Abstract
Sickness behavior was conceptualized initially as the behavioral counterpart of the fever response to infectious pathogens. It helps to raise body temperature to its higher setpoint and to maintain it at this new level and it has the additional benefit of enabling a weakened organism to protect itself from other dangers. The discovery of the behavioral effects of proinflammatory cytokines produced by activated immune cells provided a cellular and molecular basis to this phenomenon. The administration of cytokines or cytokine inducers like lipopolysaccharide to healthy rodents allowed to reveal the similarities and differences between inflammation-induced sickness behavior and the fever response. It also led to the understanding of how the inflammatory response that is triggered at the periphery can propagate into the brain and induce the behavioral manifestations of sickness. At the behavioral level, the demonstration that sickness behavior is the expression of a motivational state that reorganizes perception and action in face of a microbial pathogen just like fear in face of a predator appeared at first glance to strengthen the adaptive value of this behavior. However, all aspects of sickness behavior are not always favorable for the organism. This is the case for anorexia that is beneficial in the context of bacterial infection but detrimental in the context of viral infection. In addition, studies of sickness behavior in natural conditions revealed that like any other defensive behavior, sickness behavior requires trade-offs between its survival benefits for the sick individual and the costs incurred especially in the context of gregarious groups. Thanks to these studies, evidence is emerging that sickness behavior is much more variable in its expression than initially thought, and that part of this variability depends not only on the pathogen and the social context in which the infection develops but also on individual factors including species, sex, age, nutrition, and physiological status.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Adelman JS, Martin LB (2009) Vertebrate sickness behaviors: adaptive and integrated neuroendocrine immune responses. Integr Comp Biol 49(3):202–214. https://doi.org/10.1093/icb/icp028
Aubert A (1999) Sickness and behaviour in animals: a motivational perspective. Neurosci Biobehav Rev 23(7):1029–1036. https://doi.org/10.1016/s0149-7634(99)00034-2
Bluthe RM, Walter V, Parnet P, Laye S, Lestage J, Verrier D et al (1994) Lipopolysaccharide induces sickness behaviour in rats by a vagal mediated mechanism. C R Acad Sci III 317(6):499–503
Cross-Mellor SK, Kavaliers M, Ossenkopp KP (2004) Comparing immune activation (lipopolysaccharide) and toxin (lithium chloride)-induced gustatory conditioning: lipopolysaccharide produces conditioned taste avoidance but not aversion. Behav Brain Res 148(1–2):11–19. https://doi.org/10.1016/s0166-4328(03)00181-5
Cunningham C, Sanderson DJ (2008) Malaise in the water maze: untangling the effects of LPS and IL-1beta on learning and memory. Brain Behav Immun 22(8):1117–1127. https://doi.org/10.1016/j.bbi.2008.05.007
Cunningham C, Campion S, Teeling J, Felton L, Perry VH (2007) The sickness behaviour and CNS inflammatory mediator profile induced by systemic challenge of mice with synthetic double-stranded RNA (poly I:C). Brain Behav Immun 21(4):490–502. https://doi.org/10.1016/j.bbi.2006.12.007
Dantzer R (2021) Love and fear in the times of sickness. Comp Psychoneuroendocrinol 6. https://doi.org/10.1016/j.cpnec.2021.100032
Dantzer R, Kelley KW (1989) Stress and immunity: an integrated view of relationships between the brain and the immune system. Life Sci 44(26):1995–2008. https://doi.org/10.1016/0024-3205(89)90345-7
Dantzer R, Konsman JP, Bluthe RM, Kelley KW (2000) Neural and humoral pathways of communication from the immune system to the brain: parallel or convergent? Auton Neurosci 85(1–3):60–65. https://doi.org/10.1016/S1566-0702(00)00220-4
Davis KC, Raizen DM (2017) A mechanism for sickness sleep: lessons from invertebrates. J Physiol 595(16):5415–5424. https://doi.org/10.1113/JP273009
Demas GE, Carlton ED (2015) Ecoimmunology for psychoneuroimmunologists: considering context in neuroendocrine-immune-behavior interactions. Brain Behav Immun 44:9–16. https://doi.org/10.1016/j.bbi.2014.09.002
DiSabato DJ, Nemeth DP, Liu X, Witcher KG, O'Neil SM, Oliver B et al (2021) Interleukin-1 receptor on hippocampal neurons drives social withdrawal and cognitive deficits after chronic social stress. Mol Psychiatry 26(9):4770–4782. https://doi.org/10.1038/s41380-020-0788-3
Felger JC, Alagbe O, Hu F, Mook D, Freeman AA, Sanchez MM et al (2007) Effects of interferon-alpha on rhesus monkeys: a nonhuman primate model of cytokine-induced depression. Biol Psychiatry 62(11):1324–1333. https://doi.org/10.1016/j.biopsych.2007.05.026
Friedman EM, Boinski S, Coe CL (1995) Interleukin-1 induces sleep-like behavior and alters call structure in juvenile rhesus macaques. Am J Primatol 35(2):143–153. https://doi.org/10.1002/ajp.1350350207
Friedman EM, Reyes TM, Coe CL (1996) Context-dependent behavioral effects of interleukin-1 in the rhesus monkey (Macaca mulatta). Psychoneuroendocrinology 21(5):455–468. https://doi.org/10.1016/0306-4530(96)00010-8
Harden LM, Kent S, Pittman QJ, Roth J (2015) Fever and sickness behavior: friend or foe? Brain Behav Immun 50:322–333. https://doi.org/10.1016/j.bbi.2015.07.012
Hart BL (1988) Biological basis of the behavior of sick animals. Neurosci Biobehav Rev 12(2):123–137. https://doi.org/10.1016/s0149-7634(88)80004-6
Kent S, Bluthe RM, Kelley KW, Dantzer R (1992) Sickness behavior as a new target for drug development. Trends Pharmacol Sci 13(1):24–28
Kirsten K, Soares SM, Koakoski G, Carlos Kreutz L, Barcellos LJG (2018a) Characterization of sickness behavior in zebrafish. Brain Behav Immun 73:596–602. https://doi.org/10.1016/j.bbi.2018.07.004
Kirsten K, Fior D, Kreutz LC, Barcellos LJG (2018b) First description of behavior and immune system relationship in fish. Sci Rep 8(1):846. https://doi.org/10.1038/s41598-018-19276-3
Klawonn AM, Fritz M, Castany S, Pignatelli M, Canal C, Simila F et al (2021) Microglial activation elicits a negative affective state through prostaglandin-mediated modulation of striatal neurons. Immunity 54(2):225–34.e6. https://doi.org/10.1016/j.immuni.2020.12.016
Kluger MJ, Kozak W, Conn CA, Leon LR, Soszynski D (1996) The adaptive value of fever. Infect Dis Clin North Am 10(1):1–20. https://doi.org/10.1016/s0891-5520(05)70282-8
Konsman JP, Parnet P, Dantzer R (2002) Cytokine-induced sickness behaviour: mechanisms and implications. Trends Neurosci 25(3):154–159. https://doi.org/10.1016/s0166-2236(00)02088-9
Lasselin J, Schedlowski M, Karshikoff B, Engler H, Lekander M, Konsman JP (2020) Comparison of bacterial lipopolysaccharide-induced sickness behavior in rodents and humans: relevance for symptoms of anxiety and depression. Neurosci Biobehav Rev 115:15–24. https://doi.org/10.1016/j.neubiorev.2020.05.001
Li D, Wu M (2021) Pattern recognition receptors in health and diseases. Signal Transduct Target Ther 6(1):291. https://doi.org/10.1038/s41392-021-00687-0
Lopes PC, French SS, Woodhams DC, Binning SA (2021) Sickness behaviors across vertebrate taxa: proximate and ultimate mechanisms. J Exp Biol 224(9). https://doi.org/10.1242/jeb.225847
Matsumoto T, Takahashi H, Shiva D, Kawanishi N, Kremenik MJ, Kato Y et al (2008) The reduction of voluntary physical activity after poly I:C injection is independent of the effect of poly I:C-induced interferon-beta in mice. Physiol Behav 93(4–5):835–841. https://doi.org/10.1016/j.physbeh.2007.11.048
McFarland R, Henzi SP, Barrett L, Bonnell T, Fuller A, Young C et al (2021) Fevers and the social costs of acute infection in wild vervet monkeys. Proc Natl Acad Sci U S A 118(44). https://doi.org/10.1073/pnas.2107881118
McGarry N, Murray CL, Garvey S, Wilkinson A, Tortorelli L, Ryan L et al (2021) Double stranded RNA drives anti-viral innate immune responses, sickness behavior and cognitive dysfunction dependent on dsRNA length, IFNAR1 expression and age. Brain Behav Immun 95:413–428. https://doi.org/10.1016/j.bbi.2021.04.016
McKim DB, Niraula A, Tarr AJ, Wohleb ES, Sheridan JF, Godbout JP (2016) Neuroinflammatory dynamics underlie memory impairments after repeated social defeat. J Neurosci 36(9):2590–2604. https://doi.org/10.1523/JNEUROSCI.2394-15.2016
Meunier J (2015) Social immunity and the evolution of group living in insects. Philos Trans R Soc Lond B Biol Sci 370(1669). https://doi.org/10.1098/rstb.2014.0102
Moieni M, Eisenberger NI (2018) Effects of inflammation on social processes and implications for health. Ann N Y Acad Sci 1428(1):5–13. https://doi.org/10.1111/nyas.13864
Mojzesz M, Widziolek M, Adamek M, Orzechowska U, Podlasz P, Prajsnar TK et al (2021) Tilapia lake virus-induced neuroinflammation in zebrafish: microglia activation and sickness behavior. Front Immunol 12:760882. https://doi.org/10.3389/fimmu.2021.760882
Montanari M, Royet J (2021) Impact of microorganisms and parasites on neuronally controlled drosophila behaviours. Cell 10(9). https://doi.org/10.3390/cells10092350
Nemeth DP, Quan N (2021) Modulation of neural networks by Interleukin-1. Brain Plast 7(1):17–32. https://doi.org/10.3233/BPL-200109
O'Connor JC, Lawson MA, Andre C, Moreau M, Lestage J, Castanon N et al (2009) Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol Psychiatry 14(5):511–522. https://doi.org/10.1038/sj.mp.4002148
O'Neill LA, Kishton RJ, Rathmell J (2016) A guide to immunometabolism for immunologists. Nat Rev Immunol 16(9):553–565. https://doi.org/10.1038/nri.2016.70
Pugh CR, Kumagawa K, Fleshner M, Watkins LR, Maier SF, Rudy JW (1998) Selective effects of peripheral lipopolysaccharide administration on contextual and auditory-cue fear conditioning. Brain Behav Immun 12(3):212–229. https://doi.org/10.1006/brbi.1998.0524
Rao S, Schieber AMP, O'Connor CP, Leblanc M, Michel D, Ayres JS (2017) Pathogen-mediated inhibition of anorexia promotes host survival and transmission. Cell 168(3):503–16.e12. https://doi.org/10.1016/j.cell.2017.01.006
Reyes TM, Coe CL (1996) Interleukin-1 beta differentially affects interleukin-6 and soluble interleukin-6 receptor in the blood and central nervous system of the monkey. J Neuroimmunol 66(1–2):135–141. https://doi.org/10.1016/0165-5728(96)00038-0
Saper CB, Romanovsky AA, Scammell TE (2012) Neural circuitry engaged by prostaglandins during the sickness syndrome. Nat Neurosci 15(8):1088–1095. https://doi.org/10.1038/nn.3159
Schneider DS, Ayres JS (2008) Two ways to survive infection: what resistance and tolerance can teach us about treating infectious diseases. Nat Rev Immunol 8(11):889–895. https://doi.org/10.1038/nri2432
Shattuck EC, Muehlenbein MP (2016) Towards an integrative picture of human sickness behavior. Brain Behav Immun 57:255–262. https://doi.org/10.1016/j.bbi.2016.05.002
Sinner MP, Masurat F, Ewbank JJ, Pujol N, Bringmann H (2021) Innate immunity promotes sleep through epidermal antimicrobial peptides. Curr Biol 31(3):564–77.e12. https://doi.org/10.1016/j.cub.2020.10.076
Stockmaier S, Stroeymeyt N, Shattuck EC, Hawley DM, Meyers LA, Bolnick DI (2021) Infectious diseases and social distancing in nature. Science 371(6533). https://doi.org/10.1126/science.abc8881
Straub RH (2014) Interaction of the endocrine system with inflammation: a function of energy and volume regulation. Arthritis Res Ther 16(1):203. https://doi.org/10.1186/ar4484
Takeda K, Kaisho T, Akira S (2003) Toll-like receptors. Annu Rev Immunol 21:335–376. https://doi.org/10.1146/annurev.immunol.21.120601.141126
Tazi A, Dantzer R, Crestani F, Le Moal M (1988) Interleukin-1 induces conditioned taste aversion in rats: a possible explanation for its pituitary-adrenal stimulating activity. Brain Res 473(2):369–371. https://doi.org/10.1016/0006-8993(88)90868-2
Toda H, Williams JA, Gulledge M, Sehgal A (2019) A sleep-inducing gene, nemuri, links sleep and immune function in drosophila. Science 363(6426):509–515. https://doi.org/10.1126/science.aat1650
Vichaya EG, Malik S, Sominsky L, Ford BG, Spencer SJ, Dantzer R (2020) Microglia depletion fails to abrogate inflammation-induced sickness in mice and rats. J Neuroinflammation 17(1):172. https://doi.org/10.1186/s12974-020-01832-2
Wan W, Wetmore L, Sorensen CM, Greenberg AH, Nance DM (1994) Neural and biochemical mediators of endotoxin and stress-induced c-fos expression in the rat brain. Brain Res Bull 34(1):7–14. https://doi.org/10.1016/0361-9230(94)90179-1
Wang A, Huen SC, Luan HH, Yu S, Zhang C, Gallezot JD et al (2016) Opposing effects of fasting metabolism on tissue tolerance in bacterial and viral inflammation. Cell 166(6):1512–25.e12. https://doi.org/10.1016/j.cell.2016.07.026
Wang A, Luan HH, Medzhitov R (2019) An evolutionary perspective on immunometabolism. Science 363:6423. https://doi.org/10.1126/science.aar3932
Watkins LR, Wiertelak EP, Goehler LE, Mooney-Heiberger K, Martinez J, Furness L et al (1994) Neurocircuitry of illness-induced hyperalgesia. Brain Res 639(2):283–299. https://doi.org/10.1016/0006-8993(94)91742-6
Weber MD, Godbout JP, Sheridan JF (2017) Repeated social defeat, neuroinflammation, and behavior: monocytes carry the signal. Neuropsychopharmacology 42(1):46–61. https://doi.org/10.1038/npp.2016.102
Willette AA, Lubach GR, Coe CL (2007) Environmental context differentially affects behavioral, leukocyte, cortisol, and interleukin-6 responses to low doses of endotoxin in the rhesus monkey. Brain Behav Immun 21(6):807–815. https://doi.org/10.1016/j.bbi.2007.01.007
Wing EJ, Young JB (1980) Acute starvation protects mice against listeria monocytogenes. Infect Immun 28(3):771–776
Zhu X, Levasseur PR, Michaelis KA, Burfeind KG, Marks DL (2016) A distinct brain pathway links viral RNA exposure to sickness behavior. Sci Rep 6:29885. https://doi.org/10.1038/srep29885
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG
About this chapter
Cite this chapter
Dantzer, R. (2022). Evolutionary Aspects of Infections: Inflammation and Sickness Behaviors. In: Savitz, J., Yolken, R.H. (eds) Microorganisms and Mental Health. Current Topics in Behavioral Neurosciences, vol 61. Springer, Cham. https://doi.org/10.1007/7854_2022_363
Download citation
DOI: https://doi.org/10.1007/7854_2022_363
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-24332-5
Online ISBN: 978-3-031-24333-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)