Sickness and depressionOver the past 30years, it has become clear that the immune system plays a critical role in animal behavior. This role is tightly linked to the obvious role that immune cell activation plays in the clearance of pathogenic organisms. Systemic or central infections elicit a group of symptoms that are necessary for the organism to conserve resources, reorganize priorities and limit the spread of the infection to other members of the community. This sickness behavior is a motivational state that is common to most pathogeninduced infections ranging from viruses to multicellular parasites, but, because of its ubiquitous nature, is frequently accepted as an unavoidable and non-specific consequence of infection. However, considering the broad spectrum of symptoms -fever, nausea, decreased appetite, malaise, fatigue and achiness -it seems clear that a highly organized, although not pathogen-specific, response is being manifested to aid in the fight against infection (Dantzer, 2001;Ericsson et al., 1995).We are all familiar with the human symptoms of sickness but, to investigate changes in behavior associated with sickness, it is critical to have reliable animal measurements that relate to changes in the affective state. Using preclinical animal models, sickness behavior is best evaluated when the test involves a means to assess motivation. Sickness behavior is frequently assessed as social exploration/investigation (in rodent models, this response is frequently reported as a decrease in time actively seeking interaction with a novel animal as a result of diminished motivation for social exploration or neophobia). Social exploration is a naturalistic behavior and all animals have a strong motivation, whether driven by curiosity or sexual desire. With this strong motivational stimulus, infections cause a strong differential between time of exploration of healthy and sick animals, with less time of exploration being observed with sick animals. Another simpler but effective model is exploration of the environment [often referred to as locomotor activity (LMA), representing some level of physical movement in a novel environment such as rearing, quadrant entry, line crossings or total distance traveled; all of which are highly correlated]. LMA is best conducted in a novel environment, as the motivation to explore is stronger in this

During the past decade, the immune and endocrine systems have been discovered to interact in controlling physiologic processes as diverse as cell growth and differentiation, metabolism, and even human and animal behavior. The interaction between these two major physiological systems is a bi-directional process. While it has been well documented that hormones, including prolactin (PRL), growth hormone (GH), insulin-like growth factor-I (IGF-I), and thyroid-stimulating hormone (TSH), regulate a variety of immune events, a great deal of data have accumulated supporting the notion that cytokines from the innate immune system also affect the neuroendocrine system. Communication between these two systems coordinates processes that are necessary to maintain homeostasis. Proinflammatory cytokines often act as negative regulatory signals that temper the action of hormones and growth factors. This system of 'checks and balances' is an active, ongoing process, even in healthy individuals. Dysregulation of this process has been implicated as a potential pathogenic factor in the development of co-morbid conditions associated with several chronic inflammatory diseases, including type 2 diabetes, cardiovascular disease, cerebrovascular disease, inflammatory bowel disease, rheumatoid arthritis, major depression, and even normal aging. Over the past decade, research in our laboratory has focused on the ability of the major proinflammatory cytokines, tumor necrosis factor (TNF)alpha and interleukin (IL)-1beta, to induce a state of IGF resistance. This review will highlight these and other new findings by explaining how proinflammatory cytokines induce resistance to the major growth factor, insulin-like growth factor-I (IGF-I). We also highlight that IGF-I can induce resistance or reduce sensitivity to brain TNFalpha and discuss how TNFalpha, IL-1beta, and IGF-I interact to regulate several aspects of behavior and cognition.

Exogenous administration of insulin-like growth factor (IGF)-I has anti-depressant properties in rodent models of depression. However, nothing is known about the anti-depressant properties of IGF-I during inflammation, nor have mechanisms by which IGF-I alters behavior following activation of the innate immune system been clarified. We hypothesized that central IGF-I would diminish depressive-like behavior on a background of an inflammatory response and that it would do so by inducing expression of the brain-derived neurotrophic factor (BDNF) while decreasing pro-inflammatory cytokine expression in the brain. IGF-I (1,000 ng) was administered intracerebroventricularly (i.c.v.) to CD-1 mice. Mice were subsequently given lipopolysaccharide i.c.v. (LPS, 10 ng). Sickness and depressive-like behaviors were assessed followed by analysis of brain steady state mRNA expression. Central LPS elicited typical transient signs of sickness of mice, including body weight loss, reduced feed intake and decreased social exploration toward a novel juvenile. Similarly, LPS increased time of immobility in the tail suspension test (TST). Pretreatment with IGF-I or antidepressants significantly decreased duration of immobility in the TST in both the absence and presence of LPS. To elucidate the mechanisms underlying the anti-depressant action of IGF-I, we quantified steady-state mRNA expression of inflammatory mediators in whole brain using real-time RT-PCR. LPS increased, whereas IGF-I decreased, expression of inflammatory markers interleukin-1ß (IL-1ß), tumor necrosis factor-(TNF)α, inducible nitric oxide synthase (iNOS) and glial fibrillary acidic protein (GFAP). Moreover, IGF-I increased expression of BDNF. These results indicate that IGF-I down regulates glial activation and induces expression of an endogenous growth factor that shares anti-depressant activity. These actions of IGF-I parallel its ability to diminish depressive-like behavior.

converges on the central premise that maximal immunotherapeutic efficacy in subjects with advanced cancer requires both IDO enzyme-and non-enzyme-neutralization, which is not adequately addressed by available IDO-targeting pharmacologic approaches at this time.

GH and IGF-I control over 80% of postnatal growth. We recently established that TNFalpha impairs the ability of IGF-I to increase protein synthesis and promote expression of myogenin in myoblasts. Here we extend these results by showing that ceramide, a second messenger in both TNFalpha and IL-1beta receptor signaling pathways, is a key downstream sphingosine-based lipid that leads to IGF-I resistance. A cell-permeable ceramide analog, C2-ceramide, inhibits IGF-I-induced protein synthesis by 65% and blocks the ability of IGF-I to increase expression of two key myogenic factors, myogenin and MyoD. Identical results were obtained with both TNFalpha and IL-1beta (1 ng/ml). Consistent with these data, neutral sphingomyelinase (N-SMase), an enzyme that catalyzes formation of ceramide from sphingomyelin, blocks IGF-I-induced protein synthesis and expression of both myogenin and MyoD. The possibility that cytokine-induced ceramide production is required for disruption of IGF-I biologic activity was confirmed by treating C2C12 myoblasts with inhibitors of all three ceramide-generating pathways. A N-SMase inhibitor, glutathione, as well as an acidic sphingomyelinase (A-SMase) inhibitor, D609, reverse the cytokine inhibition of IGF-I-induced protein synthesis by 80% and 45%, respectively. Likewise, an inhibitor of de novo ceramide synthesis, FB1, causes a 50% inhibition. Similarly, all three inhibitors significantly impair the ability of both TNFalpha and IL-1beta to suppress IGF-I-driven expression of myogenin. These experiments establish that ceramide, derived both from sphingomyelin and de novo synthesis, is a key intermediate by which proinflammatory cytokines impair the ability of IGF-I to promote protein synthesis and expression of critical muscle-specific transcription factors.