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 always, [2] accompany fever and aid survival. Such illness responses include lethargy, depression, anxiety, malaise, loss of appetite, [3] [4] sleepiness, [5] hyperalgesia, [6] reduction in grooming [1] [7] and failure to concentrate. [8] 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, [10] 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 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. [11] [12] 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 ].
In 2015, Shakhar and Shakhar [13] 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. [14]
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]
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. [15] Plasma concentrations of iron are lowered for this anti-bacterial reason in fever. [16] 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]
According to the 'Eyam hypothesis', [13] 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 ]
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. [14]
Lipopolysaccharides trigger the immune system to produce proinflammatory cytokines IL-1, IL-6, and tumor necrosis factor (TNF). [17] These peripherally released cytokines act on the brain via a fast transmission pathway involving primary input through the vagus nerves, [18] [19] and a slow transmission pathway involving cytokines originating from the choroid plexus and circumventricular organs and diffusing into the brain parenchyma by volume transmission. [20] Peripheral cytokines are capable of entering the brain directly [21] [22] 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. [23] [24] Acute psychosocial stress enhances the ability of an immune response to trigger both inflammation and behavioral sickness. [25]
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. [26] [27]
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. [28] [29] [30] Moreover, chronic, but not acute, treatment with antidepressant drugs was found to attenuate sickness behavior symptoms in rodents. [31] The mood effects caused by interleukin-6 following an immune response have been linked to increased activity within the subgenual anterior cingulate cortex, [32] an area involved in the etiology of depression. [33] 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. [32]
In cancer, both the disease and the chemotherapy treatment can cause proinflammatory cytokine release which can cause sickness behavior as a side effect. [34] [35]
Tumor necrosis factor is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homologous TNF domain.
Substance P (SP) is an undecapeptide and a type of neuropeptide, belonging to the tachykinin family of neuropeptides. It acts as a neurotransmitter and a neuromodulator. Substance P and the closely related neurokinin A (NKA) are produced from a polyprotein precursor after alternative splicing of the preprotachykinin A gene. The deduced amino acid sequence of substance P is as follows:
Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by covalent bonds, and are found in the outer membrane of Gram-negative bacteria, such as E. coli and Salmonella. Today, the term endotoxin is often used synonymously with LPS, although there are a few endotoxins that are not related to LPS, such as the so-called delta endotoxin proteins produced by Bacillus thuringiensis.
Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-spanning receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have reached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses. The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Humans lack genes for TLR11, TLR12 and TLR13 and mice lack a functional gene for TLR10. The receptors TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10 are located on the cell membrane, whereas TLR3, TLR7, TLR8, and TLR9 are located in intracellular vesicles.
Somnolence is a state of strong desire for sleep, or sleeping for unusually long periods. It has distinct meanings and causes. It can refer to the usual state preceding falling asleep, the condition of being in a drowsy state due to circadian rhythm disorders, or a symptom of other health problems. It can be accompanied by lethargy, weakness and lack of mental agility.
Psychoneuroimmunology (PNI), also referred to as psychoendoneuroimmunology (PENI) or psychoneuroendocrinoimmunology (PNEI), is the study of the interaction between psychological processes and the nervous and immune systems of the human body. It is a subfield of psychosomatic medicine. PNI takes an interdisciplinary approach, incorporating psychology, neuroscience, immunology, physiology, genetics, pharmacology, molecular biology, psychiatry, behavioral medicine, infectious diseases, endocrinology, and rheumatology.
Hyperalgesia is an abnormally increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves and can cause hypersensitivity to stimulus. Prostaglandins E and F are largely responsible for sensitizing the nociceptors. Temporary increased sensitivity to pain also occurs as part of sickness behavior, the evolved response to infection.
Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine. In humans, interleukin 10 is encoded by the IL10 gene. IL-10 signals through a receptor complex consisting of two IL-10 receptor-1 and two IL-10 receptor-2 proteins. Consequently, the functional receptor consists of four IL-10 receptor molecules. IL-10 binding induces STAT3 signalling via the phosphorylation of the cytoplasmic tails of IL-10 receptor 1 + IL-10 receptor 2 by JAK1 and Tyk2 respectively.
Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the IL6 gene.
Interleukin-18 (IL-18), also known as interferon-gamma inducing factor is a protein which in humans is encoded by the IL18 gene. The protein encoded by this gene is a proinflammatory cytokine. Many cell types, both hematopoietic cells and non-hematopoietic cells, have the potential to produce IL-18. It was first described in 1989 as a factor that induced interferon-γ (IFN-γ) production in mouse spleen cells. Originally, IL-18 production was recognized in Kupffer cells, liver-resident macrophages. However, IL-18 is constitutively expressed in non-hematopoietic cells, such as intestinal epithelial cells, keratinocytes, and endothelial cells. IL-18 can modulate both innate and adaptive immunity and its dysregulation can cause autoimmune or inflammatory diseases.
Toll-like receptor 4 is a protein that in humans is encoded by the TLR4 gene. TLR4 is a transmembrane protein, member of the toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. Its activation leads to an intracellular signaling pathway NF-κB and inflammatory cytokine production which is responsible for activating the innate immune system.
The cholinergic anti-inflammatory pathway regulates the innate immune response to injury, pathogens, and tissue ischemia. It is the efferent, or motor arm of the inflammatory reflex, the neural circuit that responds to and regulates the inflammatory response.
Interleukin-17A is a protein that in humans is encoded by the IL17A gene. In rodents, IL-17A used to be referred to as CTLA8, after the similarity with a viral gene.
The Interleukin-1 family is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.
Raz Yirmiya is an Israeli behavioral neuroscientist and director of the Laboratory for Psychoneuroimmunology at the Hebrew University of Jerusalem in Israel. He is best known for providing the first experimental evidence for the role of immune system activation in depression, for discovering that disturbances in brain microglia cells underlie some forms of depression, and for elucidating the involvement of inflammatory cytokines in regulation of cognitive and emotional processes.
Immuno-psychiatry, according to Pariante, is a discipline that studies the connection between the brain and the immune system. It differs from psychoneuroimmunology by postulating that behaviors and emotions are governed by peripheral immune mechanisms. Depression, for instance, is seen as malfunctioning of the immune system.
Major depression is often associated or correlated with immune function dysregulation, and the two are thought to share similar physiological pathways and risk factors. Primarily seen through increased inflammation, this relationship is bidirectional with depression often resulting in increased immune response and illness resulting in prolonged sadness and lack of activity. This association is seen both long-term and short-term, with the presence of one often being accompanied by the other and both inflammation and depression often being co-morbid with other conditions.
Keith Kelley is an American immunophysiologist, researcher and academic. He is Professor Emeritus of Immunophysiology at the University of Illinois and Editor-In-Chief Emeritus of Brain, Behavior, and Immunity. He is a Past-President and Secretary-Treasurer of the Psychoneuroimmunology Research Society.
Staci Bilbo is an American neuroimmunologist and The Haley Family Professor of Psychology and Neuroscience at Duke University. Bilbo also holds a position as a research affiliate at Massachusetts General Hospital overseeing research within the Lurie Center for Autism. As the principal investigator of the Bilbo Lab, Bilbo investigates how environmental challenges during the perinatal period impact the immune system and further influence brain development, cognition, and affective behaviors later in life..
Interleukin 17F (IL-17F) is signaling protein that is in human is encoded by the IL17F gene and is considered a pro-inflammatory cytokine. This protein belongs to the interleukin 17 family and is mainly produced by the T helper 17 cells after their stimulation with interleukin 23. However, IL-17F can be also produced by a wide range of cell types, including innate immune cells and epithelial cells.