receptor subunit combinations in the whole brain were proposed to be α1β2γ2 and α1β2δ, and region-specific GABAA channels were also inferred. Those included telencephalic α2bβ3γ2, α2bβ3δ, α5β2γ2, α5β3γ2 and cerebellar α4β2γ2 and α4β2δ. A tissue specific expression was documented for the paralogues α6a and α6b; the former was abundantly transcribed in the retinas, the latter in the cerebellum. Proposed retinal GABAA receptors were α1βxγ2, α1βxδ, α6aβxγ2 and α6aβxδ, with either β2 or β3.

    Focus was also placed on functional aspects of the GABA signaling system in the adult zebrafish brain, and specifically on the effects of stress on GABAA receptor subunits expression. Treated animals experienced social isolation and repeated confinement, and depicted increased mRNA levels of several GABAA receptor monomers. It was deduced that a higher number of extrasynaptic, tonic-current-mediating GABAA channels was synthesized in the brain following stress. As synaptic transmission promotes extracellular acidification, interest was also placed on the acid-sensing ion channel (ASIC) subunits. The overall results presented in this PhD thesis point toward GABA and proton signaling systems in the zebrafish brain that have many common points with those of mammals. Thus, fundamental signaling pathways appear to be conserved across vertebrates.

    List of papers
    1. Neural expression patterns and protein modeling of the GABAA receptor ζ subunit in the adult zebrafish (Danio rerio Hamilton, 1822)
    Open this publication in new window or tab >>Neural expression patterns and protein modeling of the GABAA receptor ζ subunit in the adult zebrafish (Danio rerio Hamilton, 1822)
    2018 (English)In: Zebrafish, ISSN 1545-8547, E-ISSN 1557-8542Article in journal (Refereed) Submitted
    Abstract [en]

     

    The zebrafish has a repertoire of twenty-six GABAA receptor subunits, including the paralogues π and ζ, homologous to the mammalian π. The brain mRNA levels of the π subunit are low, but the ζ gene is actively transcribed in D. rerio central nervous system and retinas. With a combined quantitative and qualitative gene expression profiling approach, this research characterized the distribution of the ζ transcript in the brain and eyes of the adult zebrafish. It was demonstrated that there are regional brain differences in the production of this transcript, with the stratum periventriculare of the tecta mesencephali having the highest mRNA levels for ζ. In the adult zebrafish retinas the bipolar cell layer presented staining for the ζ transcript. The three-dimensional structure of the ζ subunit of the GABAA receptor in zebrafish was also calculated in this study, with the human β3 as template. It presented four transmembrane α-helices and an amino-terminal β-loop framed into a disulfide bridge. It was therefore possible to place ζ in the superfamily of Cys-loop membrane proteins, to which GABAA receptor subunits belong. The current study presented a thorough characterization of a unique fish GABAA receptor subunit, which might have specific functions only typical of fish.

    Keywords
    GABA signaling system, ζ subunit, neuroanatomy, retina anatomy, homologous subunits
    National Category
    Biochemistry and Molecular Biology
    Research subject
    Biochemistry
    Identifiers
    urn:nbn:se:uu:diva-348420 (URN)
    Funder
    Swedish Research Council, 621-2012-4679
    Available from: 2018-04-12 Created: 2018-04-12 Last updated: 2018-04-17
    2. Characterization of the gamma-aminobutyric acid signaling system in the zebrafish (danio rerio hamilton) central nervous system by reverse transcription-quantitative polymerase chain reaction
    Open this publication in new window or tab >>Characterization of the gamma-aminobutyric acid signaling system in the zebrafish (danio rerio hamilton) central nervous system by reverse transcription-quantitative polymerase chain reaction
    Show others...
    2017 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 343, p. 300-321Article in journal (Refereed) Published
    Abstract [en]

    In the vertebrate brain, inhibition is largely mediated by raminobutyric acid (GABA). This neurotransmitter comprises a signaling machinery of GABA(A), GABA(B) receptors, transporters, glutamate decarboxylases (gads) and 4-aminobutyrate aminotransferase (abat), and associated proteins. Chloride is intimately related to GABAA receptor conductance, GABA uptake, and GADs activity. The response of target neurons to GABA stimuli is shaped by chloride-cation co-transporters (CCCs), which strictly control Cl- gradient across plasma membranes. This research profiled the expression of forty genes involved in GABA signaling in the zebrafish (Danio rerio) brain, grouped brain regions and retinas. Primer pairs were developed for reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The mRNA levels of the zebrafish GABA system share similarities with that of mammals, and confirm previous studies in non-mammalian species. Proposed GABAA receptors are alpha(1)beta(2)gamma(2), alpha(1)beta(2)delta, alpha(2b)beta(3), alpha(2b)beta(3)delta, alpha(4)beta(2)gamma(2), alpha(4)beta(2)gamma, alpha(6b)beta(2)gamma(2) and alpha(6b)beta(2)delta. Regional brain differences were documented. Retinal hetero- or homomeric rho-composed GABAA receptors could exist, accompanying alpha(1)beta(y)gamma(2), alpha(1)beta(y)delta, alpha(6a)beta(y)gamma(2,) alpha(6a)beta(y)delta. Expression patterns of alpha(6a) and alpha(6b) were opposite, with the former being more abundant in retinas, the latter in brains. Given the stoichiometry alpha(6w)beta(y)gamma(z), alpha(6a-) or alpha(6b)-containing receptors likely have different regulatory mechanisms. Different gene isoforms could originate after the rounds of genome duplication during teleost evolution. This research depicts that one isoform is generally more abundantly expressed than the other. Such observations also apply to GABAB receptors, GABA transporters, GABA-related enzymes, CCCs and GABAA receptor associated proteins, whose presence further strengthens the proof of a GABA system in zebrafish.

    Keywords
    GABA, comparative neuroscience, teleost, zebrafish, neurotransmitter systems, receptors
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-317583 (URN)10.1016/j.neuroscience.2016.07.018 (DOI)000393269100030 ()27453477 (PubMedID)
    Funder
    Swedish Research Council
    Available from: 2017-03-24 Created: 2017-03-24 Last updated: 2018-04-17Bibliographically approved
    3. Confinement affects the mRNA levels of key elements in the γ-aminobutyric acid and proton signaling systems in the zebrafish brain
    Open this publication in new window or tab >>Confinement affects the mRNA levels of key elements in the γ-aminobutyric acid and proton signaling systems in the zebrafish brain
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-348524 (URN)
    Funder
    Swedish Research Council, 621-2012-4679
    Available from: 2018-04-15 Created: 2018-04-15 Last updated: 2018-04-17
    Download full text (pdf)
    fulltext
    Download (jpg)
    presentationsbild
    Download (pdf)
    errata
  • 59.
    Cocco, Arianna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Rönnberg, A. M. Carolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    André, Goncalo Igreja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Univ Western Australia, Ctr Evolutionary Biol, 35 Stirling Hwy, Crawley, WA 6009, Australia..
    Vossen, Laura E.
    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.
    Thörnqvist, Per-Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Characterization of the gamma-aminobutyric acid signaling system in the zebrafish (danio rerio hamilton) central nervous system by reverse transcription-quantitative polymerase chain reaction2017In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 343, p. 300-321Article in journal (Refereed)
    Abstract [en]

    In the vertebrate brain, inhibition is largely mediated by raminobutyric acid (GABA). This neurotransmitter comprises a signaling machinery of GABA(A), GABA(B) receptors, transporters, glutamate decarboxylases (gads) and 4-aminobutyrate aminotransferase (abat), and associated proteins. Chloride is intimately related to GABAA receptor conductance, GABA uptake, and GADs activity. The response of target neurons to GABA stimuli is shaped by chloride-cation co-transporters (CCCs), which strictly control Cl- gradient across plasma membranes. This research profiled the expression of forty genes involved in GABA signaling in the zebrafish (Danio rerio) brain, grouped brain regions and retinas. Primer pairs were developed for reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The mRNA levels of the zebrafish GABA system share similarities with that of mammals, and confirm previous studies in non-mammalian species. Proposed GABAA receptors are alpha(1)beta(2)gamma(2), alpha(1)beta(2)delta, alpha(2b)beta(3), alpha(2b)beta(3)delta, alpha(4)beta(2)gamma(2), alpha(4)beta(2)gamma, alpha(6b)beta(2)gamma(2) and alpha(6b)beta(2)delta. Regional brain differences were documented. Retinal hetero- or homomeric rho-composed GABAA receptors could exist, accompanying alpha(1)beta(y)gamma(2), alpha(1)beta(y)delta, alpha(6a)beta(y)gamma(2,) alpha(6a)beta(y)delta. Expression patterns of alpha(6a) and alpha(6b) were opposite, with the former being more abundant in retinas, the latter in brains. Given the stoichiometry alpha(6w)beta(y)gamma(z), alpha(6a-) or alpha(6b)-containing receptors likely have different regulatory mechanisms. Different gene isoforms could originate after the rounds of genome duplication during teleost evolution. This research depicts that one isoform is generally more abundantly expressed than the other. Such observations also apply to GABAB receptors, GABA transporters, GABA-related enzymes, CCCs and GABAA receptor associated proteins, whose presence further strengthens the proof of a GABA system in zebrafish.

    Download full text (pdf)
    fulltext
  • 60.
    Cocco, Arianna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Vossen, Laura
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Näslund, Joacim
    Stockholm University.
    Thörnqvist, Per-Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Confinement affects the mRNA levels of key elements in the γ-aminobutyric acid and proton signaling systems in the zebrafish brainManuscript (preprint) (Other academic)
  • 61.
    Cocco, Arianna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Williams, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Thörnqvist, Per-Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Neural expression patterns and protein modeling of the GABAA receptor ζ subunit in the adult zebrafish (Danio rerio Hamilton, 1822)2018In: Zebrafish, ISSN 1545-8547, E-ISSN 1557-8542Article in journal (Refereed)
    Abstract [en]

     

    The zebrafish has a repertoire of twenty-six GABAA receptor subunits, including the paralogues π and ζ, homologous to the mammalian π. The brain mRNA levels of the π subunit are low, but the ζ gene is actively transcribed in D. rerio central nervous system and retinas. With a combined quantitative and qualitative gene expression profiling approach, this research characterized the distribution of the ζ transcript in the brain and eyes of the adult zebrafish. It was demonstrated that there are regional brain differences in the production of this transcript, with the stratum periventriculare of the tecta mesencephali having the highest mRNA levels for ζ. In the adult zebrafish retinas the bipolar cell layer presented staining for the ζ transcript. The three-dimensional structure of the ζ subunit of the GABAA receptor in zebrafish was also calculated in this study, with the human β3 as template. It presented four transmembrane α-helices and an amino-terminal β-loop framed into a disulfide bridge. It was therefore possible to place ζ in the superfamily of Cys-loop membrane proteins, to which GABAA receptor subunits belong. The current study presented a thorough characterization of a unique fish GABAA receptor subunit, which might have specific functions only typical of fish.

  • 62.
    Dahl, Emma
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Population and Conservation Biology.
    Backström, T.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Laurila, Anssi
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Population and Conservation Biology.
    Is growth hormone expression correlated with variation in growth rate along a latitudinal gradient in Rana temporaria?2011In: Journal of Zoology, ISSN 0952-8369, E-ISSN 1469-7998, Vol. 285, no 2, p. 85-92Article in journal (Refereed)
    Abstract [en]

    In ectotherms, decreasing season length and lower temperature towards higher latitudes often favour higher growth and developmental rates. However, the underlying physiological mechanisms and particularly the hormonal correlates of clinal variation remain unexplored. The growth hormone (GH) plays a crucial role in growth of all vertebrates and high expression of GH is associated with rapid growth in many species. We tested the hypothesis that GH expression is correlated with a latitudinal gradient in growth in Scandinavian Rana temporaria tadpoles. Using quantitative polymerase chain reaction, we measured GH and growth hormone receptor (GHR) expression at two time points from laboratory-raised tadpoles originating from eight populations collected along the latitudinal gradient. To explore latitudinal differences in stress-induced changes in GH expression, we also compared GH expression in tadpoles raised with and without predators. In accordance with previous studies we found a clear latitudinal gradient in growth. There were no latitudinal effects, or predator-induced effects on GH or GHR expression. However, there was some indication for among-population variation in GH expression. The lack of a latitudinal pattern in GH and GHR expression may be due to that the growth promoting effects of GH is dependent on other factors including insulin-like growth factor-I (IGF), IGF-binding proteins or prolactin. Further studies on these factors may provide insight on the proximal mechanisms of differences in growth in R. temporaria tadpoles.

  • 63.
    Dahl, Emma
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Population and Conservation Biology.
    Orizaola, German
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Population and Conservation Biology.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Laurila, Anssi
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Population and Conservation Biology.
    Geographic variation in corticosterone response to chronic predator stress in tadpoles2012In: Journal of Evolutionary Biology, ISSN 1010-061X, E-ISSN 1420-9101, Vol. 25, no 6, p. 1066-1076Article in journal (Refereed)
    Abstract [en]

    Chronic stress often affects growth and development negatively, and these effects are often mediated via glucocorticoid hormones, which elevate during stress. We investigated latitudinal variation in corticosterone (CORT) response to chronic predator stress in Rana temporaria tadpoles along a 1500-km latitudinal cline in Sweden tadpoles, in a laboratory experiment. We hypothesized that more time-constrained high-latitude populations have evolved a lower CORT response to chronic stress to maintain higher growth under stressful conditions. Southern tadpoles had higher CORT content in response to predators after 1 day of exposure, whereas there was no increase in CORT in the northern populations. Two weeks later, there were no predator-induced CORT elevations. Artificially elevated CORT levels strongly decreased growth, development and survival in both northern and southern tadpoles. We suggest that the lower CORT response in high-latitude populations can be connected with avoidance of CORT-mediated reduction in growth and development, but also discuss other possible explanations.

  • 64.
    Dahlbom, Josefin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Lagman, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Lundstedt-Enkel, Katrin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Sundström, Fredrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal Ecology.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Boldness predicts social status in zebrafish (Danio rerio)2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 8, article id e23565Article in journal (Refereed)
    Abstract [en]

    This study explored if boldness could be used to predict social status. First, boldness was assessed by monitoring individual zebrafish behaviour in (1) an unfamiliar barren environment with no shelter (open field), (2) the same environment when a roof was introduced as a shelter, and (3) when the roof was removed and an unfamiliar object (Lego® brick) was introduced. Next, after a resting period of minimum one week, social status of the fish was determined in a dyadic contest and dominant/subordinate individuals were determined as the winner/loser of two consecutive contests. Multivariate data analyses showed that males were bolder than females and that the behaviours expressed by the fish during the boldness tests could be used to predict which fish would later become dominant and subordinate in the ensuing dyadic contest. We conclude that bold behaviour is positively correlated to dominance in zebrafish and that boldness is not solely a consequence of social dominance.

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  • 65.
    Dahlbom, S Josefin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bully or Bullied?: The Zebrafish as a Model for Social Stress and Depression2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The zebrafish is evaluated as a model for social stress, depression and anxiety. I conclude that it is suitable, especially for studies of sex differences. In humans, women are more prone to depression but most animal studies are performed in males. A popular way to study depression is by means of social stress, which is often a contributing factor to depression. However, social stress in female rodents is difficult to study since female aggression is mostly limited to maternal defence. Thus, there is a need for models to study depression and anxiety in females, as well as sex differences in these disorders.

    As personality is a risk factor for developing depression, I aimed at exploring correlated behaviours that together characterise personalities. My work confirmed that zebrafish, as numerous other species, show strong correlations between boldness and aggression on the one hand, and neurobiological reactions to social stress on the other. In general, males were bolder than females, but there were no differences in aggressive behaviours between the sexes. It was also confirmed that both acute and chronic social stress activates the dopamine and serotonin systems in the brain, and that subordinate individuals appear to be more stressed, based on serotonergic activity.

    Further, I studied the consequences of altered levels of serotonin during development, such as would be the case when antidepressants are used during pregnancy. Zebrafish embryos were treated with drugs that affect the serotonin system by increasing or decreasing serotonin levels. Depletion of serotonin increased the expression of several serotonin-related genes but had no effect on morphology. In contrast, increasing serotonin levels only showed small effects on gene expression, but increased the length of the myotomes in the spinal cord. Together with other studies, my results indicate that fluvoxamine might be a suitable choice for treatment of depression during pregnancy.

    In conclusion, my results show that the zebrafish is a valid model organism for studying social stress, depression and anxiety disorders and it should therefore be considered when developing new animal models for depression. It will especially be beneficial in studies of sex differences.

    List of papers
    1. Boldness predicts social status in zebrafish (Danio rerio)
    Open this publication in new window or tab >>Boldness predicts social status in zebrafish (Danio rerio)
    Show others...
    2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 8, article id e23565Article in journal (Refereed) Published
    Abstract [en]

    This study explored if boldness could be used to predict social status. First, boldness was assessed by monitoring individual zebrafish behaviour in (1) an unfamiliar barren environment with no shelter (open field), (2) the same environment when a roof was introduced as a shelter, and (3) when the roof was removed and an unfamiliar object (Lego® brick) was introduced. Next, after a resting period of minimum one week, social status of the fish was determined in a dyadic contest and dominant/subordinate individuals were determined as the winner/loser of two consecutive contests. Multivariate data analyses showed that males were bolder than females and that the behaviours expressed by the fish during the boldness tests could be used to predict which fish would later become dominant and subordinate in the ensuing dyadic contest. We conclude that bold behaviour is positively correlated to dominance in zebrafish and that boldness is not solely a consequence of social dominance.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-157531 (URN)10.1371/journal.pone.0023565 (DOI)000294121300060 ()
    Available from: 2011-08-22 Created: 2011-08-22 Last updated: 2017-12-08Bibliographically approved
    2. Aggression and monoamines: Effects of sex and social rank in zebrafish (Danio rerio)
    Open this publication in new window or tab >>Aggression and monoamines: Effects of sex and social rank in zebrafish (Danio rerio)
    2012 (English)In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 228, no 2, p. 333-338Article in journal (Refereed) Published
    Abstract [en]

    Social defeat is a common model for studies on depression. However, such models are most often used to study aggression in males and sex differences in depression may therefore be overseen. This study investigated the potential of the zebrafish (Danio rerio) as a model for male and female aggression. In addition, effects on the brain serotonergic and dopaminergic neurotransmitter systems after agonistic interaction are well studied in many species, but not in zebrafish. We wanted to explore whether the zebrafish follows the same patterns as many other species. Therefore, the effects of agonistic interaction on brain monoaminergic activity were studied in adult male and female wild-type zebrafish. The fish interacted in pairs with one of the same sex for five days during which agonistic behaviour was quantified daily. Clear dominant/subordinate relationships developed in all pairs, both in males and females. The frequency of aggressive acts increased over time but did not differ between male and female pairs. Further, we found that dyadic agonistic interaction resulted in elevated brain serotonergic activity in subordinate zebrafish, as indicated by elevated hindbrain 5-hydroxyindoleacetic acid to serotonin ratios (5-hydroxyindolacetic acid (5-HIAA)/5-hydroxytryptamine (5-HT) ratios). We also observed a sex difference in forebrain dopamine levels and forebrain 5-HIAA/5-HT ratios, with females displaying higher concentrations of dopamine but lower 5-HIAA/5-HT ratios than males. These results suggest that zebrafish is a suitable model for studies on female aggression and sex differences in brain monoaminergic neurotransmission.

    Keywords
    Dominance, Aggression, Zebrafish, Monoamine, Sex difference
    National Category
    Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-168935 (URN)10.1016/j.bbr.2011.12.011 (DOI)000301318900012 ()
    Available from: 2012-02-20 Created: 2012-02-20 Last updated: 2018-01-12Bibliographically approved
    3. Social modulation of brain monoamine levels in zebrafish
    Open this publication in new window or tab >>Social modulation of brain monoamine levels in zebrafish
    2013 (English)In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 253, p. 17-24Article in journal (Refereed) Published
    Abstract [en]

    In social species animals tend to adjust their social behaviour according to the available social information in the group, in order to optimize and improve their one social status. This changing environment requires for rapid and transient behavioural changes that relies primarily on biochemical switching of existing neural networks. Monoamines and neuropeptides are the two major candidates to mediate these changes in brain states underlying socially behavioural flexibility. In the current study we used zebrafish (Danio rerio) males to study the effects of acute social interactions on rapid regional changes in brain levels of monoamines (serotonin and dopamine). A behavioural paradigm under which male zebrafish consistently express fighting behaviour was used to investigate the effects of different social experiences: winning the interaction, losing the interaction, or fighting an unsolved interaction (mirror image). We found that serotonergic activity is significantly higher in the telencephalon of winners and in the optic tectum of losers, and no significant changes were observed in mirror fighters suggesting that serotonergic activity is differentially regulated in different brain regions by social interactions. Dopaminergic activity it was also significantly higher in the telencephalon of winners which may be representative of social reward. Together our data suggests that acute social interactions elicit rapid and differential changes in serotonergic and dopaminergic activity across different brain regions.

    National Category
    Behavioral Sciences Biology
    Identifiers
    urn:nbn:se:uu:diva-205419 (URN)10.1016/j.bbr.2013.07.012 (DOI)000324720500003 ()23850359 (PubMedID)
    Available from: 2013-08-16 Created: 2013-08-16 Last updated: 2017-12-06Bibliographically approved
    4. Effects of drugs that alter serotonin levels on morphology and expression of genes related to serotonin signalling
    Open this publication in new window or tab >>Effects of drugs that alter serotonin levels on morphology and expression of genes related to serotonin signalling
    (English)Manuscript (preprint) (Other academic)
    National Category
    Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-205421 (URN)
    Available from: 2013-08-16 Created: 2013-08-16 Last updated: 2018-01-11
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  • 66.
    Dahlbom, S. Josefin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Backström, Tobias
    Sveriges lantbruksuniversitet, Institutionen för vilt, fisk och miljö .
    Lundstedt-Enkel, Katrin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Aggression and monoamines: Effects of sex and social rank in zebrafish (Danio rerio)2012In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 228, no 2, p. 333-338Article in journal (Refereed)
    Abstract [en]

    Social defeat is a common model for studies on depression. However, such models are most often used to study aggression in males and sex differences in depression may therefore be overseen. This study investigated the potential of the zebrafish (Danio rerio) as a model for male and female aggression. In addition, effects on the brain serotonergic and dopaminergic neurotransmitter systems after agonistic interaction are well studied in many species, but not in zebrafish. We wanted to explore whether the zebrafish follows the same patterns as many other species. Therefore, the effects of agonistic interaction on brain monoaminergic activity were studied in adult male and female wild-type zebrafish. The fish interacted in pairs with one of the same sex for five days during which agonistic behaviour was quantified daily. Clear dominant/subordinate relationships developed in all pairs, both in males and females. The frequency of aggressive acts increased over time but did not differ between male and female pairs. Further, we found that dyadic agonistic interaction resulted in elevated brain serotonergic activity in subordinate zebrafish, as indicated by elevated hindbrain 5-hydroxyindoleacetic acid to serotonin ratios (5-hydroxyindolacetic acid (5-HIAA)/5-hydroxytryptamine (5-HT) ratios). We also observed a sex difference in forebrain dopamine levels and forebrain 5-HIAA/5-HT ratios, with females displaying higher concentrations of dopamine but lower 5-HIAA/5-HT ratios than males. These results suggest that zebrafish is a suitable model for studies on female aggression and sex differences in brain monoaminergic neurotransmission.

  • 67.
    Dahlbom, s Josefin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Kettunen, Petronella
    Göteborgs Universitet.
    Effects of drugs that alter serotonin levels on morphology and expression of genes related to serotonin signallingManuscript (preprint) (Other academic)
  • 68.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Roos, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Johansson, P
    Tannergren, C
    Lundqvist, A
    Langguth, P
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    The effects of three absorption-modifying critical excipients on the in vivo intestinal absorption of six model compounds in rats and dogs.2018In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 547, no 1-2, p. 158-168Article in journal (Refereed)
    Abstract [en]

    Pharmaceutical excipients that may affect gastrointestinal (GI) drug absorption are called critical pharmaceutical excipients, or absorption-modifying excipients (AMEs) if they act by altering the integrity of the intestinal epithelial cell membrane. Some of these excipients increase intestinal permeability, and subsequently the absorption and bioavailability of the drug. This could have implications for both the assessment of bioequivalence and the efficacy of the absorption-enhancing drug delivery system. The absorption-enhancing effects of AMEs with different mechanisms (chitosan, sodium caprate, sodium dodecyl sulfate (SDS)) have previously been evaluated in the rat single-pass intestinal perfusion (SPIP) model. However, it remains unclear whether these SPIP data are predictive in a more in vivo like model. The same excipients were in this study evaluated in rat and dog intraintestinal bolus models. SDS and chitosan did exert an absorption-enhancing effect in both bolus models, but the effect was substantially lower than those observed in the rat SPIP model. This illustrates the complexity of the AME effects, and indicates that additional GI physiological factors need to be considered in their evaluation. We therefore recommend that AME evaluations obtained in transit-independent, preclinical permeability models (e.g. Ussing, SPIP) should be verified in animal models better able to predict in vivo relevant GI effects, at multiple excipient concentrations.

  • 69.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Roos, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lundqvist, A
    AstraZeneca R&D, Gothenburg, Sweden.
    Tannergren, C
    AstraZeneca R&D, Gothenburg, Sweden.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Effect of absorption-modifying excipients, hypotonicity, and enteric neural activity in an in vivo model for small intestinal transport.2018In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 549, no 1-2, p. 239-248, article id S0378-5173(18)30532-5Article in journal (Refereed)
    Abstract [en]

    The small intestine mucosal barrier is physiologically regulated by the luminal conditions, where intestinal factors, such as diet and luminal tonicity, can affect mucosal permeability. The intestinal barrier may also be affected by absorption-modifying excipients (AME) in oral drug delivery systems. Currently, there is a gap in the understanding of how AMEs interact with the physiological regulation of intestinal electrolyte transport and fluid flux, and epithelial permeability. Therefore, the objective of this single-pass perfusion study in rat was to investigate the effect of three AMEs on the intestinal mucosal permeability at different luminal tonicities (100, 170, and 290 mOsm). The effect was also evaluated following luminal administration of a nicotinic receptor antagonist, mecamylamine, and after intravenous administration of a COX-2 inhibitor, parecoxib, both of which affect the enteric neural activity involved in physiological regulation of intestinal functions. The effect was evaluated by changes in intestinal lumen-to-blood transport of six model compounds, and blood-to-lumen clearance of 51Cr-EDTA (a mucosal barrier marker). Luminal hypotonicity alone increased the intestinal epithelial transport of 51Cr-EDTA. This effect was potentiated by two AMEs (SDS and caprate) and by parecoxib, while it was reduced by mecamylamine. Consequently, the impact of enteric neural activity and luminal conditions may affect nonclinical determinations of intestinal permeability. In vivo predictions based on animal intestinal perfusion models can be improved by considering these effects. The in vivo relevance can be increased by treating rats with a COX-2 inhibitor prior to surgery. This decreases the risk of surgery-induced ileus, which may affect the physiological regulation of mucosal permeability.

  • 70.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Roos, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lundqvist, A.
    Tannergren, C.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Time-dependent effects on small intestinal transport by absorption-modifying excipients2018In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 132, p. 19-28Article in journal (Refereed)
    Abstract [en]

    The relevance of the rat single-pass intestinal perfusion model for investigating in vivo time-dependent effects of absorption-modifying excipients (AMEs) is not fully established. Therefore, the dynamic effect and recovery of the intestinal mucosa was evaluated based on the lumen-to-blood flux (Jabs) of six model compounds, and the blood-to-lumen clearance of 51Cr-EDTA (CLCr), during and after 15- and 60-min mucosal exposure of the AMEs, sodium dodecyl sulfate (SDS) and chitosan, in separate experiments. The contribution of enteric neurons on the effect of SDS and chitosan was also evaluated by luminal coadministration of the nicotinic receptor antagonist, mecamylamine. The increases in Jabs and CLCr (maximum and total) during the perfusion experiments were dependent on exposure time (15 and 60 min), and the concentration of SDS, but not chitosan. The increases in Jabs and CLCr following the 15-min intestinal exposure of both SDS and chitosan were greater than those reported from an in vivo rat intraintestinal bolus model. However, the effect in the bolus model could be predicted from the increase of Jabs at the end of the 15-min exposure period, where a six-fold increase in Jabs was required for a corresponding effect in the in vivo bolus model. This illustrates that a rapid and robust effect of the AME is crucial to increase the in vivo intestinal absorption rate before the yet unabsorbed drug in lumen has been transported distally in the intestine. Further, the recovery of the intestinal mucosa was complete following 15-min exposures of SDS and chitosan, but it only recovered 50% after the 60-min intestinal exposures. Our study also showed that the luminal exposure of AMEs affected the absorptive model drug transport more than the excretion of 51Cr-EDTA, as Jabs for the drugs was more sensitive than CLCr at detecting dynamic mucosal AME effects, such as response rate and recovery. Finally, there appears to be no nicotinergic neural contribution to the absorption-enhancing effect of SDS and chitosan, as luminal administration of 0.1 mM mecamylamine had no effect.

  • 71.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Roos, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lundqvist, Anders
    AstraZeneca R&D.
    Tannergren, Christer
    AstraZeneca R&D.
    Langguth, Peter
    School of Pharmacy, Johannes Gutenberg-University, 55122 Mainz, Germany.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Preclinical Effect of Absorption Modifying Excipients on Rat Intestinal Transport of Model Compounds and the Mucosal Barrier Marker 51Cr-EDTA2017In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, no 12, p. 4243-4251Article in journal (Refereed)
    Abstract [en]

    There is a renewed interest from the pharmaceutical field to develop oral formulations of compounds, such as peptides, oligonucleotides, and polar drugs. However, these often suffer from insufficient absorption across the intestinal mucosal barrier. One approach to circumvent this problem is the use of absorption modifying excipient(s) (AME). This study determined the absorption enhancing effect of four AMEs (sodium dodecyl sulfate, caprate, chitosan, N-acetylcysteine) on five model compounds in a rat jejunal perfusion model. The aim was to correlate the model compound absorption to the blood-to-lumen clearance of the mucosal marker for barrier integrity, 51Cr-EDTA. Sodium dodecyl sulfate and chitosan increased the absorption of the low permeation compounds but had no effect on the high permeation compound, ketoprofen. Caprate and N-acetylcysteine did not affect the absorption of any of the model compounds. The increase in absorption of the model compounds was highly correlated to an increased blood-to-lumen clearance of 51Cr-EDTA, independent of the AME. Thus, 51Cr-EDTA could be used as a general, sensitive, and validated marker molecule for absorption enhancement when developing novel formulations.

  • 72.
    de Abreu, Murilo S.
    et al.
    Univ Fed Santa Maria, Programa Posgrad Farmacol, Santa Maria, RS, Brazil.
    Messias, Joao P. M.
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet, CIBIO, Porto, Portugal.
    Thörnqvist, Per-Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Winberg, Svante
    Uppsala Univ, Dept Neurosci, Uppsala, Sweden.
    Soares, Marta C.
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet, CIBIO, Porto, Portugal.
    The variable monoaminergic outcomes of cleaner fish brains when facing different social and mutualistic contexts2018In: PeerJ, ISSN 2167-8359, E-ISSN 2167-8359, Vol. 6, article id e4830Article in journal (Refereed)
    Abstract [en]

    The monoamines serotonin and dopamine are important neuromodulators present in the central nervous system, known to be active regulators of social behaviour in fish as in other vertebrates. Our aim was to investigate the region-specific brain monoaminergic differences arising when individual cleaners face a client (mutualistic context) compared to when they are introduced to another conspecific (conspecific context), and to understand the relevance of visual assessment compared to the impact of physical contact with any partner. We demonstrated that serotoninergic activity at the diencephalon responds mostly to the absence of physical contact with clients whereas cerebellar dopaminergic activity responds to actual cleaning engagement. We provide first insights on the brain's monoaminergic (region-specific) response variations, involved in the expression of cleaner fishes' mutualistic and conspecific behaviour. These results contribute to a better understanding of the monoaminergic activity in accordance to different socio-behavioural contexts.

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  • 73.
    de Haan, Roel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Lee, Yu-Jen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Nordström, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Novel Flicker-Sensitive Visual Circuit Neurons Inhibited by Stationary Patterns2013In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 33, no 21, p. 8980-8989Article in journal (Refereed)
    Abstract [en]

    Many animals use visual motion cues for navigating within their surroundings. Both flies and vertebrates compute local motion by temporal correlation of neighboring photoreceptors, via so-called elementary motion detectors (EMDs). In the fly lobula plate and the vertebrate visual cortex the output from many EMDs is pooled in neurons sensitive to wide-field optic flow. Although the EMD has been the preferred model for more than 50 years, recent work has highlighted its limitations in describing some visual behaviors, such as responses to higher-order motion stimuli. Non-EMD motion processing may therefore serve an important function in vision. Here, we describe a novel neuron class in the fly lobula plate that clearly does not derive its input from classic EMDs. The centrifugal stationary inhibited flicker excited (cSIFE) neuron is strongly excited by flicker, up to very high temporal frequencies. The non-EMD driven flicker sensitivity leads to strong, nondirectional responses to high-speed, wide-field motion. Furthermore, cSIFE is strongly inhibited by stationary patterns, within a narrow wavelength band. cSIFE's outputs overlap with the inputs of well described optic flow-sensitive lobula plate tangential cells (LPTCs). Driving cSIFE affects the active dendrites of LPTCs, and cSIFE may therefore play a large role in motion vision.

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  • 74.
    de Haan, Roel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Lee, Yu-Jen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Nordström, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Octopaminergic modulation of contrast sensitivity2012In: Frontiers in Integrative Neuroscience, ISSN 1662-5145, E-ISSN 1662-5145, Vol. 6, no Article 55Article in journal (Refereed)
    Abstract [en]

    Sensory systems adapt to prolonged stimulation by decreasing their response to continuous stimuli. Whereas visual motion adaptation has traditionally been studied in immobilized animals, recent work indicates that the animal's behavioral state influences the response properties of higher-order motion vision-sensitive neurons. During insect flight octopamine is released, and pharmacological octopaminergic activation can induce a fictive locomotor state. In the insect optic ganglia, lobula plate tangential cells (LPTCs) spatially pool input from local elementary motion detectors (EMDs) that correlate luminosity changes from two spatially discrete inputs after delaying the signal from one. The LPTC velocity optimum thereby depends on the spatial separation of the inputs and on the EMD's delay properties. Recently it was shown that behavioral activity increases the LPTC velocity optimum, with modeling suggesting this to originate in the EMD's temporal delay filters. However, behavior induces an additional post-EMD effect: the LPTC membrane conductance increases in flying flies. To physiologically investigate the degree to which activity causes presynaptic and postsynaptic effects, we conducted intracellular recordings of Eristalis horizontal system (HS) neurons. We constructed contrast response functions before and after adaptation at different temporal frequencies, with and without the octopamine receptor agonist chlordimeform (CDM). We extracted three motion adaptation components, where two are likely to be generated presynaptically of the LPTCs, and one within them. We found that CDM affected the early, EMD-associated contrast gain reduction, temporal frequency dependently. However, a CDM-induced change of the HS membrane conductance disappeared during and after visual stimulation. This suggests that physical activity mainly affects motion adaptation presynaptically of LPTCs, whereas post-EMD effects have a minimal effect.

  • 75.
    Dyakova, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology. Flinders University.
    The processing of natural images in the visual system2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Any image can be described in terms of its statistics (i.e. quantitative parameters calculated from the image, for example RMS-contrast, the skewness of image brightness distribution, and slope constant of an average amplitude spectrum).

    It was previously shown that insect and vertebrate visual systems are optimised to the statistics common among natural scenes. However, the exact mechanisms of this process are still unclear and need further investigation.

    This thesis presents the results of examining links between some image statistics and visual responses in humans and hoverflies.

    It was found that while image statistics do not play the main role when hoverflies (Eristalis tenax and Episyrphus balteatus) chose what flowers to feed on, there is a link between hoverfly (Episyrphus balteatus) active behaviours and image statistics. There is a significant difference in the slope constant of the average amplitude spectrum, RMS contrast and skewness of brightness distribution between photos of areas where hoverflies were hovering or flying. These photos were also used to create a prediction model of hoverfly behaviour. After model validation, it was concluded that photos of both the ground and the surround should be used for best prediction of behaviour. The best predictor was skewness of image brightness distribution.

    By using a trackball setup, the optomotor response in walking hoverflies (Eristalis tenax) was found to be influenced by the slope constant of an average amplitude spectrum. 

    Intracellular recording showed that the higher-order neuron cSIFE (The centrifugal stationary inhibited flicker excited) in the hoverfly (Eristalis tenax) lobula plate was inhibited by a range of natural scenes and that this inhibition was strongest in a response to visual stimuli with the slope constant of an average amplitude spectrum of 1, which is the typical value for natural environments. 

    Based on the results of psychophysics study in human subjects it was found that sleep deprivation affects human perception of naturalistic slope constants differently for different image categories (“food” and “real world scenes”).

    These results help provide a better understanding of the link between visual processes and the spatial statistics of natural scenes.

    List of papers
    1. In situ modeling of multimodal floral cues attracting wild pollinators across environments
    Open this publication in new window or tab >>In situ modeling of multimodal floral cues attracting wild pollinators across environments
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    2017 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 50, p. 13218-13223Article in journal (Refereed) Published
    Abstract [en]

    With more than 80% of flowering plant species specialized for animal pollination, understanding how wild pollinators utilize resources across environments can encourage efficient planting and maintenance strategies to maximize pollination and establish resilience in the face of environmental change. A fundamental question is how generalist pollinators recognize “flower objects” in vastly different ecologies and environments. On one hand, pollinators could employ a specific set of floral cues regardless of environment. Alternatively, wild pollinators could recognize an exclusive signature of cues unique to each environment or flower species. Hoverflies, which are found across the globe, are one of the most ecologically important alternative pollinators after bees and bumblebees. Here, we have exploited their cosmopolitan status to understand how wild pollinator preferences change across different continents. Without employing any a priori assumptions concerning the floral cues, we measured, predicted, and finally artificially recreated multimodal cues from individual flowers visited by hoverflies in three different environments (hemiboreal, alpine, and tropical) using a field-based methodology. We found that although “flower signatures” were unique for each environment, some multimodal lures were ubiquitously attractive, despite not carrying any reward, or resembling real flowers. While it was unexpected that cue combinations found in real flowers were not necessary, the robustness of our lures across insect species and ecologies could reflect a general strategy of resource identification for generalist pollinators. Our results provide insights into how cosmopolitan pollinators such as hoverflies identify flowers and offer specific ecologically based cues and strategies for attracting pollinators across diverse environments.

    Keywords
    multimodal factors, categorization, syndrome, hoverfly, multivariate
    National Category
    Horticulture Behavioral Sciences Biology
    Identifiers
    urn:nbn:se:uu:diva-328029 (URN)10.1073/pnas.1714414114 (DOI)000417806200064 ()29180408 (PubMedID)
    Funder
    Stiftelsen Olle Engkvist Byggmästare, 2014/254; 2016/348
    Available from: 2017-08-16 Created: 2017-08-16 Last updated: 2018-02-23Bibliographically approved
    2. Predicting unconstrained field flight behaviour from image statistics
    Open this publication in new window or tab >>Predicting unconstrained field flight behaviour from image statistics
    (English)In: Article in journal (Refereed) Submitted
    National Category
    Bioinformatics (Computational Biology)
    Identifiers
    urn:nbn:se:uu:diva-328030 (URN)
    Available from: 2017-08-16 Created: 2017-08-16 Last updated: 2018-02-20
    3. A higher order visual neuron tuned to the spatial amplitude spectra of natural scenes
    Open this publication in new window or tab >>A higher order visual neuron tuned to the spatial amplitude spectra of natural scenes
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    2015 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id 8522Article in journal (Refereed) Published
    Abstract [en]

    Animal sensory systems are optimally adapted to those features typically encountered in natural surrounds, thus allowing neurons with limited bandwidth to encode challengingly large input ranges. Natural scenes are not random, and peripheral visual systems in vertebrates and insects have evolved to respond efficiently to their typical spatial statistics. The mammalian visual cortex is also tuned to natural spatial statistics, but less is known about coding in higher order neurons in insects. To redress this we here record intracellularly from a higher order visual neuron in the hoverfly. We show that the cSIFE neuron, which is inhibited by stationary images, is maximally inhibited when the slope constant of the amplitude spectrum is close to the mean in natural scenes. The behavioural optomotor response is also strongest to images with naturalistic image statistics. Our results thus reveal a close coupling between the inherent statistics of natural scenes and higher order visual processing in insects.

    National Category
    Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-264173 (URN)10.1038/ncomms9522 (DOI)000364930800007 ()26439748 (PubMedID)
    Funder
    Swedish Research Council, 2012-4740
    Note

    Supplementary information available for this article at http://www.nature.com/ncomms/2015/151006/ncomms9522/suppinfo/ncomms9522_S1.html

    Available from: 2015-10-06 Created: 2015-10-06 Last updated: 2018-02-20Bibliographically approved
    4. Sleep deprivation changes our perception of naturalness
    Open this publication in new window or tab >>Sleep deprivation changes our perception of naturalness
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    (English)In: Article in journal (Refereed) Submitted
    National Category
    Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-328031 (URN)
    Available from: 2017-08-16 Created: 2017-08-16 Last updated: 2018-02-20
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  • 76.
    Dyakova, Olga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Lee, Yu-Jen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Longden, Kit D.
    Kiselev, Valerij G.
    Nordström, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    A higher order visual neuron tuned to the spatial amplitude spectra of natural scenes2015In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id 8522Article in journal (Refereed)
    Abstract [en]

    Animal sensory systems are optimally adapted to those features typically encountered in natural surrounds, thus allowing neurons with limited bandwidth to encode challengingly large input ranges. Natural scenes are not random, and peripheral visual systems in vertebrates and insects have evolved to respond efficiently to their typical spatial statistics. The mammalian visual cortex is also tuned to natural spatial statistics, but less is known about coding in higher order neurons in insects. To redress this we here record intracellularly from a higher order visual neuron in the hoverfly. We show that the cSIFE neuron, which is inhibited by stationary images, is maximally inhibited when the slope constant of the amplitude spectrum is close to the mean in natural scenes. The behavioural optomotor response is also strongest to images with naturalistic image statistics. Our results thus reveal a close coupling between the inherent statistics of natural scenes and higher order visual processing in insects.

    Download full text (pdf)
    fulltext
  • 77.
    Dyakova, Olga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Müller, Martin M
    Egelhaaf, Martin
    Nordström, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Image statistics of the environment surrounding freely behaving hoverflies2019In: Journal of Comparative Physiology A. Sensory, neural, and behavioral physiology, ISSN 0340-7594, E-ISSN 1432-1351, Vol. 205, no 3, p. 373-385Article in journal (Refereed)
    Abstract [en]

    Natural scenes are not as random as they might appear, but are constrained in both space and time. The 2-dimensional spatial constraints can be described by quantifying the image statistics of photographs. Human observers perceiv