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Jaarola, Maarit
Publications (7 of 7) Show all publications
Fritz, M., Klawonn, A., Jaarola, M. & Engblom, D. (2018). Interferon-ɣ mediated signaling in the brain endothelium is critical for inflammation-induced aversion. Brain, behavior, and immunity, 67, 54-58
Open this publication in new window or tab >>Interferon-ɣ mediated signaling in the brain endothelium is critical for inflammation-induced aversion
2018 (English)In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 67, p. 54-58Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Maryland Heights: Academic Press, 2018
Keywords
Aversion; Behavior; Chemokines; Depression; Endothelium; Interferon; Lipopolysaccharide; Sickness
National Category
Pharmacology and Toxicology Neurosciences Immunology in the medical area Immunology Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-143812 (URN)10.1016/j.bbi.2017.08.020 (DOI)000416879100007 ()28864260 (PubMedID)2-s2.0-85028972384 (Scopus ID)
Note

Funding agencies: European Research Council; Swedish Medical Research Council; Knut and Alice Wallenberg foundation; Swedish Brain foundation; Parkinsonstiftelsen; Region Ostergotland

Available from: 2017-12-19 Created: 2017-12-19 Last updated: 2019-04-10Bibliographically approved
Klawonn, A., Fritz, M., Nilsson, A., Bonaventura, J., Shionoya, K., Mirrasekhian, E., . . . Engblom, D. (2018). Motivational valence is determined by striatal melanocortin 4 receptors. Journal of Clinical Investigation, 128(7), 3160-3170
Open this publication in new window or tab >>Motivational valence is determined by striatal melanocortin 4 receptors
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2018 (English)In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 128, no 7, p. 3160-3170Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
AMER SOC CLINICAL INVESTIGATION INC, 2018
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-149861 (URN)10.1172/JCI97854 (DOI)000437234600044 ()29911992 (PubMedID)
Note

Funding Agencies|European Research Council; Swedish Medical Research Council; Knut and Alice Wallenberg Foundation; Swedish Brain foundation; County Council of Ostergotland; National Institute on Drug Abuse Intramural Research Program [ZIA000069]; Lars Hiertas Minne Foundation

Available from: 2018-08-02 Created: 2018-08-02 Last updated: 2018-08-20
Nilsson, A., Wilhelms, D., Mirrasekhian, E., Jaarola, M., Blomqvist, A. & Engblom, D. (2017). Inflammation-induced anorexia and fever are elicited by distinct prostaglandin dependent mechanisms, whereas conditioned taste aversion is prostaglandin independent.. Brain, behavior, and immunity, 61, 236-243, Article ID S0889-1591(16)30549-9.
Open this publication in new window or tab >>Inflammation-induced anorexia and fever are elicited by distinct prostaglandin dependent mechanisms, whereas conditioned taste aversion is prostaglandin independent.
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2017 (English)In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 61, p. 236-243, article id S0889-1591(16)30549-9Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
Anorexia, Conditioned place aversion, Cyclooxygenase, Fever, Inflammation, Lipopolysaccharide
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:liu:diva-136127 (URN)10.1016/j.bbi.2016.12.007 (DOI)000395365900026 ()27940259 (PubMedID)
Note

Funding agencies: Swedish Medical Research Council [20725, 07879]; European Research Council; Knut and Alice Wallenberg foundation; Swedish Brain Foundation; Swedish Cancer Foundation [213/692]; County Council of Ostergotland

Available from: 2017-03-28 Created: 2017-03-28 Last updated: 2018-05-02Bibliographically approved
Fritz, M., Klawonn, A., Nilsson, A., Kumar Singh, A., Zajdel, J., Wilhelms, D., . . . Engblom, D. (2016). Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice. Journal of Clinical Investigation, 126(2), 695-705
Open this publication in new window or tab >>Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice
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2016 (English)In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 126, no 2, p. 695-705Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
AMER SOC CLINICAL INVESTIGATION INC, 2016
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-126263 (URN)10.1172/JCI83844 (DOI)000370677300029 ()26690700 (PubMedID)
Note

Funding Agencies|European Research Council (ERC); Swedish Medical Research Council; Knut and Alice Wallenberg foundation; Swedish Brain Foundation; County Council of Ostergotland; Swedish Cancer Foundation; Veterans Administration Merit award; NIH [NS33987, NS72337]

Available from: 2016-03-21 Created: 2016-03-21 Last updated: 2019-04-29Bibliographically approved
Herman, J. S., McDevitt, A. D., Kawalko, A., Jaarola, M., Wojcik, J. M. & Searle, J. B. (2014). Land-Bridge Calibration of Molecular Clocks and the Post-Glacial Colonization of Scandinavia by the Eurasian Field Vole Microtus agrestis. PLoS ONE, 9(8), e103949
Open this publication in new window or tab >>Land-Bridge Calibration of Molecular Clocks and the Post-Glacial Colonization of Scandinavia by the Eurasian Field Vole Microtus agrestis
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 8, p. e103949-Article in journal (Refereed) Published
Abstract [en]

Phylogeography interprets molecular genetic variation in a spatial and temporal context. Molecular clocks are frequently used to calibrate phylogeographic analyses, however there is mounting evidence that molecular rates decay over the relevant timescales. It is therefore essential that an appropriate rate is determined, consistent with the temporal scale of the specific analysis. This can be achieved by using temporally spaced data such as ancient DNA or by relating the divergence of lineages directly to contemporaneous external events of known time. Here we calibrate a Eurasian field vole ( Microtus agrestis) mitochondrial genealogy from the well-established series of post-glacial geophysical changes that led to the formation of the Baltic Sea and the separation of the Scandinavian peninsula from the central European mainland. The field vole exhibits the common phylogeographic pattern of Scandinavian colonization from both the north and the south, however the southernmost of the two relevant lineages appears to have originated in situ on the Scandinavian peninsula, or possibly in the adjacent island of Zealand, around the close of the Younger Dryas. The mitochondrial substitution rate and the timescale for the genealogy are closely consistent with those obtained with a previous calibration, based on the separation of the British Isles from mainland Europe. However the result here is arguably more certain, given the level of confidence that can be placed in one of the central assumptions of the calibration, that field voles could not survive the last glaciation of the southern part of the Scandinavian peninsula. Furthermore, the similarity between the molecular clock rate estimated here and those obtained by sampling heterochronous (ancient) DNA ( including that of a congeneric species) suggest that there is little disparity between the measured genetic divergence and the population divergence that is implicit in our land-bridge calibration.

Place, publisher, year, edition, pages
Public Library of Science, 2014
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-110976 (URN)10.1371/journal.pone.0103949 (DOI)000341105100024 ()25111840 (PubMedID)
Note

Funding Agencies|National Science Centre, Poland [N N304 058340]; European Union [245737]

Available from: 2014-10-01 Created: 2014-10-01 Last updated: 2017-12-05
Beysard, M., Perrin, N., Jaarola, M., Heckel, G. & Vogel, P. (2012). Asymmetric and differential gene introgression at a contact zone between two highly divergent lineages of field voles (Microtus agrestis). Journal of Evolutionary Biology, 25(2), 400-408
Open this publication in new window or tab >>Asymmetric and differential gene introgression at a contact zone between two highly divergent lineages of field voles (Microtus agrestis)
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2012 (English)In: Journal of Evolutionary Biology, ISSN 1010-061X, E-ISSN 1420-9101, Vol. 25, no 2, p. 400-408Article in journal (Refereed) Published
Abstract [en]

Secondary contact zones have the potential to shed light on the mode and rate at which reproductive isolation accumulates during allopatric speciation. We investigated the population genetics of a contact zone between two highly divergent lineages of field voles (Microtus agrestis) in the Swiss Jura mountains. To shed light on the processes underlying introgression, we used maternally, paternally, and bi-parentally inherited markers. Though the two lineages maintained a strong genetic structure, we found some hybrids and evidence of gene flow. The extent of introgression varied with the mode of inheritance, being highest for mtDNA and absent for the Y chromosome. In addition, introgression was asymmetric, occurring only from the Northern to the Southern lineage. Both patterns seem parsimoniously explained by neutral processes linked to differences in effective sizes and sex-biased dispersal rates. The lineage with lower effective population size was also the more introgressed, and the mode-of-inheritance effect correlated with the male-biased dispersal rate of microtine rodents. We cannot exclude, however, that Haldanes effect contributed to the latter, as we found a marginally significant deficit in males (the heterogametic sex) among hybrids. We propose a possible demographic scenario to account for the patterns documented, and empirical extensions to further investigate this contact zone.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2012
Keywords
expansion, field vole, Haldanes rule, hybridization, secondary contact zone, sex-biased dispersal, speciation
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-74838 (URN)10.1111/j.1420-9101.2011.02432.x (DOI)000299043300016 ()
Note
Funding Agencies|Basler Stiftung fur Biologische Forschung||Agassiz Fondation||University of Lausanne||Swiss National Science foundation|31003A-12737731003A-108100|Available from: 2012-02-10 Created: 2012-02-10 Last updated: 2017-12-07
Pauperio, J., Herman, J. S., Melo-Ferreira, J., Jaarola, M., Alves, P. C. & Searle, J. B. (2012). Cryptic speciation in the field vole: a multilocus approach confirms three highly divergent lineages in Eurasia. Molecular Ecology, 21(24), 6015-6032
Open this publication in new window or tab >>Cryptic speciation in the field vole: a multilocus approach confirms three highly divergent lineages in Eurasia
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2012 (English)In: Molecular Ecology, ISSN 0962-1083, E-ISSN 1365-294X, Vol. 21, no 24, p. 6015-6032Article in journal (Refereed) Published
Abstract [en]

Species are generally described from morphological features, but there is growing recognition of sister forms that show substantial genetic differentiation without obvious morphological variation and may therefore be considered cryptic species. Here, we investigate the field vole (Microtus agrestis), a Eurasian mammal with little apparent morphological differentiation but which, on the basis of previous sex-linked nuclear and mitochondrial DNA (mtDNA) analyses, is subdivided into a Northern and a Southern lineage, sufficiently divergent that they may represent two cryptic species. These earlier studies also provided limited evidence for two major mtDNA lineages within Iberia. In our present study, we extend these findings through a multilocus approach. We sampled 163 individuals from 46 localities, mainly in Iberia, and sequenced seven loci, maternally, paternally and biparentally inherited. Our results show that the mtDNA lineage identified in Portugal is indeed a distinct third lineage on the basis of other markers as well. In fact, multilocus coalescent-based methods clearly support three separate evolutionary units that may represent cryptic species: Northern, Southern and Portuguese. Divergence among these units was inferred to have occurred during the last glacial period; the Portuguese lineage split occurred first (estimated at c. 70 000 bp), and the Northern and Southern lineages separated at around the last glacial maximum (estimated at c. 18 500 bp). Such recent formation of evolutionary units that might be considered species has repercussions in terms of understanding evolutionary processes and the diversity of small mammals in a European context.

Place, publisher, year, edition, pages
Blackwell Publishing, 2012
Keywords
cryptic species, demography, Microtus agrestis, phylogeography, species tree
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-86893 (URN)10.1111/mec.12024 (DOI)000312147300010 ()
Note

Funding Agencies|Programa Operacional Potencial Humano - Quadro de Referancia Estrategico Nacional funds from the European Social Fund||Portuguese Ministerio de Educacao e Ciencia (FCT)|SFRH/BD/27369/2006SFRH/BPD/43264/2008|

Available from: 2013-01-07 Created: 2013-01-07 Last updated: 2017-12-06
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