CURRENT PROJECTS IN THE LAB

Many non-tropical mammalian, as well as non-mammalian species undergo seasonal changes in a wide array of physiological and behavioral responses.   These animals have evolved specific adaptive responses to survive seasonal stressor (e.g., changes in ambient temperature, humidity, food availability).  Specifically, individuals of many species undergo regression of their reproductive systems during the winter non-breeding season, and reproductive physiology and behavior remains absent during this period.  As the spring approaches, animals “re-grow” their reproductive organs in time for the impending breeding season.   Although a variety of environmental factors fluctuate seasonally and many of these factors may act as cues with which an animal can determine the time of year, the majority of scientific studies suggest that animals rely mainly on day length (photoperiod) as a primary cue with which to estimate the time of year.  Most environmental cues other than day length vary in relatively unpredictable ways throughout the year. For example, although winter is usually associated with lower ambient temperatures compared with summer in the northern hemisphere, an unseasonably warm “Indian summer” may occur during the winter or a cold wave may roll through in the summer.  Furthermore, food and water may be available to animals only sporadically throughout the year.  In contrast to these seasonal factors, day length information is relatively “noise-free” and can be used to coordinate energetically expensive activities (e.g., breeding) to coincide with adequate energy availability.  By relying on just two pieces of information, the absolute period of daylight and the direction of change across time, animals can determine the precise time of year.  In addition to the traditionally studied seasonal changes in reproduction and energy balance, there are pronounced fluctuations in other physiological and behavioral responses, including immune function and social behavior (e.g. aggression), although considerably less is known about these changes. 

Seasonal/Photoperiodic Changes in Immunity.  Field studies of seasonal changes in immunity typically report reduced immune function and increased disease susceptibility during winter compared with spring and summer.  In addition, photoperiodic changes in immune function have been documented in several rodent species, including deer mice (Peromyscus maniculatus), prairie voles (Microtus ochrogaster), as well as Syrian (Mesocricetus auratus) and Siberian (Phodopus sungorus) hamsters.  In some species (e.g., Siberian hamsters, prairie voles), specific immune responses (e.g., antibody production) are suppressed in short days, in accordance with the majority of field studies. In contrast, individuals of other species (e.g., deer mice, Syrian hamsters), display enhanced immune function in short “winter-like” day lengths compared with long “summer-like” days. 

    Although the mechanisms underlying differences in precise seasonal response display by an individual remain unknown, they likely reflect differences in evolutionary pressures that have shaped physiological responses in these species.   It has been suggested that photoperiodic changes in immune function may represent adaptive functional responses to seasonal changes in the energetic budgets of small rodents.  In other words, all physiological responses are energetically costly; animals may have evolved to reduce immune function at certain times of the year when energy intake is low and energy expenditure is high.   Despite a growing amount of evidence in support of seasonal fluctuations in immunity as an adaptive response to cope with seasonal stressors, the precise physiological mechanisms mediating seasonal (photoperiodic) changes in immune function remain elusive.  A major focus of the Demas Lab is the study of the physiological mechanisms, both endocrine an neural, underlying seasonal changes in immune function and disease susceptibility. 

Sympathetic nervous system (SNS) control of immunity.  It is well-known that specific lymphoid tissues (e.g., spleen, thymus, lymph nodes) are innervated by the SNS.  The precise function of SNS innervation on specific immune responses, however, have not been fully elucidated.  Ongoing studies in our lab utilize the trans-neuronal tract tracer pseudorabies virus (PRV) to identify the complete neural circuit from brain to lymphoid tissue.   PRV is a self-amplifying, transynaptic retrograde tract tracer that can be injected in peripheral tissue and, given sufficient infection time, can be used to identify the hierarchical chain of neurons from the CNS-to-periphery.  We have recently used this technique to create a preliminary map the CNS innervation of the spleen in Siberian hamsters and ongoing studies in our lab will determine the colocalization of PRV-labelled neurosn with specific neurotransmitter phenotypes.  In addition, we also employ immunocytochemistry (ICC) for specific immediate early genes (e.g. c-fos) as markers ofneuronal activation to identify specific brain sites activated during immune responses.  These and future studies will allow us to determine the precise pathways from brain to lymphoid tissue, as well as the role of specific brain regions mediating  immune responses to behavioral stimuli.

Leptin as an endocrine mediator of immune-brain interactions.  The hormone leptin (pictured here as a high-power microscopic image) is a member of the cytokine family and is secreted by adipose tissue (fat) in direct proportion to total body fat.  Furthermore, leptin is generally immunoenhancing and circulating leptin concentrations likely mediate, at least in part, the effects of changes in energy balance on immune function and disease. Lastly, leptin appears to act in the brain, where is binds to receptors in specific brain regions including the hypothalamus. Recent evidence from our lab suggests that activation of central leptin receptors can regulate sympathetic nervous system outflow to peripheral lymphoid tissues and, in turn, mediate immune function.  Ongoing studies in the lab are aimed at identifying the precise role of leptin, as well as specific neurotransmitters and cytokines involved in these immune changes.

Seasonal/Photoperiodic Changes in Social Behavior.  Animals maintained in short “winter-like” days undergo gonadal regression, as well as changes in body fat, pelage, thermoregulation, and reproductive and other social behaviors compared with animals housed in long “summer-like” days.  Short-day reductions in reproductive behavior are due, in part, to reductions in gonadal steroid hormones; circulating testosterone (T) concentrations in males fall to basal levels in animals housed in short photoperiods following gonadal regression. The robust and reliable regression of the gonads that occurs in short days has traditionally served as a “functional castration” with which to study interactions between steroid hormones and behavior.  Although castration reduces aggression in long-day animals and exogenous T treatment can increase aggression in males of many vertebrate species, the relationship between T an aggression is not likely a simple one.  We and others have recently demonstrated that functional castration by maintaining animals in short days increases aggression in gonadally regressed animals, despite basal levels of T.  In fact, several studies report that administration of exogenous T to short-day animals reduces aggression to a level comparable to long days.  At an ultimate level, short-day aggression likely confers an evolutionary advantage at a time when food availability is low and competition for limited resources is high.  The proximate mechanisms underlying seasonal/photoperiodic changes in aggression remain unknown, although recent evidence from our lab suggests that adrenal steroid hormones (e.g., cortisol, DHEA) may play an important role. Ongoing studies are being conducted in our lab to address these and related questions

Sickness Behavior and Food Hoarding.  Animals acutely sick from infections commonly display a constellation of non-specific symptoms (e.g., changes in body temperature, sleep, activity and social behavior, food intake) that have traditionally been interpreted as the inability to achieve normal bodily functioning due to a debilitated state.   More recent evidence, however, suggests that the behavioral features of illness, rather than maladaptive responses or side-effects of disease, are part of a coordinated suite of behavioral adaptations that have important adaptive utility. We are currently conducting research to test the effects of experimentally-induced sickness (injections of lipopolysaccharide [LPS], a carbohydrate present on the surface of gram-negative bacteria) on food hoarding and food intake using a simulated burrow system which allows for the semi-naturalistic observation of food-related behaviors.

Photoperiodic/Seasonal Changes in Disease Susceptibility.  As discussed above, photoperiodic changes in both humoral and cell-mediated immunity have been documented in several rodent and non-rodent mammalian species, including Siberian hamsters.  Despite these important findings, the functional consequences of photoperiodic changes in immune function for resistance to infectious disease have not been addressed empirically.  In other words, do decreases in specific immune parameters actually translate into increased infection?  In order to test this idea, ongoing studies within the laboratory are aimed at addressing these questions using the specific rodent malarial parasite Plasmodium chabaudi chabaudi.  We have chosen to use this infectious agent for several reasons: 1) malaria is the third largest infectious disease killer in the world, 2) the spleen is an important target for malarial antigens, 3) marked seasonal fluctuations in injections rates have been reported in both human and non-human populations, 4) immunological measurement in response to infection have been developed and can easily be measured, 5) unlike other strains of Plasmodium, this strain results in non-lethal infections in rodents and cannot be transferred to humans. Thus, the use of P. chabaudi as an experimental model of infectious disease provides a valuable model with which to study the mechanisms underlying seasonal/photoperiodic changes in immune function and disease resistance Previous results have demonstrated that both growth and division of Plasmodium, as well as vascular sequestration of malarial parasites, can be influenced by changes in the photoperiod in laboratory mice and Syrian hamsters.  Ongoing and future studies will assess the precise physiological mechanisms underlying seasonal changes in disease susceptibility.