Robert Dantzer

From inflammation to sickness and depression: when the immune system subjugates the brain

In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour. When activation of the peripheral immune system continues unabated, such as during systemic infections, cancer or autoimmune diseases, the ensuing immune signalling to the brain can lead to an exacerbation of sickness and the development of symptoms of depression in vulnerable individuals. These phenomena might account for the increased prevalence of clinical depression in physically ill people. Inflammation is therefore an important biological event that might increase the risk of major depressive episodes, much like the more traditional psychosocial factors.

Sickness behavior as a new target for drug development

Sickness behavior refers to the nonspecific symptoms (anorexia, depressed activity, loss of interest in usual activities, disappearance of body-care activities) that accompany the response to infection. Increasing evidence suggests that these symptoms are part of an organized defense response to antigenic challenge and that they are mediated by the neural effects of cytokines such as interleukin 1. An understanding of the mechanisms involved in these effects should permit development of new drugs aimed at decreasing sickness or promoting recovery processes.

Cytokine-induced sickness behaviour: mechanisms and implications

Sickness behaviour represents the expression of the adaptive reorganization of the priorities of the host during an infectious episode. This process is triggered by pro-inflammatory cytokines produced by peripheral phagocytic cells in contact with invading micro-organisms. The peripheral immune message is relayed to the brain via a fast neural pathway and a slower humoral pathway, resulting in the expression of pro-inflammatory cytokines in macrophage-like cells and microglia in the brain. The cellular and molecular components of this previously unsuspected system are being progressively identified. These advances are opening new avenues for understanding brain disorders, including depression.

Cytokine-induced sickness behavior: Mechanisms and implications

Abstract: Sickness behavior refers to a coordinated set of behavioral changes that develop in sick individuals during the course of an infection. At the molecular level, these changes are due to the brain effects of proinflammatory cytokines such as interleukin‐1 (IL‐1) and tumor necrosis factor alpha (TNFα). Peripherally released cytokines act on the brain via a fast transmission pathway involving primary afferent nerves innervating the bodily site of inflammation and a slow transmission pathway involving cytokines originating from the choroid plexus and circumventricular organs and diffusing into the brain parenchyma by volume transmission. At the behavioral level, sickness behavior appears to be the expression of a central motivational state that reorganizes the organism priorities to cope with infectious pathogens. There is evidence that the sickness motivational state can interact with other motivational states and respond to nonimmune stimuli probably by way of sensitization and/or classical conditioning. However, the mechanisms that are involved in plasticity of the sickness motivational state are not yet understood.

Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice

Although elevated activity of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) has been proposed to mediate comorbid depression in inflammatory disorders, its causative role has never been tested. We report that peripheral administration of lipopolysaccharide (LPS) activates IDO and culminates in a distinct depressive-like behavioral syndrome, measured by increased duration of immobility in both the forced-swim and tail suspension tests. Blockade of IDO activation either indirectly with the anti-inflammatory tetracycline derivative minocycline, that attenuates LPS-induced expression of proinflammatory cytokines, or directly with the IDO antagonist 1-methyltryptophan (1-MT), prevents development of depressive-like behavior. Both minocycline and 1-MT normalize the kynurenine/tryptophan ratio in the plasma and brain of LPS-treated mice without changing the LPS-induced increase in turnover of brain serotonin. Administration of L-kynurenine, a metabolite of tryptophan that is generated by IDO, to naive mice dose dependently induces depressive-like behavior. These results implicate IDO as a critical molecular mediator of inflammation-induced depressive-like behavior, probably through the catabolism of tryptophan along the kynurenine pathway.

Cytokine-induced sickness behavior

The behavioral repertoire of humans and animals changes dramatically following infection. Sick individuals have little motivation to eat, are listless, complain of fatigue and malaise, loose interest in social activities and have significant changes in sleep patterns. They display an inability to experience pleasure, have exaggerated responses to pain and fail to concentrate. Proinflammatory cytokines acting in the brain cause sickness behaviors. These nearly universal behavioral changes are a manifestation of a central motivational state that is designed to promote recovery. Exaggerated symptoms of sickness in cancer patients, such as cachexia, can be life-threatening. However, quality of life is often drastically impaired before the cancer becomes totally debilitating. Although basic studies in psychoneuroimmunology have defined proinflammatory cytokines as the central mediators of sickness behavior, a much better understanding of how cytokine and neurotransmitter receptors communicate with each other is needed. Advances that have been made during the past decade should now be extended to clinical studies in an attempt to alleviate sickness symptoms and improve quality of life for cancer patients.

Stress and immunity: An integrated view of relationships between the brain and the immune system

The old notion that stress exacerbates the progression of physical illness via its corticosteroid-mediated immunosuppressive effects must be revised. Experimental and clinical studies demonstrate that both laboratory and natural stressors alter the activities of lymphocytes and macrophages in a complex way that depends on the type of immune response, the physical and psychological characteristics of the stressor and the timing of stress relative to the induction and expression of the immune event. The influences of stress on immunity are mediated not only by glucocorticoids but also by catecholamines, endogenous opioids and pituitary hormones such as growth hormone. Sensitivity of the immune system to stress is not simply fortuitous but is an indirect consequence of the regulatory reciprocal influences that exist between the immune system and the central nervous system. The immune system receives signals from the brain and the neuroendocrine system via the autonomic nervous system and hormones and sends information to the brain via cytokines. These connections appear to be part of a long-loop regulatory feedback system that plays an important role in the coordination of behavioral and physiological responses to infection and inflammation.

Peripheral administration of lipopolysaccharide induces the expression of cytokine transcripts in the brain and pituitary of mice

The reverse transcription polymerase chain reaction (RT-PCR) was used to assess the induction of mRNA of the proinflammatory cytokines IL-1 beta, IL-6 and TNF alpha in the spleen, pituitary, hypothalamus and hippocampus of mice after an intraperitoneal injection of lipopolysaccharide (LPS, 10 micrograms/mouse). The kinetics of cytokine gene expression induced by peripheral LPS in the pituitary and brain structures were different from that observed in the spleen. For IL-1 beta the dose-response curve was also measured and also found to be different. These results support the idea that one pathway by which peripheral immune stimuli affect brain functions includes local synthesis of proinflammatory cytokines in certain brain structures.

Differential effects of inescapable footshocks and of stimuli previously paired with inescapable footshocks on dopamine turnover in cortical and limbic areas of the rat

The effect of electric footshocks and of exposure to environmental stimuli paired with electrical shocks upon the dopaminergic activity in various cortical and limbic areas of the rat were evaluated by measuring dihydroxyphenylacetic acid (DOPAC) levels in these areas. In animals exposed to a 20 min electric footshock session DOPAC concentrations were significantly increased in the antero-medial and sulcal frontal cortices, olfactory tubercle, nucleus accumbens and amygdaloid complex (by 66, 37, 28, 55 and 90% respectively). Re-exposure of rats to an environment where they had been shocked 24 h earlier induced an elevation of DOPAC content only in the anteromedial frontal cortex (by 47%). Plasma corticosterone levels were elevated in both situations. No change in serotonin or 5-hydroxyindolacetic acid content of these areas could be detected in either situation. The results show that electric footshocks and environmental stimuli associated to previous shocks both activate central dopaminergic systems, although the patterns of activation are different.

Modulation of social memory in male rats by neurohypophyseal peptides

Adult male rats spend a great amount of time investigating novel juveniles. In contrast, rats re-exposed to the same juvenile 30 min after the initial exposure display little investigatory behavior. If the re-exposure occurs 2 h later, the juvenile is thoroughly investigated. These results have been interpreted to mean that rats form a transient memory for a particular juvenile. In the present study, memory was enhanced when the initial exposure to the juvenile was followed by another exposure to the same juvenile (retroactive facilitation) and impaired when exposure to the original juvenile was followed by exposure to another juvenile (retroactive interference). Arginine vasopressin had retroactive facilitating effects on social memory and these effects were blocked by the vasopressor antagonist dPTyr(Me)AVP. Moreover, the antagonist had retroactive interfering effects, since it impaired the recognition of a familiar juvenile. Oxytocin shared the same inhibitory pattern of action. These results suggest that neurohypophyseal peptides may have a prepotent role in modulating the mnemonic processing of chemosensory information associated with social interactions.