Psychoneuroimmunology (PNI) assesses the interactions between the nervous and immune systems in relation to behavior.
PNI includes several areas of research, which are usually interconnected, most of them being represented in Europe.
Below are short descriptions of research areas that are represented in the EPN. These serve as brief introductions into large fields and such descriptions cannot cover all aspects. Please note that not all research fields of EPN members are included.
Behavioral and neuronal consequences of immune challenges
Inflammation-induced behavioral changes (sickness behavior) promote rest and serve as a behavioral complement to the innate immune reactions triggered during an infection. The context is important for which behaviors a sick individual engages in, and sickness behavior is thus a motivational state.
In animals, sickness behavior is characterized by decreased locomotor activity, hyperalgesia, allodynia, lethargy, hypophagia, hypodipsia and weakness, accompanied by fever. Among the most pronounced sickness responses during immune challenge in humans are fatigue, hyperalgesia and increased negative mood and anxiety. Induced inflammation in humans may also reduce appetite, slow movements, affect cognitive functions and alter sleep patterns.
In animal studies, inflammation has been shown to increase activity (using c-Fos as a cellular activation marker) in the brain stem, the periaqueductal gray, the hypothalamus, the bed nucleus of the stria terminalis and the amygdala and to decrease activity in the dorsal striatum. In humans, increased activity (using e.g., BOLD fMRI and PET) in the insular cortices have been commonly described during experimental inflammation, as well as increased activation of the cingulate cortex and amygdala, possibly reflecting a greater interoceptive focus and changes in emotional processing. Sensitivity of the striatal structures to rewards and punishments is modulated by inflammation, which has been suggested as one mechanism underlying the motivational reorganization during sickness.
Suggested publications:
Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci, 2008, 9(1):46-56. doi: 10.1038/nrn2297.
Yirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun. 2011 Feb;25(2):181-213. doi: 10.1016/j.bbi.2010.10.015.
Harrison NA. Brain Structures Implicated in Inflammation-Associated Depression. Curr Top Behav Neurosci, 2017, 31:221-248. doi: 10.1007/7854_2016_30.
Schedlowski M, Engler H, Grigoleit JS. Endotoxin-induced experimental systemic inflammation in humans: a model to disentangle immune-to-brain communication. Brain Behav Immun, 2014, 35:1-8. doi: 10.1016/j.bbi.2013.09.015.
Lasselin J, Lekander M, Benson S, Schedlowski M, Engler H. Sick for Science: Experimental endotoxemia as a translational tool to develop and test new therapies for inflammation-associated depression. Molecular Psychiatry, 2020. doi: 10.1038/s41380-020-00869-2.
Immune-to-brain and brain-to-immune communication pathways
How does the immune system talk to the brain during infection and inflammation? How does psychological stress alter such communication? Basic underlying mechanisms and signaling pathways are investigated in PNI research. Models to explore such interaction evolved for example from early studies assessing fever induction pathways. Stimulation of the immune system leads to the production of immune mediators of the cytokine family. These cytokines and immune cells can act on the brain and contribute to an inflammatory response in the brain and to the induction of a central nervous system-controlled sickness response including fever. Even in absence of circulating mediators, afferent nerves can conduct a fast transmission of inflammatory information to the brain.
Importantly, the interaction between the immune system and the brain is bidirectional. Efferent signals include endogenous inhibitory feedback mechanisms such as the sympathetic nervous system, and the hypothalamus-pituitary-adrenal (HPA)-axis. Corticotropin-releasing hormone (CRH) is released from the hypothalamus and induces the secretion of adrenocorticotropic hormone (ACTH), which in turn induce the release of glucocorticoids from the adrenal gland. Glucocorticoids can dampen the activated immune system and feed back to the central part of the HPA-axis.
Suggested publications:
Dantzer R. Neuroimmune Interactions: From the Brain to the Immune System and Vice Versa. Physiol Rev, 2018, 98(1):477-504. doi: 10.1152/physrev.00039.2016.
D’Mello C, Swain MG. Immune-to-Brain Communication Pathways in Inflammation-Associated Sickness and Depression. Curr Top Behav Neurosci, 2017, 31:73-94. doi: 10.1007/7854_2016_37.
Rummel C. Inflammatory transcription factors as activation markers and functional readouts in immune-to-brain communication. Brain Behav Immun, 2016, 54:1-14. doi: 10.1016/j.bbi.2015.09.003.
Wohleb ES, McKim DB, Sheridan JF, Godbout JP. Monocyte trafficking to the brain with stress and inflammation: a novel axis of immune-to-brain communication that influences mood and behavior. Front Neurosci, 2015, 8:447. doi: 10.3389/fnins.2014.00447.
Konsman JP, Parnet P, Dantzer R. Cytokine-induced sickness behaviour: mechanisms and implications. Trends Neurosci, 2002, 25(3):154-9. doi: https://doi.org/10.1016/S0166-2236(00)02088-9
Pavlov VA, Tracey KJ. Neural regulation of immunity: molecular mechanisms and clinical translation. Nat Neurosci. 2017 Feb;20(2):156-166. doi: 10.1038/nn.4477.
Pongratz G, Straub RH. The sympathetic nervous response in inflammation. Arthritis Res Ther. 2014;16(6):504. doi: 10.1186/s13075-014-0504-2.
Immunopsychiatry
Immunopsychiatry aims at understanding the role of the immune system in the pathophysiology of neuropsychiatric diseases, such as depression. The PNI perspective of psychiatry has highlighted the role of cytokines and immune cells (including microglia, immune cells of the CNS) in the development of neuropsychiatric symptoms and depression. Altered immune profile of depressed patients has also been found to relate to increased resistance to antidepressants. Current research focuses on understanding better the mechanisms underlying the psychiatric effects of immune factors, and on how to implement these findings clinically, such as developing treatments for depression that target the immune system.
Suggested publications:
Yirmiya R, Rimmerman N, Reshef R. Depression as a microglial disease. Trends Neurosci. 2015 Oct;38(10):637-658. doi: 10.1016/j.tins.2015.08.001.
Zunszain PA, Hepgul N, Pariante CM. Inflammation and depression. Curr Top Behav Neurosci, 2013, 14:135-51. doi: 10.1007/7854_2012_211.
Capuron L, Miller AH. Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther, 2011, 130(2):226-38. doi: 10.1016/j.pharmthera.2011.01.014.
Wohleb ES, Franklin T, Iwata M, Duman RS. Integrating neuroimmune systems in the neurobiology of depression. Nat Rev Neurosci, 2016, 17(8):497-511. doi: 10.1038/nrn.2016.69.
Laumet G, Edralin JD, Chiang AC, Dantzer R, Heijnen CJ, Kavelaars A. Resolution of inflammation-induced depression requires T lymphocytes and endogenous brain interleukin-10 signaling. Neuropsychopharmacology, 2018. doi: 10.1038/s41386-018-0154-1.
Kappelmann N, Lewis G, Dantzer R, Jones PB, Khandaker GM. Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol Psychiatry, 2018, 23(2):335-343. doi: 10.1038/mp.2016.167.
Role of the immune system in pain disorders
Common for chronic pain disorders are central neuroimmune mechanisms and psychological processes that drive and modulate the persistence and experience of pain. A psychoneuroimmunological perspective on pain disorders highlights signaling within the central nervous system driven by immune components both in the periphery (blood) and centrally (cerebrospinal fluid and brain tissue), and the psychological effects thereof. Inflammatory mechanisms have also been suggested as mechanisms for the pronounced psychological comorbidity in pain disorders, and the fact that inflammatory disease often leads to comorbid pain disorders.
Suggested publications:
Walker AK, Kavelaars A, Heijnen CJ, Dantzer R. Neuroinflammation and Comorbidity of Pain and Depression. Pharmacol Rev, 2014, 66(1): 80–101. doi: 10.1124/pr.113.008144.
Karshikoff B, Lekander M, Soop A, Lindstedt F, Ingvar M, Kosek E, Olgart Höglund C, Axelsson J. Modality and sex differences in pain sensitivity during human endotoxemia. Brain Behav Immun, 2015, 46:35-43. doi: 10.1016/j.bbi.2014.11.014.
Benson S, Rebernik L, Wegner A, Kleine-Borgmann J, Engler H, Schlamann M, Forsting M, Schedlowski M, Elsenbruch S. Neural circuitry mediating inflammation-induced central pain amplification in human experimental endotoxemia. Brain Behav Immun, 2015, 48:222-31. doi: 10.1016/j.bbi.2015.03.017.
Watkins LR, Maier SF. The pain of being sick: implications of immune-to-brain communication for understanding pain. Annu Rev Psychol, 2000, 51:29-57. doi: 10.1146/annurev.psych.51.1.29.
Role of the immune system in motivational processes and fatigue
Reduced motivation and fatigue are core symptoms of sickness, and only slight immune activation is needed to induce them. The feeling of fatigue is believed to partly result from changes in motivational processes. Sickness induces a reorganization of motivational priorities, which are redirected towards preserving energy to fight pathogens and taking care of the sick body rather than engaging in explorative or reproductive behaviors. Motivational changes during the activation of the immune system are found to be context- and task-dependent. Reduction in motivation can for instance be overcome when other priorities predominate (e.g. to escape an imminent threat) or when the task to be performed can benefit the sick individual (e.g. to obtain care, comfort or rest). This area of research opens up to interesting perspectives on the role of inflammation in pathological reduction of motivation and in maladaptive fatigue.
Suggested publications:
Dantzer R, Heijnen CJ, Kavelaars A, Laye S, Capuron L. The neuroimmune basis of fatigue. Trends Neurosci, 2014, 37(1):39-46. doi: 10.1016/j.tins.2013.10.003.
Karshikoff B, Sundelin T, Lasselin J. Role of Inflammation in Human Fatigue: Relevance of Multidimensional Assessments and Potential Neuronal Mechanisms. Front Immunol, 2017, 8:21. doi: 10.3389/fimmu.2017.00021.
Vichaya EG, Dantzer R. Inflammation-induced motivational changes: Perspective gained by evaluating positive and negative valence systems. Curr Opin Behav Sci, 2018, 22:90-95. doi: 10.1016/j.cobeha.2018.01.008.
Lacourt TE, Vichaya EG, Chiu GS, Dantzer R, Heijnen CJ. The High Costs of Low-Grade Inflammation: Persistent Fatigue as a Consequence of Reduced Cellular-Energy Availability and Non-adaptive Energy Expenditure. Front Behav Neurosci, 2018, 12:78. doi: 10.3389/fnbeh.2018.00078.
Role of the immune system in the diseases of the central nervous system
Although the central nervous system can be considered an immune-privileged site, this does not mean that it is devoid of immune response. In fact, full blown immune responses reminiscent of those encountered in peripheral tissues can be observed in the brain meninges, circumventricular organs and choroid plexus. The term neuroinflammation refers to innate immune response occurring in the brain in response to insults to the central nervous tissue, for example in multiple sclerosis, Alzheimer’s and Parkinson’s disease or secondary to systemic inflammation, for instance after severe sepsis. Neuroinflammation includes increased pro-inflammatory cytokine production, microglial cell activation, leukocyte recruitment, and can be accompanied by increased blood-brain barrier permeability. Some components of neuroinflammation, such as increased cytokine production and glial activation have been shown to occur during systemic inflammation or to persist even after full-blown sepsis has subsided. Although it is complicated to disentangle whether changes in behavior, mood and cognition in multiple sclerosis, Alzheimer’s and Parkinson’s disease are due to an initial still ongoing insult or inflammation, this may be easier to do during severe sepsis as brain damage is secondary to inflammation.
Suggested publications:
Masgrau R, Guaza C, Ransohoff RM, Galea E. Should We Stop Saying ‘Glia’ and ‘Neuroinflammation’? Trends Mol Med, 2017, 23(6):486-500. doi: 10.1016/j.molmed.2017.04.005.
Hamasaki MY, Machado MCC, Pinheiro da Silva F. Animal models of neuroinflammation secondary to acute insults originated outside the brain. J Neurosci Res, 2018, 96(3):371-378. doi: 10.1002/jnr.24184.
Estes ML, McAllister AK. Alterations in immune cells and mediators in the brain: it’s not always neuroinflammation! Brain Pathol, 2014, 24(6):623-30. doi: 10.1111/bpa.12198.
Annane D, Sharshar T. Cognitive decline after sepsis. Lancet Respir Med, 2015, 3(1):61-9. doi: 10.1016/S2213-2600(14)70246-2.
Brain-gut and gut-brain axes
The exploration of connections between the gut and brain has a long history. Although early psychologists, William James and Carl Lange, are considered by some seen as forerunners of brain-gut-axis research (e.g., Eisenstein 2016), they most of all insisted that ‘visceral stirrings’ had to be conceptualized as part of emotions (James, 1884). In the 1980s, the term “brain-gut axis” was become a common label for investigations of these connections and the converse “gut-brain axis” indicating gut effects on brain functioning also started to come into use. The gut has its own nervous system, in addition to being heavily innervated by the peripheral nervous system, and contains the majority of immune cells in the body. Brain-gut and gut-brain axes (neural and humoral) are therefore thought to constitute major neuroimmune communication channels mediating parts of the effects of stress on immunity and important immune-to-brain signaling pathways underlying changes in behavior and physiology in response to micro-organisms present in the gut lumen or that have infected bodily tissues.
Suggested publications:
Bonaz BL, Bernstein CN. Brain-gut interactions in inflammatory bowel disease. Gastroenterology, 2013, 144(1):36-49. doi: 10.1053/j.gastro.2012.10.003.
Forsythe P, Bienenstock J, Kunze WA. Vagal pathways for microbiome-brain-gut axis communication. Adv Exp Med Biol, 2014, 817:115-33. doi: 10.1007/978-1-4939-0897-4_5.
Powell N, Walker MM, Talley NJ. The mucosal immune system: master regulator of bidirectional gut-brain communications. Nat Rev Gastroenterol Hepatol, 2017, 14(3):143-159. doi: 10.1038/nrgastro.2016.191.
Hooks K, Konsman JP, O’Malley M. Microbiota-gut-brain research: a critical analysis. Brain Behav Sci, in press.
Nutritional modulation of behavior
Nutrition has substantial effects on brain health and a variety of brain disorders. Developmental alterations are commonly described to modulate behavior. The PNI perspective includes, for example, modulation of behavior by deficiency or supplementation of omega 3 fatty acids. Indeed, omega 3 fatty acids modulate immune responses, brain inflammation and behavior. They also represent precursors of an emerging group of small resolving mediators with promising potential for treatment strategies. In addition, numerous other nutritional compounds such as resveratrol can influence inflammation and behavior.
Suggested publications:
Bazinet RP, Layé S. Polyunsaturated fatty acids and their metabolites in brain function and disease. Nat Rev Neurosci, 2014, 15(12):771-85. doi: 10.1038/nrn3820.
Dalli J, Serhan CN. Immunoresolvents signaling molecules at intersection between the brain and immune system. Curr Opin Immunol, 2018, 50:48-54. doi: 10.1016/j.coi.2017.10.007.
Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature, 2014, 510(7503):92-101. doi: 10.1038/nature13479.
Obesity and neuro-immune interactions
Obesity is a risk factor for cardiovascular diseases, diabetes, development of infection and brain pathologies. Low-grade systemic inflammation and signs of neuroinflammation accompany obesity, in particular in metabolically unhealthy individuals, and represents a possible link to increased risk for psychiatric illnesses. White adipose tissue-derived mediators, including leptin and other adipokines (or adipocytokines), modulate neuro-immune interactions and are studied in a PNI perspective. Moreover, a role for the gut microbiome has emerged for systemic and hypothalamic inflammation during obesity.
Suggested publications:
Rummel C, Bredehöft J, Damm J, Schweighöfer H, Peek V, Harden LM. Obesity Impacts Fever and Sickness Behavior During Acute Systemic Inflammation. Physiology (Bethesda), 2016, 31(2):117-30. doi: 10.1152/physiol.00049.2015.
Aguilar-Valles A, Inoue W, Rummel C, Luheshi GN. Obesity, adipokines and neuroinflammation. Neuropharmacology, 2015, 96:124-34. doi: 10.1016/j.neuropharm.2014.12.023.
Bray N. Neuroimmunology: Obesity inflames memory circuits. Nat Rev Neurosci, 2014, 15(4):204. doi: 10.1038/nrn3713.
Capuron L, Lasselin J, Castanon N. Role of adiposity-driven inflammation in depressive morbidity. Neuropsychopharmacology, 2017, 42(1):115-128. doi: 10.1038/npp.2016.123.
Immune consequences of stress
A stressful stimulus activates the hypothalamo-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), which coordinate the fight-or-flight response. The immune system constitutes one of the targets of these two systems. Acute stress induces a redistribution of immune cells and increased production of cytokines, which is believed to prepare the body for possible wounding and infection. On the other hand, chronic stress appears to dysregulate immune functions with an overall immunosuppression. Understanding the effects of acute and chronic stress on immune functions can provide information about the vulnerability to infectious and inflammatory diseases including accompanying changes of stress on the brain.
Suggested publications:
Dhabhar F. Effects of stress on immune function: the good, the bad, and the beautiful. Immunol Res, 2014, 58(2-3):193-210. doi: 10.1007/s12026-014-8517-0.
Segerstrom SC, Miller GE. Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry. Psychol Bull, 2004,130(4):601-30. doi: 10.1037/0033-2909.130.4.601.
Böbel TS, Hackl SB, Langgartner D, Jarczok MN, Rohleder N, Rook GA, Lowry CA, Gündel H, Waller C, Reber SO. Less immune activation following social stress in rural vs. urban participants raised with regular or no animal contact, respectively. Proc Natl Acad Sci U S A, 2018, 115(20):5259-5264. doi: 10.1073/pnas.1719866115.
Rohleder N. Stimulation of systemic low-grade inflammation by psychosocial stress. Psychosom Med, 2014, 76(3):181-9. doi: 10.1097/PSY.0000000000000049.
Placebo immunomodulation
The influence of the brain on the immune system is remarkably illustrated by the possibility to modulate immune functions by a placebo, i.e., a substance pharmacologically inactive. Such effect has been demonstrated in animal and human studies that use the paradigm of behavioral immunoconditioning. A conditioned stimulus (such as a novel-tasting drink solution) is paired with the injection of an immunosuppressant, representing the unconditioned stimulus. After several pairings, the mere consumption of the conditioned stimulus leads to an immunosuppressive response that closely resembles the effect of the immunosuppressant. This effect and its underlying mechanisms are highly relevant clinically, as they could for instance help reducing the dose of immunosuppressive drugs in transplant patients.
Suggested publications:
Schedlowski M, Pacheco-López G. The learned immune response: Pavlov and beyond. Brain Behav Immun, 2010, 24(2):176-85. doi: 10.1016/j.bbi.2009.08.007.
Goebel MU, Trebst AE, Steiner J, Xie YF, Exton MS, Frede S, Canbay AE, Michel MC, Heemann U, Schedlowski M. Behavioral conditioning of immunosuppression is possible in humans. FASEB J, 2002, 16(14):1869-73. doi: 10.1096/fj.02-0389com.
Kirchhof J, Petrakova L, Brinkhoff A, Benson S, Schmidt J, Unteroberdörster M, Wilde B, Kaptchuk TJ, Witzke O, Schedlowski M. Learned immunosuppressive placebo responses in renal transplant patients. Proc Natl Acad Sci U S A, 2018, 115(16):4223-4227. doi: 10.1073/pnas.1720548115.
Lückemann L, Unteroberdörster M, Kirchhof J, Schedlowski M, Hadamitzky M. Applications and limitations of behaviorally conditioned immunopharmacological responses. Neurobiol Learn Mem, 2017, 142:91-98. doi: 10.1016/j.nlm.2017.02.012.