Experience-independent development of the hamster circadian visual system.

Experience-dependent functional plasticity is a hallmark of the primary visual system, but it is not known if analogous mechanisms govern development of the circadian visual system. Here we investigated molecular, anatomical, and behavioral consequences of complete monocular light deprivation during extended intervals of postnatal development in Syrian hamsters. Hamsters were raised in constant darkness and opaque contact lenses were applied shortly after eye opening and prior to the introduction of a light-dark cycle. In adulthood, previously-occluded eyes were challenged with visual stimuli. Whereas image-formation and motion-detection were markedly impaired by monocular occlusion, neither entrainment to a light-dark cycle, nor phase-resetting responses to shifts in the light-dark cycle were affected by prior monocular deprivation. Cholera toxin-b subunit fluorescent tract-tracing revealed that in monocularly-deprived hamsters the density of fibers projecting from the retina to the suprachiasmatic nucleus (SCN) was comparable regardless of whether such fibers originated from occluded or exposed eyes. In addition, long-term monocular deprivation did not attenuate light-induced c-Fos expression in the SCN. Thus, in contrast to the thalamocortical projections of the primary visual system, retinohypothalamic projections terminating in the SCN develop into normal adult patterns and mediate circadian responses to light largely independent of light experience during development. The data identify a categorical difference in the requirement for light input during postnatal development between circadian and non-circadian visual systems.

Peripheral tumors induce depressive-like behaviors and cytokine production and alter hypothalamic-pituitary-adrenal axis regulation.

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.

Influence of the olfactory bulbs on blood leukocytes and behavioral responses to infection in Siberian hamsters.

Surgical removal of the olfactory bulb alters several aspects of immunological activity. This study investigated the role of the olfactory bulbs in the control of behavioral responses to simulated infection, and the environmental modulation of sickness behaviors by changes in day length. Adult male Siberian hamsters (Phodopus sungorus) were subjected to bilateral olfactory bulbectomy (OBx) or a sham surgical procedure, and were then exposed to long(15 h light/day; LD) or short (9 h light/day; SD) photoperiods for 8­12 weeks, after which circulating leukocytes and behavioral responses (anorexia, anhedonia, cachexia) to simulated gram-negative bacterial infections (i.p. lipopolysaccharide [LPS] treatment;0.625 mg/kg) were quantified. OBx treatment altered the effects of photoperiod on immune function in a trait-specific manner. LPS-induced anorexia was exacerbated in SD-OBx hamsters; LPS-induced anhedonia was exacerbated in LD-OBx hamsters; and photoperiodic differences in circulating leukocytes and LPS-induced cachexia were eliminated by OBx. Plasma cortisol concentrations did not differ between LD and SD hamsters, irrespective of olfactory bulb integrity. The data indicate that photoperiod affects immune function via OB-dependent and -independent mechanisms, and that changes in cortisol production are not required for photoperiodic changes in sickness behaviors to manifest.

Intermediate-duration day lengths unmask reproductive responses to nonphotic environmental cues.

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.

Reproductive responses to photoperiod persist in olfactory bulbectomized Siberian hamsters (Phodopus sungorus).

In reproductively photoperiodic Syrian hamsters, removal of the olfactory bulbs (OBx) leads to a marked and sustained increase in gonadotrophin secretion which prevents normal testicular regression in short photoperiods. In contrast, among reproductively nonphotoperiodic laboratory strains of rats and mice, bulbectomy unmasks reproductive responses to photoperiod. The role of the olfactory bulbs has been proposed to have opposite effects on responsiveness to photoperiod, depending on the photoperiodicity of the reproductive system; however, Syrian hamsters are the only reproductively photoperiodic rodent species for which the role of the olfactory bulb in reproductive endocrinology has been assessed. This experiment evaluated the role of the olfactory bulbs in the photoperiodic control of reproduction in Siberian hamsters (Phodopus sungorus), an established model species for the study of neural substrates mediating seasonality. Relative to control hamsters housed in long days (15 h light/day), exposure of adult male hamsters to short days (9h light/day) for 8 weeks led to a temporal expansion of the pattern of nocturnal locomotor activity, testicular regression, decreases in testosterone (T) production, and undetectable levels of plasma follicle-stimulating hormone (FSH). Bilateral olfactory bulbectomy failed to affect any of these responses to short days. The patterns of entrainment to long and short days suggests that pre-pineal mechanisms involved in photoperiodic timekeeping are functioning normally in OBx hamsters. The absence of increases in FSH following bulbectomy in long days is incompatible with the hypothesis that the olfactory bulbs provide tonic inhibition of the HPG axis in this species. In marked contrast to Syrian hamsters, the olfactory bulbs of Siberian hamsters play essentially no role in the modulation of tonic gonadotrophin production or gonadotrophin responses to photoperiod.

Melatonin acts at the suprachiasmatic nucleus to attenuate behavioral symptoms of infection.

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.

Winter day lengths enhance T lymphocyte phenotypes, inhibit cytokine responses, and attenuate behavioral symptoms of infection in laboratory rats.

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 (Escherichia coli LPS; 125 microg/kg) the severity of several acute-phase sickness behaviors (anorexia, cachexia, neophobia, and social withdrawal) were attenuated in short days. LPS-stimulated IL-1beta and IL-6 production were comparable between photoperiods, but plasma TNFalpha was higher in long-day 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.