NEUROENDOCRINE/IMMUNE INTERACTIONS: ROLE OF MELATONIN

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DESCRIPTION (applicant's abstract): Physiological adaptations anticipate and coincide with changes in season. Failures to adapt are associated with increased incidence of disease, mortality and mental dysfunctions that include seasonal affective disorders and depression. Day length is the primary environmental cue that regulates a variety of physiological adaptations that anticipate seasonal challenges. Preliminary studies indicate that day length selectively regulates immune functions in the Siberian hamster, a seasonal breeding species in which the mechanism that controls physiological adaptations to day length has been extensively studied. Hamsters in short days (analogous to winter) had increased numbers of leukocytes, T helper cells and eosinophils; natural killer cell cytolytic activity and spontaneous lymphoblastogenesis were also enhanced. In contrast, other indices of immune cell functions were reduced, including T cell-dependent antibody production, as well as phagocytosis and oxidative burst activities by granulocytes and monocytes. Since the neuroendocrine system that mediates the influence of day length on seasonal reproductive physiology involves the circadian pineal melatonin rhythm, the major focus of the proposal is to test the hypothesis that the pineal melatonin rhythm mediates photoperiod control of innate and adaptive immune system functions. An integrative approach to this hypothesis is based upon assessment of the magnitude and tempo of immune responses to changes in day length. The possibility that daily rhythms in immune cell functions are driven by changes in specific immunophenotypes will be addressed. To determine whether photoperiod effects on immune functions depend on the melatonin rhythm, hamsters will be pinealectomized and administered timed treatments to replace specific aspects of the melatonin rhythm. Measures were developed for this seasonal animal model to assess multiple immune system indices by highly sensitive and sophisticated flow cytometry methods for phenotyping, cell-mediated cytolysis, antibody isotype switching and phagocytic cell function. Regulation of specific immune system parameters by photoperiod may potentiate disease resistance, promote adaptations to seasonal challenges in the environment, and provide the foundation to address the therapeutic value of such treatments to selectively modulate immune function in other species. Fundamental knowledge of circadian time keeping and neuroimmune interactions may lead to development of novel approaches to maximize immune responsiveness or slow the deterioration of immune system function that is associated with immunodeficiency, autoimmunity, sleep disturbances, aging and seasonality in behavioral disorders.