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1.  Leptin mediates seasonal variation in some but not all symptoms of sickness in Siberian hamsters 
Hormones and behavior  2014;66(5):802-811.
Many seasonally breeding species, including Siberian hamsters (Phodopus sungorus), exhibit seasonal variation in sickness responses. One hypothesis regarding the mechanism of this variation is that sickness intensity tracks an animal's energetic state, such that sickness is attenuated in the season that an animal has the lowest fat stores. Energetic state may be signaled via leptin, an adipose hormone that provides a signal of fat stores. Siberian hamsters respond to extended housing in short, winter-like days by reducing fat stores and leptin levels, relative to those housed in long, summer-like days. Sickness responses are also attenuated in short-day hamsters as compared to long-day hamsters. We hypothesized that leptin provides a physiological signal by which seasonally breeding animals modulate sickness responses, such that animals with higher leptin levels show increased sickness intensity. To test this, we provided short-day hamsters with a long-day-like leptin signal and assessed their responses to lipopolysaccharide (LPS), a sickness-inducing antigen. We compared these responses to short-day vehicle-, long-day vehicle-, and long-day leptin-treated hamsters. Unexpectedly, LPS induced a hypothermic response (rather than fever) in all groups. Short-day vehicle-treated hamsters exhibited the greatest LPS-induced hypothermia, and leptin treatment attenuated this response, making hypothermia more long-day-like. Contrary to our hypothesis, short-day leptin-treated hamsters showed the least pronounced LPS-induced anorexia among all groups. These results suggest that leptin may mediate some but not all aspects of seasonal sickness variation in this species. Future studies should be targeted at determining roles of other energetic hormones in regulating seasonal sickness response variation.
PMCID: PMC4262702  PMID: 25461974
lipopolysaccharide; energetic; seasonality; ecoimmunology; infection-induced hypothermia; infection-induced anorexia
2.  Leptin regulates energetic tradeoffs between body fat and humoural immunity 
Mounting an immune response requires a relatively substantial investment of energy and marked reductions in energy availability can suppress immune function and presumably increase disease susceptibility. We have previously demonstrated that a moderate reduction in energy stores via partial surgical lipectomy (LIPx) impairs humoural immunity of Siberian hamsters (Phodopus sungorus). Here we tested the hypothesis that LIPx-induced decreases in immunity are mediated by changes in the adipose tissue hormone leptin. Hamsters received bilateral surgical removal of inguinal white adipose tissue (IWATx) or sham surgeries (Sham). Half the animals in each group received osmotic minipumps containing murine leptin (0.5 μl h−1 for 10 days) whereas the remaining animals received minipumps containing vehicle alone; all animals were subsequently challenged with the novel antigen keyhole limpet haemocyanin (KLH). In general, serum leptin and anti-KLH antibodies were significantly correlated with one another with higher levels generally indicating enhanced immunity. In addition, IWATx hamsters had significantly lower serum anti-KLH IgG compared with sham animals. Exogenous leptin, however, attenuated LIPx-induced immune suppression but did not affect humoural immunity in sham animals. These results suggest that reductions in energy availability lead to impairments in humoural immunity and that leptin can serve as a neuroendocrine signal between body fat and immunity regulating humoural immune responses.
PMCID: PMC1559861  PMID: 16096098
body fat; adipose tissue; seasonal; immune; energetics
3.  The glutamate agonist, NMDA blocks gonadal regression and enhances antibody response to an immune challenge in Siberian hamsters (Phodopus sungorus) 
Seasonal variation in behavior and physiology, including changes in immune function, are common. This variability is elicited by changes in photoperiod and often covaries with fluctuations in both energy reserves and reproductive state. It is unclear, however, whether changes in either variable alone drive seasonal changes in immunity. We investigated the relative contributions of reproduction and energy balance to changes in immune function. To accomplish this, we uncoupled seasonal changes in reproduction from those related to energy balance via daily injections of N-methyl-D-Aspartate (NMDA) in Siberian hamsters (Phodopus sungorus). NMDA is a glutamatergic agonist that blocks short-day induced gonadal regression while leaving short-day declines in body mass unaffected. In Experiment 1, we examined the effect of differing doses of NMDA on testosterone production as a proxy for NMDA effects on reproduction; a dose-dependent rise in testosterone was observed. In Experiment 2, animals were maintained on long or short days and received daily injections of NMDA. After eight weeks all animals underwent a humoral immune challenge. Short-day animals receiving daily injections of NMDA maintained long-day-like gonads, however contrary to our predictions, no trade-off between reproduction or energy balance and immune function was observed. Unexpectedly, NMDA treatment increased immunoglobulin levels in all groups, suggesting NMDA may provide an immunomodulatory signal, presumably through actions on peripheral glutamate receptors. These results support a previous finding that NMDA blocks reproductive regression. In addition, these findings demonstrate a general immunoenhancing effect of NMDA that appears independent of changes in reproductive or energetic state of the animal.
PMCID: PMC2809793  PMID: 19820951
4.  Exogenous kisspeptin does not alter photoperiod-induced gonadal regression in Siberian hamsters (Phodopus sungorus) 
In order to reproduce successfully, animals must integrate multiple environmental cues to synchronize breeding with favorable conditions. In temperate seasonally breeding rodents, photoperiod acts as the primary seasonal cue. Long days are associated with reproductive development and maturation of the gonads whereas short days induce gonadal regression. The neuropeptide kisspeptin has potent stimulatory effects on reproductive development. Kisspeptin potently stimulates GnRH release and kisspeptin expression co-varies with photoperiod in seasonally breeding animals. Here we tested the hypothesis that reproductive involution in response to inhibitory day lenghts results from reduced kisspeptin stimulation of the reproductive axis in seasonally breeding Siberian hamsters (Phodopus sungorus). If true, gonadal regrowth should be hastened by kisspeptin treatment in regressed hamsters and prevented in hamsters by treatment prior to and during regression. In Experiment 1 and Experiment 2 we tested the ability of kisspeptin to reverse gonadal regression. In Experiment 1, reproductively regressed hamsters received chronic kisspeptin via osmotic mini-pumps for 4 weeks. In Experiment 2, daily injections of kisspeptin were administered to regressed hamsters for 6 weeks. In Experiment 3, the ability of kisspeptin to block gonadal regression was tested; hamsters transferred to short days received daily injections of kisspeptin for 6 weeks. In all three studies, short day animals receiving exogenous kisspeptin did not differ from short-day controls. Collectively, these results provide evidence that mechanisms in addition to those that converge on the kisspeptin system are likely critical for seasonal changes in the reproductive axis.
PMCID: PMC2430753  PMID: 18405899
metastin; seasonal reproduction; gonadal recrudescence; GPR54; puberty
5.  Photoperiodic Changes in Endocannabinoid Levels and Energetic Responses to Altered Signalling at CB1 Receptors in Siberian Hamsters 
Journal of neuroendocrinology  2012;24(7):1030-1039.
Siberian hamsters (Phodopus sungorus) adapt to seasonal environmental conditions with marked changes in body mass, primarily in the form of adiposity. Winter-like conditions (e.g. short days) are sufficient to decrease body mass by approximately 30% in part via reductions in food intake. The neuroendocrine mechanisms responsible for these changes are not well understood, and homeostatic orexigenic/anorexigenic systems of the hypothalamus provide little explanation. We investigated the potential role of endocannabinoids, which are known modulators of appetite and metabolism, in mediating seasonal changes in energy balance. Specifically, we housed hamsters in long or short days for 0, 3, or 9 weeks and measured endocannabinoid levels in the hypothalamus, brainstem, liver and retroperitoneal white adipose tissue (RWAT). An additional group of males housed in short days for 25 weeks were also compared with long-day controls. Following 9 weeks in short days, levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) were significantly elevated in RWAT and reduced in brainstem, although they returned to long-day levels by week 25 in short-day males that had cycled back to summer-like energy balance. Endocannabinoid levels in these tissues correlated significantly with adiposity and change in body mass. No photoperiodic changes were observed in the hypothalamus or liver; however, sex differences in 2-AG levels were found in the liver (males > females). We further tested the effects of CB1 receptor signalling on ingestive behaviour. Five daily injections of CB1 antagonist SR141716 significantly reduced food intake and body mass but not food hoarding. Although the CB1 agonist arachidonyl-2-chloroethylamide did not appreciably affect either ingestive behaviour, body mass was significantly elevated following 2 days of injections. Taken altogether, these findings demonstrate that endocannabinoid levels vary with sex and photoperiod in a site-specific manner, and that altered signalling at CB1 receptors affects energy balance in Siberian hamsters.
PMCID: PMC4060156  PMID: 22420341
energy balance; adiposity; seasonality; sex differences; 2-AG
6.  Suppression of Kisspeptin Expression and Gonadotropic Axis Sensitivity Following Exposure to Inhibitory Day Lengths in Female Siberian Hamsters 
Hormones and behavior  2007;52(4):492-498.
To avoid breeding during unsuitable environmental or physiological circumstances, the reproductive axis adjusts its output in response to fluctuating internal and external conditions. The ability of the reproductive system to alter its activity appropriately in response to these cues has been well established. However, the means by which reproductively relevant cues are interpreted, integrated, and relayed to the reproductive axis remain less well specified. The neuropeptide kisspeptin has been shown to be a potent positive stimulator of the hypothalamo-pituitary-gonadal (HPG) axis, suggesting a possible neural locus for the interpretation/integration of these cues. Because a failure to inhibit reproduction during winter would be maladaptive for short-lived female rodents, female Siberian hamsters (Phodopus sungorus) housed in long and short days hamsters were examined. In long, ‘summer’ photoperiods, kisspeptin is highly expressed in the anteroventral periventricular nucleus (AVPV), with low expression in the arcuate nucleus (Arc). A striking reversal in this pattern is observed in animals held in short, ‘winter’ photoperiods, with negligible kisspeptin expression in the AVPV and marked staining in the Arc. Although all studies to date suggest that both populations act to stimulate the reproductive axis, these contrasting expression patterns of AVPV and Arc kisspeptin suggest disparate roles for these two cell populations. Additionally, we found that the stimulatory actions of exogenous kisspeptin are blocked by acyline, a gonadotropin-releasing hormone (GnRH) receptor antagonist, suggesting an action of kisspeptin on the GnRH system rather than pituitary gonadotropes. Finally, females held in short day lengths exhibit a reduced response to exogenous kisspeptin treatment relative to long-day animals. Together, these findings indicate a role for kisspeptin in the AVPV and Arc as an upstream integration center for reproductively-relevant stimuli and point to a dual mechanism of reproductive inhibition in which kisspeptin expression is reduced concomitant with reduced sensitivity of the HPG axis to this peptide.
PMCID: PMC2717891  PMID: 17706968
metastin; GPR54; photoperiod; Siberian hamster; seasonal; reproduction
7.  Effect of Exercise on Photoperiod-Regulated Hypothalamic Gene Expression and Peripheral Hormones in the Seasonal Dwarf Hamster Phodopus sungorus 
PLoS ONE  2014;9(3):e90253.
The Siberian hamster (Phodopus sungorus) is a seasonal mammal responding to the annual cycle in photoperiod with anticipatory physiological adaptations. This includes a reduction in food intake and body weight during the autumn in anticipation of seasonally reduced food availability. In the laboratory, short-day induction of body weight loss can be reversed or prevented by voluntary exercise undertaken when a running wheel is introduced into the home cage. The mechanism by which exercise prevents or reverses body weight reduction is unknown, but one hypothesis is a reversal of short-day photoperiod induced gene expression changes in the hypothalamus that underpin body weight regulation. Alternatively, we postulate an exercise-related anabolic effect involving the growth hormone axis. To test these hypotheses we established photoperiod-running wheel experiments of 8 to 16 weeks duration assessing body weight, food intake, organ mass, lean and fat mass by magnetic resonance, circulating hormones FGF21 and insulin and hypothalamic gene expression. In response to running wheel activity, short-day housed hamsters increased body weight. Compared to short-day housed sedentary hamsters the body weight increase was accompanied by higher food intake, maintenance of tissue mass of key organs such as the liver, maintenance of lean and fat mass and hormonal profiles indicative of long day housed hamsters but there was no overall reversal of hypothalamic gene expression regulated by photoperiod. Therefore the mechanism by which activity induces body weight gain is likely to act largely independently of photoperiod regulated gene expression in the hypothalamus.
PMCID: PMC3946023  PMID: 24603871
8.  Metabolic stressors and signals differentially affect energy allocation between reproduction and immune function 
Most free-living animals have finite energy stores that they must allocate to different physiological and behavioral processes. In times of energetic stress, trade-offs in energy allocation among these processes may occur. The manifestation of trade-offs may depend on the source (e.g., glucose, lipids) and severity of energy limitation. In this study, we investigated energetic trade-offs between the reproductive and immune systems by experimentally limiting energy availability to female Siberian hamsters (Phodopus sungorus) with 2-Deoxy-D-glucose, a compound that disrupts cellular utilization of glucose. We observed how glucoprivation at two levels of severity affected allocation to reproduction and immunity. Additionally, we treated a subset of these hamsters with leptin, an adipose hormone that provides a direct signal of available fat stores, in order to determine how increasing this signal of fat stores influences glucoprivation-induced trade-offs. We observed trade-offs between the reproductive and immune systems and that these trade-offs depended on the severity of energy limitation and exogenous leptin signaling. The majority of the animals experiencing mild glucoprivation entered anestrus, whereas leptin treatment restored estrous cycling in these animals. Surprisingly, virtually all animals experiencing more severe glucoprivation maintained normal estrous cycling throughout the experiment; however, exogenous leptin resulted in lower antibody production in this group. These data suggest that variation in these trade-offs may be mediated by shifts between glucose and fatty acid utilization. Collectively, the results of the present study highlight the context-dependent nature of these trade-offs, as trade-offs induced by the same metabolic stressor can manifest differently depending on its intensity.
PMCID: PMC4253682  PMID: 25125082
trade-offs; leptin; glucoprivation; 2-Deoxy-D-glucose; Siberian hamsters
9.  Photoperiod History Differentially Impacts Reproduction and Immune Function in Adult Siberian Hamsters 
Journal of biological rhythms  2009;24(6):509-522.
Seasonal changes in numerous aspects of mammalian immune function arise as a result of the annual variation in environmental day length (photoperiod), but it is not known if absolute photoperiod or relative change in photoperiod drives these changes. This experiment tested the hypothesis that an individual’s history of exposure to day length determines immune responses to ambiguous, intermediate-duration day lengths. Immunological (blood leukocytes, delayed-type hypersensitivity reactions [DTH]), reproductive, and adrenocortical responses were assessed in adult Siberian hamsters (Phodopus sungorus) that had been raised initially in categorically long (15-h light/day; 15L) or short (9L) photoperiods and were subsequently transferred to 1 of 7 cardinal experimental photoperiods between 9L and 15L, inclusive Initial photoperiod history interacted with contemporary experimental photoperiods to determ.ine reproductive responses: 11L, 12L, and 13L caused gonadal regression in hamsters previously exposed to 15L, but elicited growth in hamsters previously in 9L. In hamsters with a 15L photoperiod history, photoperiods ≤ 11L elicited sustained enhancement of DTH responses, whereas in hamsters with a 9L photoperiod history, DTH responses were largely unaffected by increases in day length. Enhancement and suppression of blood leukocyte concentrations occurred at 13L in hamsters with photoperiod histories of 15L and 9L, respectively; however, prior exposure to 9L imparted marked hysteresis effects, which suppressed baseline leukocyte concentrations. Cortisol concentrations were only enhanced in 15L hamsters transferred to 9L and, in common with DTH, were unaffected by photoperiod treatments in hamsters with a 9L photoperiod history. Photoperiod history acquired in adulthood impacts immune responses to photoperiod, but manifests in a markedly dissimilar fashion as compared to the reproductive system. Prior photoperiod exposure has an enduring impact on the ability of the immune system to respond to subsequent changes in day length.
PMCID: PMC3965335  PMID: 19926810
delayed-type hypersensitivity (DTH); blood leukocyte; cortisol; neural-immune interactions; seasonality; reproduction
10.  Reductions in total body fat decrease humoral immunity. 
Mounting an immune response requires substantial energy, and it is well known that marked reductions in energy availability (e.g. starvation) can suppress immune function, thus increasing disease susceptibility and compromising survival. We tested the hypothesis that moderate reductions in energy availability impair humoral immunity. Specifically, we examined the effects of partial lipectomy (LIPx) on humoral immunity in two seasonally breeding rodent species, prairie voles (Microtus ochrogaster) and Siberian hamsters (Phodopus sungorus). Animals received bilateral surgical removal of epididymal white adipose tissue (EWATx), inguinal white adipose tissue (IWATx) or sham surgeries and were injected with the antigen keyhole limpet haemocyanin (KLH) either four or 12 weeks after surgery. In prairie voles, serum anti-KLH immunoglobulin G (IgG) did not differ significantly at four weeks. At 12 weeks, serum IgG was significantly reduced in IWATx, but not EWATx animals, compared with sham-operated animals. In Siberian hamsters, both IWATx and EWATx animals reduced serum IgG at four weeks. At 12 weeks, EWATx hamsters displayed a significant compensatory increase in IWAT pad mass compared with sham-operated hamsters, and serum IgG no longer differed from sham-operated animals. There was no significant increase in EWAT in IWATx hamsters compared with sham animals and IgG remained significantly reduced in IWATx hamsters. These results suggest that reductions in energy availability can impair humoral immunity.
PMCID: PMC1691330  PMID: 12803904
11.  Reproductive Responses to Photoperiod Persist in Olfactory Bulbectomized Siberian Hamsters (Phodopus sungorus) 
Behavioural brain research  2008;198(1):159-164.
In reproductively photoperiodic Syrian hamsters, removal of the olfactory bulbs leads to a marked and sustained increase in gonadotrophin secretion which prevents normal testicular regression in short photoperiods. In contrast, among reproductively non-photoperiodic 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 (9 h 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.
PMCID: PMC2661624  PMID: 19027041
photoperiodism; biological rhythms; reproduction; brain lesion
12.  Behavioral Tolerance to Endotoxin is Enhanced by Adaptation to Winter Photoperiods 
Psychoneuroendocrinology  2008;33(4):540-545.
Seasonal changes in day length enhance or suppress aspects of immune function in mammals. Following adaptation to short, winter-like short photoperiods, cytokine and behavioral responses to lipopolysaccharide (LPS)-induced simulated infections are attenuated in LPS-naive Siberian hamsters. This experiment examined whether diminished initial responses to LPS in short days are accompanied by decrements in the development of innate immunological memory that leads to endotoxin tolerance. Male hamsters exposed to short days (9h-light/day; SD) or kept in their natal long-day photoperiod (15h-light/day; LD) for 12–13 weeks were injected with bacterial LPS (625 µg/kg, i.p.) or sterile saline. Ten days later all hamsters were challenged with LPS (625 ug/kg, i.p.), and behavioral sickness responses (anorexia and reductions in nest building) were assessed. In LD hamsters, behavioral responses to the second LPS injection were markedly attenuated but still evident, indicative of partial tolerance. SD hamsters, in contrast, failed to exhibit anorexic or thermoregulatory responses to the second LPS injection, indicative of complete behavioral tolerance to LPS. Thus despite engaging greater naive responses to LPS, LD hamsters exhibited incomplete LPS tolerance relative to SD hamsters. The expression of behavioral tolerance to endotoxin is relatively diminished during the breeding season, a time of year when naive responses to endotoxin are at their greatest. During winter, enhancements in behavioral endotoxin tolerance may conserve energy and facilitate survival in the face of energetically-challenging conditions.
PMCID: PMC2705996  PMID: 18291598
seasonality; sickness behavior; endotoxin tolerance; photoperiodism; Siberian hamster
13.  Pineal-dependent and -independent effects of photoperiod on immune function in Siberian hamsters (Phodopus sungorus) 
Hormones and Behavior  2006;51(1):31-39.
Siberian hamsters (Phodopus sungorus) exhibit reproductive and immunological responses to photoperiod. Short (<10-h light/day) days induce gonadal atrophy, increase leukocyte concentrations, and attenuate thermoregulatory and behavioral responses to infection. Whereas hamster reproductive responses to photoperiod are dependent on pineal melatonin secretion, the role of the pineal in short-day induced changes in immune function is not fully understood. To examine this, adult hamsters were pinealectomized (PINx) or sham-PINx, and transferred to short days (9-h light/day; SD) or kept in their natal long-day (15-h light/day; LD) photoperiod. Intact and PINx hamsters housed in LD maintained large testes over the next 12 weeks; sham-PINx hamsters exhibited gonadal regression in SD, and PINx abolished this effect. Among pineal-intact hamsters, blood samples revealed increases in leukocyte, lymphocyte, CD62L+ lymphocyte, and T cell counts in SD relative to LD; PINx did not affect leukocyte numbers in LD hamsters, but abolished the SD increase in these measures. Hamsters were then treated with bacterial lipopolysaccharide (LPS), which induced thermoregulatory (fever), behavioral (anorexia, reductions in nest building), and somatic (weight loss) sickness responses in all groups. Among pineal-intact hamsters, febrile and behavioral responses to LPS were attenuated in SD relative to LD. PINx did not affect sickness responses to LPS in LD hamsters, but abolished the ameliorating effects of SD on behavioral responses to LPS. Surprisingly, PINx failed to abolish the effect of SD on fever. In common with the reproductive system, PINx induces the LD phenotype in most aspects of the immune system. The pineal gland is required for photoperiodic regulation of circulating leukocytes and neural-immune interactions that mediate select aspects of sickness behaviors.
PMCID: PMC3345196  PMID: 17022983
Melatonin; Seasonality; Sickness behaviors; Neural-immune interactions
14.  Photic and non-photic seasonal cues differentially engage hypothalamic kisspeptin and RFamide-related peptide mRNA expression in Siberian hamsters 
Journal of neuroendocrinology  2009;21(12):1007-1014.
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 neuropeptide-specific activity of RFamides may provide a mechanism for integration of multi-modal environmental information in the seasonal control of reproduction.
PMCID: PMC2789174  PMID: 19840238
RFamide; seasonality; energetics; reproduction; neuropeptides
15.  Adaptation to short photoperiods augments circadian food anticipatory activity in Siberian hamsters 
Hormones and behavior  2014;66(1):159-168.
Both the light-dark cycle and the timing of food intake can entrain circadian rhythms. Entrainment to food is mediated by a food entrainable circadian oscillator (FEO) that is formally and mechanistically separable from the hypothalamic light-entrainable oscillator. This experiment examined whether seasonal changes in day length affect the function of the FEO in male Siberian hamsters (Phodopus sungorus). Hamsters housed in long (LD; 15 h light/day) or short (SD; 9 h light/day) photoperiods were subjected to a timed-feeding schedule for 10 days, during which food was available only during a 5 h interval of the light phase. Running wheel activity occurring within a 3 h window immediately prior to actual or anticipated food delivery was operationally-defined as food anticipatory activity (FAA). After the timed-feeding interval, hamsters were fed ad libitum, and FAA was assessed 2 and 7 days later via probe trials of total food deprivation. During timed-feeding, all hamsters exhibited increases FAA, but FAA emerged more rapidly in SD; in probe trials, FAA was greater in magnitude and persistence in SD. Gonadectomy in LD did not induce the SD-like FAA phenotype, indicating that withdrawal of gonadal hormones is not sufficient to mediate the effects of photoperiod on FAA. Entrainment of the circadian system to light markedly affects the functional output of the FEO via gonadal hormone-independent mechanisms. Rapid emergence and persistent expression of FAA in SD may reflect a seasonal adaptation that directs behavior toward sources of nutrition with high temporal precision at times of year when food is scarce.
PMCID: PMC4051861  PMID: 24666779
energy balance; seasonality; food intake; gonadal hormones; circadian rhythms
16.  Housing condition alters immunological and reproductive responses to day length in Siberian hamsters (Phodopus sungorus) 
Hormones and behavior  2007;52(2):261-266.
During winter, increased thermoregulatory demands coincide with limited food availability necessitating physiological trade offs among expensive physiological processes resulting in seasonal breeding among small mammals. In the laboratory, short winter-like day lengths induce regression of the reproductive tract, but also enhance many aspects of immune function. It remains unspecified the extent to which bolstered immune responses in short days represent enhanced immune function per se compared to long days or represents energetic disinhibition mediated by the regression of the reproductive tract. Cohabitation of male Siberian hamsters with intact female conspecifics can block short-day reproductive regression. We sought to determine whether female cohabitation could also block the enhanced immune function associated with short days. Adult male Siberian hamsters were housed in long or short day lengths in one of three housing conditions: (1) single-housed, (2) housed with a same sex littermate, or (3) housed with an ovariectomized female. Delayed-type hypersensitivity (DTH) responses were assessed after 8 wk of photoperiod treatment. Housing with an ovariectomized female was not sufficient to block short-day reproductive regression, but prevented short-day enhancement of DTH responses. Housing with a male littermate did not alter reproductive or immune responses in either photoperiod. These data suggest that short day enhancement of immune function is independent of photoperiod-mediated changes in the reproductive system.
PMCID: PMC1955688  PMID: 17583707
Seasonality; photoperiodism; social-housing; immune function; Siberian hamsters; delayed-type hypersensitivity; steroid hormones
17.  Immune challenge retards seasonal reproductive regression in rodents: evidence for terminal investment 
Biology Letters  2006;2(3):393-396.
Animals must balance investments in different physiological activities to allow them to maximize fitness in the environments they inhabit. These adjustments among reproduction, growth and survival are mandated because of the competing high costs of each process. Seasonally breeding rodents generally bias their investments towards reproduction when environmental conditions are benign, but shift these investments towards processes that promote survival, including immune activity, when environmental conditions deteriorate. Because survival probability of non-tropical small mammals is generally low in winter, under certain circumstances, these animals may not allocate resources to survival mechanisms in an effort to produce as many offspring as possible in the face of increased probability of death. Such ‘terminal investments’ have been described in passerines, but there are few examples of such phenomena in small mammals. Here, we show that male Siberian hamsters (Phodopus sungorus) challenged with lipopolysaccharide (a component of gram-negative bacteria that activates the immune system) induced a small, but significant, retardation of seasonal regression of the reproductive system relative to saline-injected hamsters. This delayed reproductive regression likely reflects a strategy to maintain reproductive function when survival prospects are compromised by infection.
PMCID: PMC1686181  PMID: 17148412
photoperiodism; seasonality; Siberian hamsters; terminal investment; life history
18.  Influence of the olfactory bulbs on blood leukocytes and behavioral responses to infection in Siberian hamsters 
Brain research  2009;1268:48-57.
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 8–12 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.
PMCID: PMC3749255  PMID: 19368847
Immune function; Olfactory bulbectomy; Photoperiodism; Inflammation; Sickness behavior; Seasonality; Cortisol
19.  Leptin increases maternal investment 
The primary goal of virtually all organisms is to produce genetic offspring, thereby passing on their genes to future generations. Offspring production, however, is limited by available resources within an environment. Moreover, distributing sufficient energy among competing physiological systems is challenging and can result in trade-offs between self-maintenance and offspring investment when resources are limited. In the current study, we tested the hypothesis that the adipose hormone leptin is involved in mediating energetic trade-offs between competing physiological systems. Specifically, we tested the effects of elevated maternal leptin on investment into offspring production versus self maintenance (immune function), in the Siberian hamster (Phodopus sungorus). The current study provides the first evidence that leptin serves as a signal to mothers of available energy resulting in epigenetic effects. Therefore, elevated leptin allows females to retain more embryos to parturition, and rear more offspring to weaning via reduced maternal infanticide. Innate immune response was suppressed seemingly as a result of these enlarged litters, suggesting that the observed fitness increase is not without costs to the mother. Collectively, these findings suggest that leptin plays a critical role in allowing mothers to determine how much energy to invest in the production and care of young versus self-maintenance.
PMCID: PMC2825785  PMID: 19710064
energy; immunity; reproduction; trade-offs
20.  Photoperiod and Testosterone Interact to Drive Seasonal Changes in Kisspeptin Expression in Siberian Hamsters (Phodopus sungorus) 
Journal of neuroendocrinology  2008;20(12):1339-1347.
Kisspeptin, a neuropeptide product of the KiSS-1 gene, has recently been implicated in the regulation of seasonal breeding in a number of species, including Siberian hamsters. In this species, kisspeptin expression is reduced in the anteroventral periventricular nucleus (AVPV) following exposure to inhibitory day lengths, and exogenous kisspeptin activates the reproductive neuroendocrine axis of reproductively quiescent animals. Because sex steroids can impact kisspeptin expression, it is unclear whether changes in kisspeptin occur in direct response to photoperiodic cues or secondarily in response to changes in sex steroid concentrations resulting from the transition to reproductive quiescence. The present study aimed to assess the relative contributions of photoperiod and testosterone in regulating kisspeptin expression in Siberian hamsters. Animals housed in long or short day lengths for 8 weeks were either castrated or received sham surgeries. Half of the hamsters in each photoperiod were given testosterone to mimic long-day sex steroid concentrations. The results obtained indicate that kisspeptin neurones in the AVPV and arcuate nuclei were influenced by both photoperiod and testosterone. In the AVPV, removal of testosterone or exposure to inhibitory day lengths led to a marked reduction in kisspeptin-immunoreactive cells, and testosterone treatment increased cell numbers across conditions. Importantly, long-day castrates exhibited significantly more kisspeptin cells than short-day castrates or intact short-day animals with empty capsules, suggesting the influences of photoperiod, independent of gonadal steroids. In general, the opposite pattern emerged for the arcuate nuclei. Collectively, these data suggest a role for both gonadal-dependent and independent (i.e. photoperiodic) mechanisms regulating seasonal changes in kisspeptin expression in Siberian hamsters.
PMCID: PMC2636859  PMID: 19094081
KiSS-1; reproduction; RF amide; seasonal breeding; gonadal steroids
21.  Seasonal pelage changes are synchronized by simulated natural photoperiods in Siberian hamsters (Phodopus sungorus) 
The extent to which changing day lengths synchronize the seasonal molt was assessed in nine cohorts of male and female Siberian hamsters (Phodopus sungorus) born into a simulated natural photoperiod (SNP) beginning 4 weeks before and ending 12 weeks after the summer solstice. Hamsters in early cohorts displayed rapid somatic and gonadal growth and early puberty, whereas those in later cohorts delayed puberty until the next spring. Despite the varying birth dates and puberty strategies, the seasonal pattern of change in pelage is much better predicted by calendar date than by age in both sexes. Males born over the course of 16 weeks first made the transition to the winter pelage during a 5 week interval beginning on October 25; the autumn molt, however, was not significantly synchronized by either age or calendar date. The autumn molt of females on the other hand began 2 weeks later, and was significantly synchronized to calendar date with no detectable age effects. In both sexes, the autumn molt lagged gonadal and somatic seasonal changes by many weeks. Date of birth did not affect the timing of the spring molt, which was significantly synchronized by calendar date in both sexes. Incrementally changing photoperiods exert a strong organizing effect on the seasonal molt by providing hamsters with timing cues that are absent in laboratory analyses that employ static day lengths and abrupt transitions from summer to winter day lengths, thereby extending and validating conclusions derived from previous analyses.
PMCID: PMC3864830  PMID: 19425044
natural day length; molt; fur
22.  Photoperiod-dependent modulation of anti-Müllerian hormone in female Siberian hamsters, Phodopus sungorus 
Reproduction (Cambridge, England)  2008;135(3):335-342.
Fertility and fecundity decline with advancing age in female mammals, but reproductive aging was decelerated in Siberian hamsters (Phodopus sungorus) raised in a short day (SD) photoperiod. Litter success was significantly improved in older hamsters when reared in SD and the number of primordial follicles was twice that of females held in long days (LD). Because anti-Müllerian hormone (AMH) appears to inhibit the recruitment of primordial follicles in mice, we sought to determine if the expression patterns of AMH differ in the ovaries and serum of hamsters raised in SD versus LD. Ovaries of SD female hamsters are characterized by a paucity of follicular development beyond the secondary stage and are endowed with an abundance of large eosinophilic cells, which may derive from granulosa cells of oocyte-depleted follicles. In ovaries from 10 week-old SD hamsters, we found the so-called “hypertrophied granulosa cells” were immunoreactive for AMH, as were granulosa cells within healthy appearing primary and secondary follicles. Conversely, ovaries from age-matched LD animals lack the highly eosinophilic cells present in SD ovaries. Therefore, AMH staining in LD was limited to primary and secondary follicles, which are comparable in number to those found in SD ovaries. The substantially greater AMH expression in SD ovaries probably reflects the abundance of hypertrophied granulosa cells in SD ovaries and their relative absence in LD ovaries. The modulation of ovarian AMH by day length is a strong mechanistic candidate for the preservation of primordial follicles in female hamsters raised in a SD photoperiod.
PMCID: PMC2346561  PMID: 18299426
anti-Mullerian hormone; Ovary; Photoperiod; hamster
23.  Pineal and gonadal influences on ultradian locomotor rhythms of male Siberian hamsters 
Hormones and behavior  2012;63(1):54-64.
The extent to which changes in ultradian and circadian rhythms (URs and CRs) reflect seasonal variations in pineal melatonin secretion was assessed in male Siberian hamsters transferred from long to short day lengths. The period of the locomotor activity UR increased from 2.5 h in long days to 4.5 h in short day lengths, but this and most other features of the short-day ultradian phenotype were unaffected by pinealectomy; only the short-day increase in UR amplitude was counteracted by pineal extirpation. Virtually all UR components were unaffected by gonadectomy or replacement testosterone or estradiol treatment; changes in testicular hormone secretion appear insufficient to account for seasonal fluctuation in URs. Pinealectomy did not affect activity onsets and offsets or phase angles of CR entrainment in short and long day lengths; the duration of nocturnal activity was equivalently longer in short than long days in both pinealectomized and pineal-intact hamsters. CR robustness of pinealectomized hamsters in short days was intermediate between values of long-day and short-day sham-pinealectomized males. Hourly nocturnal locomotor activity was markedly reduced in SD, and this effect was completely reversed by PINx. We conclude that seasonal transitions in UR and CR waveforms controlled by day length are mediated primarily by melatonin-independent mechanisms, with lesser contributions from melatonin-dependent processes. Most seasonal changes in ultradian and circadian rhythms in males of this species are not influenced by gonadal hormones. URs may allow animals to respond appropriately to changing environmental contingencies. In winter reduced activity combined with temporal restructuring of activity to include longer intervals of rest may be adaptive in maintaining body temperature at lower values and down-regulating energy expenditure when above ground temperatures are extremely low.
PMCID: PMC3660102  PMID: 23142326
Pinealectomy; Melatonin; Castration; Testosterone; Estradiol; Circadian rhythms
24.  Differential Ovarian Expression of KiSS-1 and GPR-54 During the Estrous Cycle and Photoperiod Induced Recrudescence in Siberian Hamsters (Phodopus sungorus) 
Kisspeptins, coded by the KiSS-1 gene, regulate aspects of the reproductive axis by stimulating GnRH release via the G protein coupled receptor, GPR54. Recent reports show that KiSS/GPR54 may be key mediators in photoperiod-controlled reproduction in seasonal breeders, and that KiSS-1/GPR54 are expressed in the hypothalamus, ovaries, placenta, and pancreas. This study examined the expression of KiSS-1/GPR54 mRNA and protein in ovaries of Siberian hamsters (Phodopus sungorus). Ovaries from cycling hamsters were collected during proestrus (P), estrus (E), diestrus I (DI), and diestrus II (DII). To examine KiSS-1/GPR54 during stimulated recrudescence, additional hamsters were maintained either in long day (LD 16L:8D, control) or short day (SD 8L:16D) for 14 weeks and then transferred to LD for 0–8 weeks. Staining of KiSS-1/GPR54 protein was detected by immunohistochemistry in steroidogenic cells of preantral and antral follicles, and corpora lutea. Immunostaining peaked in P and E, but decreased in the diestrus stages (p<0.05). In recrudescing ovaries, KiSS-1/GPR54 immunostaining was low after 14 wks of SD exposure (post transfer [PT] wk0), and increased during the early weeks of recrudescence. Expression of KiSS-1/GPR54 mRNA was low with short day exposure, but increased during recrudescence and was higher at PT wk8 as compared to PTwks 0 and 2 (p<0.05). The elevated KiSS-1/ GPR54 expression during P and E suggests a potential role in ovulation in Siberian hamsters. Transient increases in KiSS-1/GPR54 expression following LD stimulation are also suggestive of possible involvement in ovulation and/or restoration of ovarian function.
PMCID: PMC2660602  PMID: 18937338
Seasonal reproduction; Ovary; Kisspeptin
25.  Photoperiodic Regulation of the Orexigenic Effects of Ghrelin in Siberian Hamsters 
Hormones and behavior  2010;58(4):647-652.
Animals living in temperate climates with predictable seasonal changes in food availability may use seasonal information to engage different metabolic strategies. Siberian hamsters decrease costs of thermoregulation during winter by reducing food intake and body mass in response to decreasing or short day lengths (SD). These experiments examined whether SD reductions in food intake in hamsters is driven, at least in part, by altered behavioral responses to ghrelin, a gut-derived orexigenic peptide which induces food intake via NPY-dependent mechanisms. Relative to hamsters housed in long day (LD) photoperiods, SD hamsters consumed less food in response to i.p. treatment with ghrelin across a range of doses from 0.03 to 3 mg/kg. To determine whether changes in photoperiod alter behavioral responses ghrelin-induced activation of NPY neurons, c-Fos and NPY expression were quantified in the arcuate nucleus (ARC) via double-label fluorescent immunocytochemistry following i.p. treatment with 0.3 mg/kg ghrelin or saline. Ghrelin induced c-Fos immunoreactivity (-ir) in a greater proportion of NPY-ir neurons of LD relative to SD hamsters. In addition, following ghrelin treatment, a greater proportion of ARC c-Fos-ir neurons were identifiable as NPY-ir in LD relative to SD hamsters. Changes in day length markedly alter the behavioral response to ghrelin. The data also identify photoperiod-induced changes in the ability of ghrelin to activate ARC NPY neurons as a possible mechanism by which changes in day length alter food intake.
PMCID: PMC3660103  PMID: 20600050
food intake; arcuate nucleus; seasonality; neuropeptide Y; c-fos

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