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Sickness behavior

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Title: Sickness behavior  
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Sickness behavior

Ancher, Michael, "The Sick Girl", 1882, Statens Museum for Kunst.

Sickness behavior is a coordinated set of pathogens.[8][9] It has been suggested as relevant to understanding depression, and some aspects of the suffering that occurs in cancer.


  • History 1
  • Advantages 2
    • General advantage 2.1
    • Specific advantages 2.2
  • Immune control 3
  • Behavioral conditioning 4
  • Medical conditions 5
    • Depression 5.1
    • Cancer side effect 5.2
  • See also 6
  • References 7


Sick animals have long been recognized by farmers as having different behavior. Initially it was thought that this was due to physical weakness that resulted from diverting energy to the body processes needed to fight infection. However, in the 1960s, it was shown that animals produced a blood-carried ‘‘factor X’’ that acted upon the brain to cause sickness behavior.[10][11] In 1987, Benjamin L. Hart brought together a variety of research findings that argued for them being survival adaptations that if prevented would disadvantage an animal’s ability to fight infection. In the 1980s, the blood borne factor was shown to be proinflammatory cytokines produced by activated leukocytes in the immune system in response to lipopolysaccharides (a cell wall component of Gram-negative bacteria). These cytokines acted by various humoral and nerve routes upon the hypothalamus and other areas of the brain. Further research showed that the brain can also learn to control the various components of sickness behavior independently of immune activation.


General advantage

Sickness behavior in its different aspects causes an animal to limit its movement; the metabolic energy not expended in activity is diverted to the fever responses, which involves raising body temperature.[1] This also limits an animal’s exposure to predators while it is cognitively and physically impaired.[1]

Specific advantages

The individual components of sickness behavior have specific individual advantages. Anorexia limits food ingestion and therefore reduces the availability of iron in the gut (and from gut absorption). Iron may aid bacterial reproduction, so its reduction is useful during sickness.[12] Plasma concentrations of iron are lowered for this anti-bacterial reason in fever.[13] Lowered threshold for pain ensures that an animal is attentive that it does not place pressure on injured and inflamed tissues that might disrupt their healing.[1] Reduced grooming is adaptive since it reduces water loss.[1]

Immune control

Lipopolysaccharides trigger the volume transmission.[16] Peripheral cytokines may enter the brain directly.[17][18] They may also induce the expression of other cytokines in the brain that cause sickness behavior.[19][20] Acute psychosocial stress enhances the ability of an immune response to trigger both inflammation and behavioral sickness.[21]

Behavioral conditioning

The components of sickness behavior can be learned by conditional association. For example, if a saccharin solution is given with a chemical that triggers a particular aspect of sickness behavior, on later occasions the saccharin solution will trigger it by itself.[22][23]

Medical conditions


It has been proposed that major depressive disorder is near-identical with sickness behavior, so raising the possibility that it is a maladaptive manifestation of sickness behavior due to abnormalities in circulating cytokines.[24][25][26][27] Moreover, chronic, but not acute treatment with antidepressant drugs was found to attenuate sickness behavior symptoms in rodents.[28] The mood effects caused by interleukin-6 following an immune response have been linked to increased activity within the subgenual anterior cingulate cortex,[29] an area involved in the etiology of depression.[30] Inflammation-associated mood change can also produce a reduction in the functional connectivity of this part of the brain to the amygdala, medial prefrontal cortex, nucleus accumbens, and superior temporal sulcus.[29]

Cancer side effect

In cancer, both the disease and the chemotherapy treatment can cause proinflammatory cytokine release which can cause sickness behavior as a side effect.[31][32]

See also


  1. ^ a b c d e f Hart, BL (1988). "Biological basis of the behavior of sick animals". Neuroscience and biobehavioral reviews 12 (2): 123–37.  
  2. ^ a b Kent, S.; Bluthe, R. M.; Dantzer, R.; Hardwick, A. J.; Kelley, K. W.; Rothwell, N. J.; Vannice, J. L. (1992). "Different receptor mechanisms mediate the pyrogenic and behavioral effects of interleukin 1". Proceedings of the National Academy of Sciences of the United States of America 89 (19): 9117–9120.  
  3. ^ Exton, M. S. (1997). "Infection-Induced Anorexia: Active Host Defence Strategy". Appetite 29 (3): 369–383.  
  4. ^ Murray, M. J.; Murray, A. B. (1979). "Anorexia of infection as a mechanism of host defense". The American journal of clinical nutrition 32 (3): 593–596.  
  5. ^ Mullington, J.; Korth, C.; Hermann, D. M.; Orth, A.; Galanos, C.; Holsboer, F.; Pollmächer, T. (2000). "Dose-dependent effects of endotoxin on human sleep". American journal of physiology. Regulatory, integrative and comparative physiology 278 (4): R947–R955.  
  6. ^ Maier, SF; Wiertelak, EP; Martin, D; Watkins, LR (1993). "Interleukin-1 mediates the behavioral hyperalgesia produced by lithium chloride and endotoxin". Brain Research 623 (2): 321–4.  
  7. ^ Dantzer R, Kelley KW (February 2007). "Twenty years of research on cytokine-induced sickness behavior".  
  8. ^ a b Kelley, KW; Bluthé, RM; Dantzer, R; Zhou, JH; Shen, WH; Johnson, RW; Broussard, SR (2003). "Cytokine-induced sickness behavior". Brain, behavior, and immunity. 17 Suppl 1: S112–8.  
  9. ^ Johnson, R. W. (2002). "The concept of sickness behavior: A brief chronological account of four key discoveries". Veterinary immunology and immunopathology 87 (3–4): 443–450.  
  10. ^ Holmes, J. E.; Miller, N. E. (1963). "Effects of Bacterial Endotoxin on Water Intake, Food Intake, and Body Temperature in the Albino Rat". The Journal of experimental medicine 118 (4): 649–658.  
  11. ^ Miller, N. (1964) "Some psychophysiological studies of motivation and of the behavioral effects of illness". Bull. Br. Psychol. Soc. 17: 1-20
  12. ^ Kluger, M. J.; Rothenburg, B. A. (1979). "Fever and reduced iron: Their interaction as a host defense response to bacterial infection". Science 203 (4378): 374–376.  
  13. ^ Weinberg, E. D. (1984). "Iron withholding: A defense against infection and neoplasia". Physiological reviews 64 (1): 65–102.  
  14. ^ Goehler, L. E.; Gaykema, R. P.; Nguyen, K. T.; Lee, J. E.; Tilders, F. J.; Maier, S. F.; Watkins, L. R. (1999). "Interleukin-1beta in immune cells of the abdominal vagus nerve: A link between the immune and nervous systems?". The Journal of neuroscience : the official journal of the Society for Neuroscience 19 (7): 2799–2806.  
  15. ^ Goehler, L. E.; Relton, J. K.; Dripps, D.; Kiechle, R.; Tartaglia, N.; Maier, S. F.; Watkins, L. R. (1997). "Vagal paraganglia bind biotinylated interleukin-1 receptor antagonist: A possible mechanism for immune-to-brain communication". Brain research bulletin 43 (3): 357–364.  
  16. ^ Konsman, J. P.; Kelley, K.; Dantzer, R. (1999). "Temporal and spatial relationships between lipopolysaccharide-induced expression of Fos, interleukin-1beta and inducible nitric oxide synthase in rat brain". Neuroscience 89 (2): 535–548.  
  17. ^ Banks, W. A.; Kastin, A. J.; Gutierrez, E. G. (1994). "Penetration of interleukin-6 across the murine blood-brain barrier". Neuroscience letters 179 (1–2): 53–56.  
  18. ^ Banks, W. A.; Ortiz, L.; Plotkin, S. R.; Kastin, A. J. (1991). "Human interleukin (IL) 1 alpha, murine IL-1 alpha and murine IL-1 beta are transported from blood to brain in the mouse by a shared saturable mechanism". The Journal of pharmacology and experimental therapeutics 259 (3): 988–996.  
  19. ^ Ban, E.; Haour, F.; Lenstra, R. (1992). "Brain interleukin 1 gene expression induced by peripheral lipopolysaccharide administration". Cytokine 4 (1): 48–54.  
  20. ^ Van Dam, A. M.; Brouns, M.; Louisse, S.; Berkenbosch, F. (1992). "Appearance of interleukin-1 in macrophages and in ramified microglia in the brain of endotoxin-treated rats: A pathway for the induction of non-specific symptoms of sickness?". Brain research 588 (2): 291–296.  
  21. ^ Brydon, L.; Walker, C.; Wawrzyniak, A.; Whitehead, D.; Okamura, H.; Yajima, J.; Tsuda, A.; Steptoe, A. (2009). "Synergistic effects of psychological and immune stressors on inflammatory cytokine and sickness responses in humans". Brain, Behavior, and Immunity 23 (2): 217–224.  
  22. ^ Exton, M. S.; Bull, D. F.; King, M. G. (1995). "Behavioral conditioning of lipopolysaccharide-induced anorexia". Physiology & behavior 57 (2): 401–405.  
  23. ^ Exton, M. S.; Bull, D. F.; King, M. G.; Husband, A. J. (1995). "Modification of body temperature and sleep state using behavioral conditioning". Physiology & behavior 57 (4): 723–729.  
  24. ^ Yirmiya, R.; Weidenfeld, J.; Pollak, Y.; Morag, M.; Morag, A.; Avitsur, R.; Barak, O.; Reichenberg, A.; Cohen, E.; Shavit, Y.; Ovadia, H. (1999). "Cytokines, Stress, and Depression". Advances in experimental medicine and biology. Advances in Experimental Medicine and Biology 461: 283–316.  
  25. ^ Charlton, B. G. (2000). "The malaise theory of depression: Major depressive disorder is sickness behavior and antidepressants are analgesic". Medical Hypotheses 54 (1): 126–130.  
  26. ^ Dantzer, R.; O'Connor, J. C.; Freund, G. G.; Johnson, R. W.; Kelley, K. W. (2008). "From inflammation to sickness and depression: When the immune system subjugates the brain". Nature Reviews Neuroscience 9 (1): 46–56.  
  27. ^ Maes, M. (2008). "The cytokine hypothesis of depression: Inflammation, oxidative & nitrosative stress (IO&NS) and leaky gut as new targets for adjunctive treatments in depression". Neuro endocrinology letters 29 (3): 287–291.  
  28. ^ Yirmiya, R. (1996). "Endotoxin produces a depressive-like episode in rats". Brain research 711 (1–2): 163–174.  
  29. ^ a b Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Critchley HD (September 2009). "Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity". Biol Psychiatry 66 (5): 407–14.  
  30. ^ Drevets WC, Savitz J, Trimble M (August 2008). "The subgenual anterior cingulate cortex in mood disorders". CNS Spectr 13 (8): 663–81.   PDF:
  31. ^ Cleeland, C. S.; Bennett, G. J.; Dantzer, R.; Dougherty, P. M.; Dunn, A. J.; Meyers, C. A.; Miller, A. H.; Payne, R.; Reuben, J. M.; Wang, X. S.; Lee, B. N. (2003). "Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism?". Cancer 97 (11): 2919–2925.  
  32. ^ Myers, J. S. (2008). "Proinflammatory Cytokines and Sickness Behavior: Implications for Depression and Cancer-Related Symptoms". Oncology Nursing Forum 35 (5): 802–807.  
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