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Interactions between the brain and the immune system in pain and inflammation
Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0002-6662-7709
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Reciprocal interactions between the nervous and immune systems have gained a lot of attention in the last two decades, especially after demonstrating that cytokine immunotherapies can induce depression and after describing the inflammatory reflex. A lot of effort has been dedicated to understanding how the signals from the immune system reach the brain and vice versa, and on their role in health and disease. However, it is not well-known which of the brain circuits, receptors and signalling molecules give rise to behavioural and affective changes induced by inflammation, such as reduced food intake and induction of negative mood. Moreover, although it is well established that early life stress leads to an increased risk of developing inflammatory diseases in adulthood, the acute effects of stress on the inflammatory response in childhood are not well described. Using mouse models of systemic and local inflammation, I studied (1) how inflammatory pain elicits negative affect, (2) if CGRPα is necessary for parabrachial-amygdaloid pathway-mediated behaviours associated with pain and inflammation, and finally, (3) what are the effects of stress on the inflammatory process during early life. The results indicate that (1) the negative affect of inflammatory pain is triggered by inhibition of serotonergic neurons of the dorsal raphe nucleus, as a result of prostaglandin E2 binding to EP3 receptors; (2) CGRPα is dispensable for most pain- and inflammation-related protective behaviours; (3) acute stress potentiates the pro-inflammatory cytokine expression after an inflammatory challenge in mouse pups. The phenomena studied here can contribute to understanding how immune system activation induces changes in mood and behaviour common for inflammation and depression.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2019.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1679
Keywords [en]
inflammation, pain, EP3Rs, serotonin, CGRP, conditioned taste aversion, maternal separation, maternal buffering
National Category
Immunology Neurosciences
Identifiers
URN: urn:nbn:se:liu:diva-156181DOI: 10.3384/diss.diva-156181ISBN: 978-91-7685-084-8 (print)OAI: oai:DiVA.org:liu-156181DiVA, id: diva2:1303016
Public defence
2019-05-10, Hasselquistsalen, Växthuset, Campus US, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2019-04-08 Created: 2019-04-08 Last updated: 2019-04-11Bibliographically approved
List of papers
1. Prostaglandin-mediated inhibition of serotonin signaling controls the affective component of inflammatory pain
Open this publication in new window or tab >>Prostaglandin-mediated inhibition of serotonin signaling controls the affective component of inflammatory pain
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2017 (English)In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 127, no 4, p. 1370-1374Article in journal (Refereed) Published
Abstract [en]

Pain is fundamentally unpleasant and induces a negative affective state. The affective component of pain is mediated by circuits that are distinct from those mediating the sensory-discriminative component. Here, we have investigated the role of prostaglandins in the affective dimension of pain using a rodent pain assay based on conditioned place aversion to formalin injection, an inflammatory noxious stimulus. We found that place aversion induced by inflammatory pain depends on prostaglandin E-2 that is synthesized by cyclooxygenase 2 in neural cells. Further, mice lacking the prostaglandin E-2 receptor EP3 selectively on serotonergic cells or selectively in the area of the dorsal raphe nucleus failed to form an aversion to formalininduced pain, as did mice lacking the serotonin transporter. Chemogenetic manipulations revealed that EP3 receptor activation elicited conditioned place aversion to pain via inhibition of serotonergic neurons. In contrast to their role in inflammatory pain aversion, EP3 receptors on serotonergic cells were dispensable for acute nociceptive behaviors and for aversion induced by thermal pain or a kappa opioid receptor agonist. Collectively, our findings show that prostaglandin-mediated modulation of serotonergic transmission controls the affective component of inflammatory pain.

Place, publisher, year, edition, pages
AMER SOC CLINICAL INVESTIGATION INC, 2017
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-136568 (URN)10.1172/JCI90678 (DOI)000398183300026 ()28287401 (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 of Neurological Disorders and Stroke (NINDS)

Available from: 2017-04-24 Created: 2017-04-24 Last updated: 2019-04-08
2. Acute maternal separation potentiates the gene expression and corticosterone response induced by inflammation
Open this publication in new window or tab >>Acute maternal separation potentiates the gene expression and corticosterone response induced by inflammation
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2019 (English)In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 77, p. 141-149Article in journal (Refereed) Published
Abstract [en]

Maternal care is crucial for infants and profoundly affects their responses to different kinds of stressors. Here, we examined how maternal separation affects inflammatory gene expression and the corticosterone response to an acute immune challenge induced by lipopolysaccharide (LPS; 40 µg/kg ip) in mouse pups, 8–9 days old. Maternal separation initially attenuated LPS-induced hypothalamic pro-inflammatory gene expression, but later, at 3 h after immune challenge, robustly augmented such gene expression and increased serum corticosterone levels. Providing the pups with a warm and soft object prevented the separation-induced augmented hypothalamic-pituitary-adrenal (HPA)-axis response. It also prevented the potentiated induction of some, but not all, inflammatory genes to a similar extent as did the dam. Our results show that maternal separation potentiates the inflammatory response and the resulting HPA-axis activation, which may have detrimental effects if separation is prolonged or repeated.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Lipopolysaccharide, Hypothalamus, Cytokines, Inflammation, Maternal separation, Corticosterone
National Category
Pharmacology and Toxicology Developmental Biology Medical Biotechnology Immunology
Identifiers
urn:nbn:se:liu:diva-154886 (URN)10.1016/j.bbi.2018.12.016 (DOI)30590109 (PubMedID)2-s2.0-85059128986 (Scopus ID)
Available from: 2019-03-04 Created: 2019-03-04 Last updated: 2019-04-08Bibliographically approved

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Zajdel, Joanna

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