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Main article: Illness behavior

Sickness behavior is a coordinated set of adaptive behavioral changes that develop in ill individuals during the course of an infection.[1] They usually (but not necessarily)[2] accompany fever and aid survival. Such illness responses include lethargy, depression, anorexia,[3][4] sleepiness, hyperalgesia,[5] reduction in grooming[1][6] and failure to concentrate.[7] Sickness behavior is a motivational state that reorganizes the organism’s priorities to cope with infectious pathogens.[8][9] It has been suggested as relevant to understanding depression, and some aspects of the suffering that occurs in cancer.


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 from 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 this such 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 cytockines acted by various humeral and nerve routes upon the hypothalmus 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 cauess an animal to limit its movement and so reduce its energy expenditure allowing this to be diverted to mobilize the fever response which involves raising body temperature.[1] They 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 the ingestion of foods and so the availability in the gut and from gut absorption of iron and zinc that might aid bacterial reproduction.[12] Plasma concentrations of iron and zinc are lowered for this reason in fever.[13] Lowered threshold for pain ensures that an animal is attentive that it does not place pressure of injuried and inflammed tissues that might disrupt their healing.[1] Reduced grooming is adaptive since it reduces water loss.[1]

Immune control[]

Lipopolysaccharides trigger the immune system to produce proinflammatory cytokines IL-1, IL-6, and tumor necrosis factor (TNF).[14] These peripherally released cytokines act on the brain via a fast transmission pathway involving primary input through the vegus nerves,[15][16] and a slow transmission pathway involving cytokines originating from the choroid plexus and circumventricular organs and diffusing into the brain parenchyma by volume transmission.[17] Peripheral cytokines may enter directly the brain.[18][19] They may also induce the expression of other cytokines in the brain that cause sickness behavior.[20][21]


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


It has been proposed that major depressive disorder is near-identical with sickness behavior so raising the possibility that is a maladaptive manifestation of sickness behavior due to abnormalities in circulating cytokines.[24][25]

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.[26][27]

See also[]


  1. 1.0 1.1 1.2 1.3 1.4 1.5 Hart, B. L. (1988) "Biological basis of the behavior of sick animals". Neurosci Biobehav Rev. 12: 123-137. PMID 3050629
  2. 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". Proc Natl Acad Sci U S A. 89: 9117-9120. PMID 1409612
  3. Exton, M. S. (1997) "Infection-induced anorexia: active host defence strategy". Appetite. 29: 369-383. PMID 9468766
  4. Murray, M. J. Murray, A. B. (1979) "Anorexia of infection as a mechanism of host defense". Am J Clin Nutr. 32: 593-596. PMID 283688
  5. Maier, S. F., Wiertelak, E. P., Martin, D. Watkins, L. R. (1993) "Interleukin-1 mediates the behavioral hyperalgesia produced by lithium chloride and endotoxin". Brain Res. 623: 321-324. PMID 8221116
  6. Dantzer, R. Kelley, K. W. (2007) "Twenty years of research on cytokine-induced sickness behavior". Brain Behav Immun. 21: 153-160 PMID 17088043
  7. Kelley, K. W., Bluthe, R. M., Dantzer, R., Zhou, J. H., Shen, W. H., Johnson, R. W. Broussard, S. R. (2003) "Cytokine-induced sickness behavior". Brain Behav Immun. 17 Suppl 1: S112-118. PMID 12615196
  8. Johnson, R. (2002) "The concept of sickness behavior: a brief chronological account of four key discoveries". Veterinary Immunology and Immunopathology. 87: 443-450 Elsevier {{PMID|
  9. Kelley, K. W., Bluthe, R. M., Dantzer, R., Zhou, J. H., Shen, W. H., Johnson, R. W. Broussard, S. R. (2003) "Cytokine-induced sickness behavior". Brain Behav Immun. 17 Suppl 1: S112-118 PMID 12615196
  10. Holmes, J. E. Miller, N. E. (1963) "Effects of Bacterial Endotoxin on Water Intake, Food Intake, and Body Temperature in the Albino Rat". J Exp Med. 118: 649-658 PMID 14067912
  11. Miller, N. (1964) "Some psychophysiological studies of motivation and of the behavioral effects of illness". Bull. Br. Psychol. Soc. 17: 1-20 {{PMID|
  12. Kluger, M. J. Rothenburg, B. A. (1979) "Fever and reduced iron: their interaction as a host defense response to bacterial infection". Science. 203: 374-376. PMID 760197
  13. Weinberg, E. D. (1984) "Iron withholding: a defense against infection and neoplasia". Physiol Rev. 64: 65-102. PMID 6420813
  14. 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". Proc Natl Acad Sci U S A. 89: 9117-9120 PMID 1409612
  15. 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?" J Neurosci. 19: 2799-2806 PMID 10087091
  16. 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 Res Bull. 43: 357-364 PMID 9227848
  17. 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: 535-548 PMID 10077334
  18. Banks, W. A., Kastin, A. J. Gutierrez, E. G. (1994) "Penetration of interleukin-6 across the murine blood-brain barrier". Neurosci Lett. 179: 53-56 PMID 7845624
  19. 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". J Pharmacol Exp Ther. 259: 988-996 PMID 1762091
  20. Ban, E., Haour, F. Lenstra, R. (1992) "Brain interleukin 1 gene expression induced by peripheral lipopolysaccharide administration". Cytokine. 4: 48-54 PMID 1535519
  21. 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 Res. 588: 291-296 PMID 1393581
  22. Exton, M. S., Bull, D. F. King, M. G. (1995) "Behavioral conditioning of lipopolysaccharide-induced anorexia". Physiol Behav. 57: 401-405. PMID 7716224
  23. Exton, M. S., Bull, D. F., King, M. G. Husband, A. J. (1995) "Modification of body temperature and sleep state using behavioral conditioning". Physiol Behav. 57: 723-729. PMID 7777610
  24. Charlton, B. G. (2000) "The malaise theory of depression: major depressive disorder is sickness behavior and antidepressants are analgesic". Med Hypotheses. 54: 126-130 PMID 10790737
  25. 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". Nat Rev Neurosci. 9: 46-56 PMID 18073775
  26. 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? A cytokine-immunologic model of cancer symptoms". Cancer. 97: 2919-2925 PMID 12767108
  27. Myers, J. S. (2008) "Proinflammatory cytokines and sickness behavior: implications for depression and cancer-related symptoms". Oncol Nurs Forum. 35: 802-807 PMID 18765326
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