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Nilsson, Anna
Publications (9 of 9) Show all publications
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
Ruud, J., Nilsson, A., Engström Ruud, L., Wang, W., Nilsberth, C., Iresjo, B.-M., . . . Blomqvist, A. (2013). Cancer-induced anorexia in tumor-bearing mice is dependent on cyclooxygenase-1. Brain, behavior, and immunity, 29, 124-135
Open this publication in new window or tab >>Cancer-induced anorexia in tumor-bearing mice is dependent on cyclooxygenase-1
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2013 (English)In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 29, p. 124-135Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
Cancer anorexia-cachexia, Cyclooxygenase, Microsomal prostaglandin E synthase-1, Prostaglandin E2
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-90188 (URN)10.1016/j.bbi.2012.12.020 (DOI)000315365400013 ()
Note

Funding Agencies|Swedish Cancer Foundation||Swedish Research Council||Swedish Brain Foundation||

Available from: 2013-04-04 Created: 2013-03-21 Last updated: 2017-12-06Bibliographically approved
Ruud, J., Björk, D., Nilsson, A., Eskilsson, A., Tang, Y.-j., Stroehle, P., . . . Blomqvist, A. (2013). Inflammation- and tumor-induced anorexia and weight loss require MyD88 in hematopoietic/myeloid cells but not in brain endothelial or neural cells. The FASEB Journal, 27(5), 1973-1980
Open this publication in new window or tab >>Inflammation- and tumor-induced anorexia and weight loss require MyD88 in hematopoietic/myeloid cells but not in brain endothelial or neural cells
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2013 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 27, no 5, p. 1973-1980Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Federation of American Society of Experimental Biology (FASEB), 2013
Keywords
lipopolysaccharide; methylcholanthrene-induced sarcoma; food intake; chimeric mice; Cre-LoxP; inducible cell-specific deletion
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-96147 (URN)10.1096/fj.12-225433 (DOI)000318226100017 ()
Available from: 2013-08-14 Created: 2013-08-14 Last updated: 2017-12-06
Nilsson, A., Norgard, M., Andersson, G. & Fahlgren, A. (2012). Fluid pressure induces osteoclast differentiation comparably to titanium particles but through a molecular pathway only partly involving TNFa. Journal of Cellular Biochemistry, 113(4), 1224-1234
Open this publication in new window or tab >>Fluid pressure induces osteoclast differentiation comparably to titanium particles but through a molecular pathway only partly involving TNFa
2012 (English)In: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 113, no 4, p. 1224-1234Article in journal (Refereed) Published
Abstract [en]

In contrast to the well-understood inflammatory pathway driven by TNFa, by which implant-derived particles induce bone resorption, little is known about the process in which loosening is generated as a result of force-induced mechanical stimulus at the boneimplant interface. Specifically, there is no knowledge as to what cells or signaling pathways couple mechanical stimuli to bone resorption in context of loosening. We hypothesized that different stimuli, i.e., fluid flow versus wear particles, act through different cytokine networks for activation and localization of osteoclasts. By using an animal model in which osteoclasts and bone resorption were induced by fluid pressure or particles, we were able to detect distinct differences in osteoclast localization and inflammatory gene expression between fluid pressure and titanium particles. Fluid pressure recruits and activates osteoclasts with bone marrow contact away from the fluid pressure exposure zone, whereas titanium particles recruit and activate osteoclasts in areas in direct contact to particles. Fluid pressure induced weaker expression of the selected inflammatory related genes, although the eventual degree of osteoclast induction was similar in both models. Using TNFaRa (4?mg/kg) (Enbrel) and dexamethasone (2?mg/kg) as specific and more general suppressors of inflammation we showed that the TNFaRa failed to generate statistically impaired osteoclast generation while dexamethasone was much more potent. These results demonstrate that fluid pressure induces osteoclasts at a different localization than titanium particles by a molecular pathway less associated with TNFa and the innate system, which open up for other pathways controlling pressure induced osteoclastogenesis.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2012
Keywords
PRESSURE; FLOW; OSTEOCLASTOGENESIS; CYTOKINES; OSTEOLYSIS
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-86565 (URN)10.1002/jcb.23456 (DOI)000300719000016 ()
Available from: 2012-12-19 Created: 2012-12-19 Last updated: 2017-12-06
Fahlgren, A., Nilsson, A., Norgard, M. & Andersson, G. (2011). FLUID PRESSURE AND TITANIUM PARTICLES INDUCES OSTEOCLAST ACTIVATION VIA ALTERNATIVE PATHWAYS in OSTEOPOROSIS INTERNATIONAL, vol 22, issue , pp 33-33. In: OSTEOPOROSIS INTERNATIONAL (pp. 33-33). Springer Science Business Media, 22
Open this publication in new window or tab >>FLUID PRESSURE AND TITANIUM PARTICLES INDUCES OSTEOCLAST ACTIVATION VIA ALTERNATIVE PATHWAYS in OSTEOPOROSIS INTERNATIONAL, vol 22, issue , pp 33-33
2011 (English)In: OSTEOPOROSIS INTERNATIONAL, Springer Science Business Media , 2011, Vol. 22, p. 33-33Conference paper, Published paper (Refereed)
Abstract [en]

n/a

Place, publisher, year, edition, pages
Springer Science Business Media, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-68339 (URN)000288662000054 ()
Available from: 2011-05-20 Created: 2011-05-20 Last updated: 2012-03-22
Ruud, J., Nilsson, A., Engström, L., Wang, W., Nilsberth, C., Iresjö, B.-M., . . . Blomqvist, A.A putative role for Cox-1 in the initiation of cancer anorexia independent of mPGES-1, PGE2 and neuronal EP4 receptors.
Open this publication in new window or tab >>A putative role for Cox-1 in the initiation of cancer anorexia independent of mPGES-1, PGE2 and neuronal EP4 receptors
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

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

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-77751 (URN)
Available from: 2012-05-28 Created: 2012-05-28 Last updated: 2016-05-04Bibliographically approved
Ruud, J., Björk Wilhelms, D., Nilsson, A., Eskilsson, A., Yan-Juan, T., Bäckhed, F., . . . Blomqvist, A.MyD88 in hematopoietic cells, but not in cerebrovascular endothelial cells or neural cells, is critical for inflammation- and cancer-induced loss of appetite.
Open this publication in new window or tab >>MyD88 in hematopoietic cells, but not in cerebrovascular endothelial cells or neural cells, is critical for inflammation- and cancer-induced loss of appetite
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

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

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-77753 (URN)
Available from: 2012-05-28 Created: 2012-05-28 Last updated: 2012-05-28Bibliographically approved
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