Honors & Awards


  • Best Scientific Paper Award, The Health University Research Symposium (HURS), Linköping University (March 2018)
  • The Linköping University Academic Society Foundation Price, Linköping University Academic Society (Akademiska Föreningen) (March 2017)
  • Best Scientific Paper Award, The Health University Research Symposium (HURS), Linköping University (March 2016)
  • 1. Prize winner in the Danish national “Young Scientists Competition”, Unge Forskere, Denmark (March 2007)

Professional Education


  • Doctor of Philosophy, Universitetet I Linkoping (2018)

Current Research and Scholarly Interests


When exploring the circuits of the brain, one gets the same feeling of infinity as when gazing at the stars on a Scandinavian winters night…. The reason for this is the vast amounts of neural connectivity and complexity of the brain.

My research evolves around deciphering the neural circuits of affective disorders. I am particularly interested in how affective and motivational states relate to each other and are encoded in the mesolimbic reward system. More specifically, I would like to find the neurocircuitry responsible for pathologies such as drug addiction, depression and negative affect during inflammatory disorders, in the hope that we can find better treatments against these.

Lab Affiliations


All Publications


  • Muscarinic M4 Receptors on Cholinergic and Dopamine D1 Receptor-Expressing Neurons Have Opposing Functionality for Positive Reinforcement and Influence Impulsivity FRONTIERS IN MOLECULAR NEUROSCIENCE Klawonn, A. M., Wilhelms, D. B., Lindstrom, S. H., Singh, A., Jaarola, M., Wess, J., Fritz, M., Engblom, D. 2018; 11: 139

    Abstract

    The neurotransmitter acetylcholine has been implicated in reward learning and drug addiction. However, the roles of the various cholinergic receptor subtypes on different neuron populations remain elusive. Here we study the function of muscarinic M4 receptors (M4Rs) in dopamine D1 receptor (D1R) expressing neurons and cholinergic neurons (expressing choline acetyltransferase; ChAT), during various reward-enforced behaviors and in a "waiting"-impulsivity test. We applied cell-type-specific gene deletions targeting M4Rs in D1RCre or ChATCre mice. Mice lacking M4Rs in D1R-neurons displayed greater cocaine seeking and drug-primed reinstatement than their littermate controls in a Pavlovian conditioned place preference (CPP) paradigm. Furthermore, the M4R-D1RCre mice initiated significantly more premature responses (PRs) in the 5-choice-serial-reaction-time-task (5CSRTT) than their littermate controls, indicating impaired waiting impulse control. In contrast, mice lacking M4Rs in cholinergic neurons did not acquire cocaine Pavlovian conditioning. The M4R-ChATCre mice were also unable to learn positive reinforcement to either natural reward or cocaine in an operant runway paradigm. Immediate early gene (IEG) expression (cFos and FosB) induced by repeated cocaine injections was significantly increased in the forebrain of M4R-D1RCre mice, whereas it remained normal in the M4R-ChATCre mice. Our study illustrates that muscarinic M4Rs on specific neural populations, either cholinergic or D1R-expressing, are pivotal for learning processes related to both natural reward and drugs of abuse, with opposing functionality. Furthermore, we found that neurons expressing both M4Rs and D1Rs are important for signaling impulse control.

    View details for DOI 10.3389/fnmol.2018.00139

    View details for Web of Science ID 000430840200001

    View details for PubMedID 29740282

    View details for PubMedCentralID PMC5928231

  • Motivational valence is determined by striatal melanocortin 4 receptors. The Journal of clinical investigation Klawonn, A. M., Fritz, M., Nilsson, A., Bonaventura, J., Shionoya, K., Mirrasekhian, E., Karlsson, U., Jaarola, M., Granseth, B., Blomqvist, A., Michaelides, M., Engblom, D. 2018

    Abstract

    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 κ opioid receptor-induced 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.

    View details for DOI 10.1172/JCI97854

    View details for PubMedID 29911992

    View details for PubMedCentralID PMC6026003

  • Interferon-ɣ mediated signaling in the brain endothelium is critical for inflammation-induced aversion. Brain, behavior, and immunity Fritz, M., Klawonn, A. M., Jaarola, M., Engblom, D. 2018; 67: 54–58

    Abstract

    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.

    View details for DOI 10.1016/j.bbi.2017.08.020

    View details for PubMedID 28864260

  • Prostaglandin-mediated inhibition of serotonin signaling controls the affective component of inflammatory pain JOURNAL OF CLINICAL INVESTIGATION Singh, A. K., Zajdel, J., Mirrasekhian, E., Almoosawi, N., Frisch, I., Klawonn, A. M., Jaarola, M., Fritz, M., Engblom, D. 2017; 127 (4): 1370-1374

    Abstract

    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 E2 that is synthesized by cyclooxygenase 2 in neural cells. Further, mice lacking the prostaglandin E2 receptor EP3 selectively on serotonergic cells or selectively in the area of the dorsal raphe nucleus failed to form an aversion to formalin-induced 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 κ opioid receptor agonist. Collectively, our findings show that prostaglandin-mediated modulation of serotonergic transmission controls the affective component of inflammatory pain.

    View details for DOI 10.1172/JCI90678

    View details for Web of Science ID 000398183300026

    View details for PubMedID 28287401

    View details for PubMedCentralID PMC5373882

  • The Sigma-2 Receptor Selective Agonist Siramesine (Lu 28-179) Decreases Cocaine-Reinforced Pavlovian Learning and Alters Glutamatergic and Dopaminergic Input to the Striatum. Frontiers in pharmacology Klawonn, A. M., Nilsson, A., Rådberg, C. F., Lindström, S. H., Ericson, M., Granseth, B., Engblom, D., Fritz, M. 2017; 8: 714

    Abstract

    Drug addiction is a chronic, debilitating disease that affects millions of people around the world causing a substantial societal burden. Despite decades of research efforts, treatment possibilities remain limited and relapse represents the most treatment-resistant element. Neurosteroid sigma-1 receptors have been meticulously studied in psychostimulant reinforced Pavlovian learning, while the sigma-2 receptor subtype has remained unexplored. Recent development of selective sigma-2 receptor ligands have now made it possible to investigate if the sigma-2 receptor system is a potential target to treat drug addiction. We examined the effect of the sigma-2 receptor agonist Siramesine (Lu 28-179) on cocaine-associated locomotion, Pavlovian learning, and reward neurocircuitry using electrophysiology recordings and in vivo microdialysis. We found that Siramesine significantly attenuated conditioned place preference acquisition and expression, as well as it completely blocked cocaine-primed reinstatement. Siramesine, in a similar manner as the selective sigma-1 receptor antagonist BD 1063, decreased acute locomotor responses to cocaine. Immunohistochemistry suggests co-expression of progesterone receptor membrane component 1/sigma-2 receptors and vesicular glutamate transporter 1 in presynaptic boutons of the nucleus accumbens (NAc). Whole-cell voltage clamp recordings of neurons in the NAc indicated that Siramesine decreases the presynaptic release probability of glutamate. Further, we demonstrated, via in vivo microdialysis, that Siramesine significantly decreased cocaine-evoked dopamine release in the striatum of freely moving mice. Collectively, these findings demonstrate that sigma-2 receptors regulate neurocircuitry responsible for positive reinforcement and thereby play a role in cocaine-reinforced Pavlovian behaviors.

    View details for DOI 10.3389/fphar.2017.00714

    View details for PubMedID 29066971

    View details for PubMedCentralID PMC5641388

  • Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice JOURNAL OF CLINICAL INVESTIGATION Fritz, M., Klawonn, A. M., Nilsson, A., Singh, A. K., Zajdel, J., Wilhelms, D. B., Lazarus, M., Lofberg, A., Jaarola, M., Kugelberg, U. O., Billiar, T. R., Hackam, D. J., Sodhi, C. P., Breyer, M. D., Jakobsson, J., Schwaninger, M., Schuetz, G., Parkitna, J. R., Saper, C. B., Blomqvist, A., Engblom, D. 2016; 126 (2): 695-705

    Abstract

    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 E2 (PGE2) synthesis. Further, we showed that inflammation-induced PGE2 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 PGE2-mediated modulation of the dopaminergic motivational circuitry is a key mechanism underlying the negative affect induced by inflammation.

    View details for DOI 10.1172/JCI83844

    View details for Web of Science ID 000370677300029

    View details for PubMedID 26690700

    View details for PubMedCentralID PMC4731170

  • siRNA knock down of glutamate dehydrogenase in astrocytes affects glutamate metabolism leading to extensive accumulation of the neuroactive amino acids glutamate and aspartate NEUROCHEMISTRY INTERNATIONAL Skytt, D. M., Klawonn, A. M., Stridh, M. H., Pajecka, K., Patruss, Y., Quintana-Cabrera, R., Bolanos, J. P., Schousboe, A., Waagepetersen, H. S. 2012; 61 (4): 490-497

    Abstract

    Glutamate is the most abundant excitatory neurotransmitter in the brain and astrocytes are key players in sustaining glutamate homeostasis. Astrocytes take up the predominant part of glutamate after neurotransmission and metabolism of glutamate is necessary for a continuous efficient removal of glutamate from the synaptic area. Glutamate may either be amidated by glutamine synthetase or oxidatively metabolized in the mitochondria, the latter being at least to some extent initiated by oxidative deamination by glutamate dehydrogenase (GDH). To explore the particular importance of GDH for astrocyte metabolism we have knocked down GDH in cultured cortical astrocytes employing small interfering RNA (siRNA) achieving a reduction of the enzyme activity by approximately 44%. The astrocytes were incubated for 2h in medium containing either 1.0mM [(15)NH(4)(+)] or 100 μM [(15)N]glutamate. For those exposed to [(15)N]glutamate an additional 100 μM was added after 1h. Metabolic mapping was performed from isotope incorporation measured by mass spectrometry into relevant amino acids of cell extracts and media. The contents of the amino acids were measured by HPLC. The (15)N incorporation from [(15)NH(4)(+)] into glutamate, aspartate and alanine was decreased in astrocytes exhibiting reduced GDH activity. However, the reduced GDH activity had no effect on the cellular contents of these amino acids. This supports existing in vivo and in vitro studies that GDH is predominantly working in the direction of oxidative deamination and not reductive amination. In contrast, when exposing the astrocytes to [(15)N]glutamate, the reduced GDH activity led to an increased (15)N incorporation into glutamate, aspartate and alanine and a large increase in the content of glutamate and aspartate. Surprisingly, this accumulation of glutamate and net-synthesis of aspartate were not reflected in any alterations in either the glutamine content or labeling, but a slight increase in mono labeling of glutamine in the medium. We suggest that this extensive net-synthesis of aspartate due to lack of GDH activity is occurring via the concerted action of AAT and the part of TCA cycle operating from α-ketoglutarate to oxaloacetate, i.e. the truncated TCA cycle.

    View details for DOI 10.1016/j.neuint.2012.04.014

    View details for Web of Science ID 000309623600007

    View details for PubMedID 22542772