Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression.

Several lines of evidence implicate the pro-inflammatory cytokine interleukin-1 (IL-1) in the etiology and pathophysiology of major depression. To explore the role of IL-1 in chronic stress-induced depression and some of its underlying biological mechanisms, we used the chronic mild stress (CMS) model of depression. Mice subjected to CMS for 5 weeks exhibited depressive-like symptoms, including decreased sucrose preference, reduced social exploration and adrenocortical activation, concomitantly with increased IL-1 beta levels in the hippocampus. In contrast, mice with deletion of the IL-1 receptor type I (IL-1rKO) or mice with transgenic, brain-restricted overexpression of IL-1 receptor antagonist did not display CMS-induced behavioral or neuroendocrine changes. Similarly, whereas in wild-type (WT) mice CMS significantly reduced hippocampal neurogenesis, measured by incorporation of bromodeoxyuridine (BrdU) and by doublecortin immunohistochemistry, no such decrease was observed IL-1rKO mice. The blunting of the adrenocortical activation in IL-1rKO mice may play a causal role in their resistance to depression, because removal of endogenous glucocorticoids by adrenalectomy also abolished the depressive-like effects of CMS, whereas chronic administration of corticosterone for 4 weeks produced depressive symptoms and reduced neurogenesis in both WT and IL-1rKO mice. The effects of CMS on both behavioral depression and neurogenesis could be mimicked by exogenous subcutaneous administration of IL-1 beta via osmotic minipumps for 4 weeks. These findings indicate that elevation in brain IL-1 levels, which characterizes many medical conditions, is both necessary and sufficient for producing the high incidence of depression found in these conditions. Thus, procedures aimed at reducing brain IL-1 levels may have potent antidepressive actions.

The role of endogenous interleukin-1 in stress-induced adrenal activation and adrenalectomy-induced adrenocorticotropic hormone hypersecretion.

To examine the role of IL-1 in the regulation of the hypothalamo-pituitary-adrenal (HPA) axis, mice with knockout of the IL-1 receptor type I (IL-1rKO) were exposed to psychological and metabolic stressors. When exposed to mild stressors (auditory stress or a low dose of 2-deoxyglucose), IL-1rKO mice displayed a significantly diminished corticosterone secretion, compared with wild-type (WT) controls. In response to more severe stressors (60-min restraint or a high dose of 2-deoxyglucose), both groups exhibited a similar increase in corticosterone secretion. To examine the role of IL-1 in HPA axis feedback regulation, serum ACTH levels were measured after adrenalectomy (ADX) in IL-1rKO mice and in mice with transgenic overexpression of IL-1 receptor antagonist within the brain (IL-1raTG). As expected, WT controls exhibited ADX-induced ACTH hypersecretion, whereas IL-1rKO and IL-1raTG mice showed no increase in ACTH levels, suggesting that brain IL-1 has a critical role in ADX-associated ACTH hypersecretion. Similarly, WT mice that were chronically exposed to IL-1ra in utero displayed a diminished ADX-induced ACTH hypersecretion, compared with vehicle-treated controls, suggesting a developmental role of IL-1 in HPA axis regulation. In conclusion, our results suggest that endogenous IL-1 plays a critical role in HPA axis activation after stress and ADX.

Behavioral aspects of experimental autoimmune encephalomyelitis.

Acute inflammation is known to induce a depressive-like sickness behavior syndrome in humans and in experimental animals. In the present study, we sought to determine whether a chronic neuroautoimmune inflammation is also associated with a similar behavioral syndrome. Experimental autoimmune encephalomyelitis (EAE) was induced in SJL/J female mice by adoptive transfer of lymph node cells, and sickness behavior symptoms, including anorexia, loss of body weight, reduced social exploration, and decreased preference for sucrose solution were measured. We report that these components of sickness behavior were induced during the acute phase of the disease, and recovered in later phases. Moreover, the onset and recovery of the behavioral symptoms preceded the onset and recovery of the neurological signs, respectively. Since EAE is considered a model for multiple sclerosis (MS), it is suggested that EAF-induced behavioral changes may serve as a model for the depressive symptomatology that characterizes most MS patients.

Interleukin-1 signaling modulates stress-induced analgesia.

Exposure to stressful stimuli is often accompanied by reduced pain sensitivity, termed "stress-induced analgesia" (SIA). In the present study, the hypothesis that interleukin-1 (IL-1) may play a modulatory role in SIA was examined. Two genetic mouse models impaired in IL-1-signaling and their wild-type (WT) controls were employed. Another group of C57 mice was acutely administered with IL-1 receptor antagonist (IL-1ra). Mice were exposed to 2min swim stress at one of three water temperatures: 32 degrees C (mild stress), 20-23 degrees C (moderate stress), or 15 degrees C (severe stress); and then tested for pain sensitivity using the hot-plate test. Corticosterone levels were assessed in separate groups of WT and mutant mice following exposure to the three types of stress. Mild stress induced significant analgesia in the two WT strains and saline-treated mice, but not in the mutant strains or the IL-1ra-treated mice. Similarly, mild stress induced significantly elevated corticosterone levels in WT mice, and blunted corticosterone response in mutant mice. In contrast, both WT and mutant strains, as well as IL-1ra-treated mice, displayed analgesic and corticosterone responses following moderate and severe stress. Interestingly, the analgesic response to moderate stress was markedly potentiated in the mutant strains, as compared with their WT controls. The present results support our previous findings that in the absence of IL-1, stress response to mild stress is noticeably diminished. However, the analgesic response to moderate stress is markedly potentiated in mice with impaired IL-1 signaling, corroborating the anti-analgesic role of IL-1 in several pain modulatory conditions, including SIA.

Brain interleukin-1 is involved in spatial memory and passive avoidance conditioning.

Within the brain, the inflammatory cytokine interleukin-1 (IL-1) mediates illness-associated neural, neuroendocrine, and behavioral responses; however, its role in normal neurobehavioral processes is not clear. To examine the role of IL-1 signaling in memory, we infused Long-Evans rats intracerebroventricularly with IL-1beta (10 ng/rat), IL-1 receptor antagonist (IL-1ra, 100 microg/rat), or saline immediately following a learning task and tested memory functioning 1-8 days later. In the Morris water maze (MWM), IL-1ra caused memory impairment in the hippocampus-dependent, spatial version, whereas IL-1beta had no effect. Neither IL-1beta nor IL-1ra influenced the hippocampus-independent, nonspatial version of the MWM. In the passive avoidance response, which also depends on hippocampal functioning, IL-1ra caused memory impairment, and IL-1beta caused memory improvement. These results suggest that IL-1 signaling within the hippocampus plays a critical role in learning and memory processes.

Experimental autoimmune encephalomyelitis-associated behavioral syndrome as a model of 'depression due to multiple sclerosis'.

Many medical conditions, including inflammatory diseases such as multiple sclerosis (MS), are often accompanied by a high prevalence of depressive episodes. Inflammatory mediators, such as cytokines, were implicated in illness-associated depressive conditions, both in humans and in animals. For example, MS-associated depression (MSD) was attributed to pathophysiological processes such as immune dysregulation and cerebral inflammation. We have recently documented a depressive-like behavioral syndrome in mice with experimental autoimmune encephalomyelitis (EAE), an established model of MS. In the present paper, we discuss the similarities between the EAE-associated behavioral syndrome (EBS) and MSD, in terms of phenomenology, putative mechanisms and responsiveness to anti-depressive therapy. In particular, we show that: (1) EAE and depression are associated not only with similar behavioral symptomatology, but also with common physiological alterations, including impaired serotonergic neurotransmission, and activation of neuroendocrine (e.g., adrenocortical) and inflammatory cytokine systems; (2) the EBS precedes any neurological deficit during the initial EAE attack, as well as further exacerbations, and remits during recovery and between relapses. Similarly, in many MS patients depression precedes and accompanies the attacks and wanes during remissions; (3) females show increased susceptibility to EBS. Similarly, depression is much more prevalent in women than in men; (4) chronic treatment with the tricyclic anti-depressant imipramine reduced EAE-induced mortality, body-weight loss and behavioral suppression. Similarly, anti-depressant drugs have been used effectively in treating MSD. These findings suggest that the EBS may serve as an animal model for MSD.