Sickness behavior

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.{{Cite journal | last1 = Holmes | first1 = J. E. | last2 = Miller | first2 = N. E. | title = Effects of Bacterial Endotoxin on Water Intake, Food Intake, and Body Temperature in the Albino Rat | journal = The Journal of Experimental Medicine | volume = 118 | issue = 4 | pages = 649–658 | year = 1963 | pmid = 14067912 | pmc = 2137667 | doi=10.1084/jem.118.4.649}}Miller, N. (1964) "Some psychophysiological studies of motivation and of the behavioral effects of illness". Bull. Br. Psychol. Soc. 17: 1–20 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.{{citation needed|date=January 2014}}

In 2015, Shakhar and Shakhar{{cite journal |vauthors=Shakhar K, Shakhar G | date = Oct 2015 | title = Why Do We Feel Sick When Infected-Can Altruism Play a Role? | journal = PLOS Biol. | volume = 13 | issue = 10| page = e1002276 | doi = 10.1371/journal.pbio.1002276 | pmid = 26474156 | pmc=4608734 | doi-access = free }} suggested instead that sickness behavior developed primarily because it protected the kin of infected animals from transmissible diseases. According to this theory, termed the Eyam hypothesis, after the English Parish of Eyam, sickness behavior protects the social group of infected individuals by limiting their direct contacts, preventing them from contaminating the environment, and broadcasting their health status. Kin selection would help promote such behaviors through evolution. In a highly prosocial species like humans, however, sickness behavior may act as a signal to motivate others to help and care for the sick individual.{{cite journal |vauthors=Steinkopf L | date = Aug 2015 | title = The Signaling Theory of Symptoms: An Evolutionary Explanation of the Placebo Effect | journal = Evolutionary Psychology | volume = 13 | issue = 3| page = 100 | doi = 10.1177/1474704915600559 | doi-access = free | pmid = 37924177 | pmc = 10480909 }}

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. This also limits an animal's exposure to predators while it is cognitively and physically impaired.

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.{{Cite journal | last1 = Kluger | first1 = M. J. | last2 = Rothenburg | first2 = B. A. | title = Fever and reduced iron: Their interaction as a host defense response to bacterial infection | journal = Science | volume = 203 | issue = 4378 | pages = 374–376 | year = 1979 | pmid = 760197 | doi=10.1126/science.760197| bibcode = 1979Sci...203..374K }} Plasma concentrations of iron are lowered for this anti-bacterial reason in fever.{{Cite journal | last1 = Weinberg | first1 = E. D. | title = Iron withholding: A defense against infection and neoplasia | journal = Physiological Reviews | volume = 64 | issue = 1 | pages = 65–102 | year = 1984 | pmid = 6420813 | doi=10.1152/physrev.1984.64.1.65}} 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. Reduced grooming is adaptive since it reduces water loss.

According to the 'Eyam hypothesis', sickness behavior, by promoting immobility and social disinterest, limits the direct contacts of individuals with their relatives. By reducing eating and drinking, it limits diarrhea and defecation, reducing environmental contamination. By reducing self-grooming and changing stance, gait and vocalization, it also signals poor health to kin. All in all, sickness behavior reduces the rate of further infection, a trait that is likely propagated by kin selection.{{citation needed|date=December 2021}}

Humans helped each other in case of sickness or injury throughout their hunter-gatherer past and afterwards. Convincing others of being badly in need of relief, assistance, and care heightened the chance of survival of the sick individual. High direct costs, such as energy spent on fever and potential harm caused by high body temperatures, and high opportunity costs, as caused by inactivity, social disinterest, and lack of appetite, make sickness behavior a highly costly and therefore credible signal of need.

Lipopolysaccharides trigger the immune system to produce proinflammatory cytokines IL-1, IL-6, and tumor necrosis factor (TNF).{{cite journal|last1=Konsman|first1=JP|last2=Parnet|first2=P|last3=Dantzer|first3=R|title=Cytokine-induced sickness behaviour: mechanisms and implications.|journal=Trends in Neurosciences|date=March 2002|volume=25|issue=3|pages=154–159|pmid=11852148|doi=10.1016/s0166-2236(00)02088-9|s2cid=29779184}} These peripherally released cytokines act on the brain via a fast transmission pathway involving primary input through the vagus nerves,{{Cite journal | last1 = Goehler | first1 = L. E. | last2 = Gaykema | first2 = R. P. | last3 = Nguyen | first3 = K. T. | last4 = Lee | first4 = J. E. | last5 = Tilders | first5 = F. J. | last6 = Maier | first6 = S. F. | last7 = Watkins | first7 = L. R. | title = Interleukin-1beta in immune cells of the abdominal vagus nerve: A link between the immune and nervous systems? | journal = The Journal of Neuroscience | volume = 19 | issue = 7 | pages = 2799–2806 | year = 1999 | pmid = 10087091| doi = 10.1523/JNEUROSCI.19-07-02799.1999 | pmc = 6786076 | doi-access = free }}{{Cite journal | last1 = Goehler | first1 = L. E. | last2 = Relton | first2 = J. K. | last3 = Dripps | first3 = D. | last4 = Kiechle | first4 = R. | last5 = Tartaglia | first5 = N. | last6 = Maier | first6 = S. F. | last7 = Watkins | first7 = L. R. | title = Vagal paraganglia bind biotinylated interleukin-1 receptor antagonist: A possible mechanism for immune-to-brain communication | journal = Brain Research Bulletin | volume = 43 | issue = 3 | pages = 357–364 | year = 1997 | pmid = 9227848 | doi=10.1016/s0361-9230(97)00020-8| s2cid = 22591654 }} and a slow transmission pathway involving cytokines originating from the choroid plexus and circumventricular organs and diffusing into the brain parenchyma by volume transmission.{{Cite journal | last1 = Konsman | first1 = J. P. | last2 = Kelley | first2 = K. | last3 = Dantzer | first3 = R. | title = Temporal and spatial relationships between lipopolysaccharide-induced expression of Fos, interleukin-1beta and inducible nitric oxide synthase in rat brain | journal = Neuroscience | volume = 89 | issue = 2 | pages = 535–548 | year = 1999 | pmid = 10077334 | doi=10.1016/s0306-4522(98)00368-6| s2cid = 25173830 }} Peripheral cytokines are capable of entering the brain directly{{Cite journal | last1 = Banks | first1 = W. A. | last2 = Kastin | first2 = A. J. | last3 = Gutierrez | first3 = E. G. | title = Penetration of interleukin-6 across the murine blood-brain barrier | journal = Neuroscience Letters | volume = 179 | issue = 1–2 | pages = 53–56 | year = 1994 | pmid = 7845624 | doi=10.1016/0304-3940(94)90933-4| s2cid = 22712577 }}{{Cite journal | last1 = Banks | first1 = W. A. | last2 = Ortiz | first2 = L. | last3 = Plotkin | first3 = S. R. | last4 = Kastin | first4 = A. J. | title = 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 | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 259 | issue = 3 | pages = 988–996 | year = 1991 | pmid = 1762091}} but are large lipophilic polypeptide proteins that generally do not easily passively diffuse across the blood-brain barrier. They may also induce the expression of other cytokines in the brain that cause sickness behavior.{{Cite journal | last1 = Ban | first1 = E. | last2 = Haour | first2 = F. | last3 = Lenstra | first3 = R. | title = Brain interleukin 1 gene expression induced by peripheral lipopolysaccharide administration | journal = Cytokine | volume = 4 | issue = 1 | pages = 48–54 | year = 1992 | pmid = 1535519 | doi=10.1016/1043-4666(92)90036-Q}}{{Cite journal | last1 = Van Dam | first1 = A. M. | last2 = Brouns | first2 = M. | last3 = Louisse | first3 = S. | last4 = Berkenbosch | first4 = F. | title = 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? | journal = Brain Research | volume = 588 | issue = 2 | pages = 291–296 | year = 1992 | pmid = 1393581 | doi=10.1016/0006-8993(92)91588-6| s2cid = 35583973 }} Acute psychosocial stress enhances the ability of an immune response to trigger both inflammation and behavioral sickness.{{Cite journal | last1 = Brydon | first1 = L. | last2 = Walker | first2 = C. | last3 = Wawrzyniak | first3 = A. | last4 = Whitehead | first4 = D. | last5 = Okamura | first5 = H. | last6 = Yajima | first6 = J. | last7 = Tsuda | first7 = A. | last8 = Steptoe | first8 = A. | doi = 10.1016/j.bbi.2008.09.007 | title = Synergistic effects of psychological and immune stressors on inflammatory cytokine and sickness responses in humans | journal = Brain, Behavior, and Immunity | volume = 23 | issue = 2 | pages = 217–224 | year = 2009 | pmid = 18835437 | pmc =2637301 }}

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.{{Cite journal | last1 = Exton | first1 = M. S. | last2 = Bull | first2 = D. F. | last3 = King | first3 = M. G. | title = Behavioral conditioning of lipopolysaccharide-induced anorexia | journal = Physiology & Behavior | volume = 57 | issue = 2 | pages = 401–405 | year = 1995 | pmid = 7716224 | doi=10.1016/0031-9384(94)00249-5| s2cid = 41061406 }}{{Cite journal | last1 = Exton | first1 = M. S. | last2 = Bull | first2 = D. F. | last3 = King | first3 = M. G. | last4 = Husband | first4 = A. J. | title = Modification of body temperature and sleep state using behavioral conditioning | journal = Physiology & Behavior | volume = 57 | issue = 4 | pages = 723–729 | year = 1995 | pmid = 7777610 | doi=10.1016/0031-9384(94)00314-9| s2cid = 927502 }}

It has been proposed that major depressive disorder is nearly identical with sickness behavior, raising the possibility that it is a maladaptive manifestation of sickness behavior due to abnormalities in circulating cytokines.{{Cite book | last1 = Yirmiya | first1 = R. | last2 = Weidenfeld | first2 = J. | last3 = Pollak | first3 = Y. | last4 = Morag | first4 = M. | last5 = Morag | first5 = A. | last6 = Avitsur | first6 = R. | last7 = Barak | first7 = O. | last8 = Reichenberg | first8 = A. | last9 = Cohen | first9 = E. | last10 = Shavit | first10 = Y. | last11 = Ovadia | first11 = H. | chapter = Cytokines, "Depression Due to a General Medical Condition," and Antidepressant Drugs | doi = 10.1007/978-0-585-37970-8_16 | title = Cytokines, Stress, and Depression | series = Advances in Experimental Medicine and Biology | volume = 461 | pages = 283–316 | year = 1999 | isbn = 978-0-306-46135-4 | pmid = 10442179 }}{{Cite journal | last1 = Dantzer | first1 = R. | last2 = O'Connor | first2 = J. C. | last3 = Freund | first3 = G. G. | last4 = Johnson | first4 = R. W. | last5 = Kelley | first5 = K. W. | title = From inflammation to sickness and depression: When the immune system subjugates the brain | doi = 10.1038/nrn2297 | journal = Nature Reviews Neuroscience | volume = 9 | issue = 1 | pages = 46–56 | year = 2008 | pmid = 18073775 | pmc =2919277 }}{{Cite journal | last1 = Maes | first1 = M. | title = The cytokine hypothesis of depression: Inflammation, oxidative & nitrosative stress (IO&NS) and leaky gut as new targets for adjunctive treatments in depression | journal = Neuro Endocrinology Letters | volume = 29 | issue = 3 | pages = 287–291 | year = 2008 | pmid = 18580840}} Moreover, chronic, but not acute, treatment with antidepressant drugs was found to attenuate sickness behavior symptoms in rodents.{{Cite journal | last1 = Yirmiya | first1 = R. | title = Endotoxin produces a depressive-like episode in rats | journal = Brain Research | volume = 711 | issue = 1–2 | pages = 163–174 | year = 1996 | pmid = 8680860 | doi=10.1016/0006-8993(95)01415-2| s2cid = 46133689 }} High rates of depression have been observed in patients treated with cytokines like interferon-α and serve experimental evidence of immunologically-induced depression in humans.{{Cite journal |last=Lasselin |first=Julie |date=2021-12-01 |title=Back to the future of psychoneuroimmunology: Studying inflammation-induced sickness behavior |url=https://www.sciencedirect.com/science/article/pii/S2666354621001824 |journal=Brain, Behavior, & Immunity - Health |volume=18 |pages=100379 |doi=10.1016/j.bbih.2021.100379 |issn=2666-3546}} The mood effects caused by interleukin-6 following an immune response have been linked to increased activity within the subgenual anterior cingulate cortex,{{cite journal |vauthors=Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Critchley HD | title = Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity | journal = Biol Psychiatry | volume = 66 | issue = 5 | pages = 407–414 |date=September 2009 | pmid = 19423079 | doi = 10.1016/j.biopsych.2009.03.015 | pmc = 2885494 }} an area involved in the etiology of depression.{{cite journal |vauthors=Drevets WC, Savitz J, Trimble M | title = The subgenual anterior cingulate cortex in mood disorders | journal = CNS Spectr | volume = 13 | issue = 8 | pages = 663–681 |date=August 2008 | pmid = 18704022 | pmc = 2729429 | doi=10.1017/s1092852900013754}} PDF:http://mbldownloads.com/0808CNS_BrainRegions.pdf 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.

In cancer, both the disease and the chemotherapy treatment can cause proinflammatory cytokine release which can cause sickness behavior as a side effect.{{Cite journal | last1 = Cleeland | first1 = C. S. | last2 = Bennett | first2 = G. J. | last3 = Dantzer | first3 = R. | last4 = Dougherty | first4 = P. M. | last5 = Dunn | first5 = A. J. | last6 = Meyers | first6 = C. A. | last7 = Miller | first7 = A. H. | last8 = Payne | first8 = R. | last9 = Reuben | first9 = J. M. | last10 = Wang | doi = 10.1002/cncr.11382 | first10 = X. S. | last11 = Lee | first11 = B. N. | title = Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism? | journal = Cancer | volume = 97 | issue = 11 | pages = 2919–2925 | year = 2003 | pmid = 12767108 | s2cid = 23198802 }}{{Cite journal | last1 = Myers | first1 = J. S. | title = Proinflammatory Cytokines and Sickness Behavior: Implications for Depression and Cancer-Related Symptoms | doi = 10.1188/08.ONF.802-807 | journal = Oncology Nursing Forum | volume = 35 | issue = 5 | pages = 802–807 | year = 2008 | pmid = 18765326 }}

• Evolutionary medicine
• Proinflammatory cytokines

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Category:Symptoms

Category:Evolutionary biology

Category:Cytokines