A strong and positive correlation exists between chronic disease and affective disorders, but the biological mechanisms underlying this relationship are not known. Here we show that rats with mammary cancer exhibit depression-and anxiety-like behaviors in the absence of overt sickness behaviors. The production of proinflammatory cytokines, known to induce depressive-like behaviors, was elevated in the periphery and in the hippocampus of rats with tumors compared with controls. In tumor-bearing rats, circulating corticosterone, which inhibits cytokine signaling, was suppressed following a stressor, and gene expression of hippocampal glucocorticoid receptors was elevated. The results establish that tumors alone are sufficient to trigger changes in emotional behaviors. Dampened glucocorticoid responses to stressors may exacerbate the deleterious effects of tumor-induced cytokines on affective states.cancer ͉ depression ͉ HPA ͉ hippocampus P hysical and psychological health share a bidirectional relationship (1-4). Individuals suffering from major peripheral illnesses (e.g., cancer, cardiovascular disease, AIDS, etc.) are at greater risk for depression and anxiety disorders relative to the healthy population (5-7). For example, mood disorders are reported in up to 60% of breast cancer patients (8-10). Co-morbid depression is associated with decreased cancer survivorship (11) and increased treatment noncompliance (12); therefore, understanding the mechanisms underlying cancer-associated depression is of profound clinical significance. Despite the strong association between cancer and mood disorders, the respective contributions of: (i) subjective disease awareness, (ii) toxic side-effects of chemotherapy, and (iii) direct biological effects of tumors in the pathogenesis of cancerassociated affective disorders have remained largely unexamined and undifferentiated (13)(14)(15).Tumor cells secrete cytokines and chemokines locally (16,17). Proinflammatory cytokines (primarily IL-1, IL-6, and TNF␣) induce depressive-like behavior (e.g., anhedonia, anorexia, lethargy) (18) via humoral and neural signaling from the periphery to the brain (19). The overwhelming majority of data relating peripheral proinflammatory cytokine production to alterations in behavior and affective states are generated using acute bacterial infection models (18, 19), not chronic disease models. Information on the effects of tumors or tumor-induced cytokines on behavior, on the other hand, is limited to the study of cancer-induced anorexia or cachexia (20). Thus, the hypothesis that tumor-derived cytokines contribute to cancer-induced depression has never been examined.Cytokine signaling can be regulated by neuroendocrine activity, principally through the production of glucocorticoids (21). Corticosterone suppresses the synthesis and actions of proinflammatory cytokines and can thereby inhibit the effects of proinflammatory cytokines on depressive-like behaviors (22-25). Because glucocorticoid production changes during progression of chronic disease ...
Seasonally breeding animals use a combination of photic (i.e., day length) and non-photic (e.g., food availability, temperature) cues to regulate their reproduction. How these environmental cues are integrated is not understood. To assess the potential role of two candidate neuropeptides, kisspeptin and RFamide-related peptide-3 (RFRP), we monitored regional changes in their gene expression in a seasonally breeding mammal exposed to moderate changes in photoperiod and food availability. Adult male Siberian hamsters (Phodopus sungorus) were housed in a long (16 h light/day; 16L) or intermediate (13.5L) photoperiod and fed ad libitum or a progressive food restriction schedule (FR; reduced to 80% of ad libitum) for 11 weeks. Gonadal regression occurred only in FR hamsters housed in 13.5L. Immunohistochemistry was used to identify diencephalic populations of kisspeptin-and RFRP-immunoreactive cells, and quantitative PCR was used to measure gene expression in adjacent coronal brain sections. Photoperiod but not food availability altered RFRP mRNA expression in the dorsomedial sections, whereas food availability but not photoperiod altered Kiss1 expression in the arcuate sections; intermediate photoperiods elevated RFRP expression, and food restriction suppressed Kiss1 expression. Regional-and neuropeptidespecific activity of RFamides may provide a mechanism for integration of multi-modal environmental information in the seasonal control of reproduction.
Many animals time their breeding to the seasons, using the changing day length to forecast those months when environmental conditions favor reproductive success; in Siberian hamsters (Phodopus sungorus), long summer days stimulate, whereas short winter days inhibit, reproductive physiology and behavior. Nonphotic environmental cues are also thought to influence the timing of breeding, but typically their effects on reproduction are minor and more variable under categorically long and short photoperiods. We hypothesized that the influence of nonphotic cues might be more prominent during intermediate photoperiods (early spring and late summer), when day length is an unreliable predictor of year-to-year fluctuations in food availability. In hamsters housed in an intermediate photoperiod (13.5 h light/day), two nonphotic seasonal cues, mild food restriction and same-sex social housing, induced gonadal regression, amplified photoperiod history-dependent reproductive responses to decreasing day lengths, and prevented pubertal development indefinitely. These cues were entirely without effect in hamsters maintained under a long photoperiod (16 h light/day). Thus intermediate photoperiods reveal a heightened responsiveness of the reproductive axis to nonphotic cues. This photoperiod-dependent efficacy of nonphotic cues may explain how animals integrate long-term photic and short-term nonphotic cues in nature: intermediate day lengths open a seasonal window of increased reproductive responsiveness to nonphotic cues at a time when such cues may be of singular relevance, thereby allowing for precise synchronization of the onset and offset of the breeding season to local conditions.
Annual variations in day length (photoperiod) trigger changes in the immune and reproductive system of seasonally-breeding animals. The purpose of this study was to determine whether photoperiodic changes in immunity depend on concurrent photoperiodic responses in the reproductive system, or whether immunological responses to photoperiod occur independent of reproductive responses. Here we report photoperiodic changes in enumerative, functional, and behavioral aspects of the immune system, and in immunomodulatory glucocorticoid secretion, in reproductively non-photoperiodic Wistar rats. T-cell numbers (CD3+, CD8+, CD8+CD25+, CD4+CD25+) were higher in the blood of rats housed in short as opposed to long day lengths for 10 weeks. Following a simulated bacterial infection (E. coli LPS; 125 μg/kg) the severity of several acute-phase sickness behaviors (anorexia, cachexia, neophobia, and social withdrawal) were attenuated in short days. LPS-stimulated IL-1β and IL-6 production were comparable between photoperiods, but plasma TNFα was higher in longday relative to short-day rats. In addition, corticosterone concentrations were higher in short-day relative to long-day rats. The data are consistent with the hypothesis that photoperiodic regulation of the immune system can occur entirely independently of photoperiodic regulation of the reproductive system. In the absence of concurrent reproductive responses, short days increase the numbers of leukocytes capable of immunosurveillance and inhibition of inflammatory responses, increase proinflammatory cytokine production, increase immunomodulatory glucocorticoid secretion, and ultimately attenuate behavioral responses to infection. Seasonal changes in the host immune system, endocrine system, and behavior may contribute to the seasonal variability in disease outcomes, even in reproductively non-photoperiodic mammals.
In common with reproduction, immune function exhibits strong seasonal patterns, which are driven by annual changes in day length (photoperiod) and melatonin secretion. Whereas changes in melatonin communicate seasonal time into the reproductive axis via subcortical receptors, the relevant melatonin targets for communicating seasonal time into the immune system remain unspecified. The authors report that melatonin implants targeting the hypothalamic suprachiasmatic nuclei (SCN) induced a winter phenotype in the immune system. SCN melatonin implants attenuated infection-induced anorexia and cachexia, indicating that the SCN mediate the effects of melatonin on these behavioral and metabolic symptoms of infection. However, SCN melatonin implants failed to induce winter-like peripheral leukocyte concentrations or behavioral thermoregulatory responses to infection. In contrast, subcutaneous melatonin implants induced winter-like changes in all behavioral and immunological parameters. Melatonin acts directly at the SCN to induce seasonal changes in neural-immune systems that regulate behavior. The data identify anatomical overlap between neural substrates mediating the effects of melatonin on the reproductive and immune systems but also suggest that the SCN are not the sole mediator of photoperiodic effects of melatonin on immunity.
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