The immune system and the central nervous system interact in a bidirectional manner. Activity of the central nervous system can direct marked changes in immune function. Likewise, peripheral inflammation is associated with pathological changes in motivational states and behavior, mood and cognition. Circadian and seasonal clocks in the hypothalamus yield high-amplitude rhythms in immune function and afford direct investigation of mechanisms mediating brain-to-immune interactions. Daily and seasonal rhythms in morbidity in response to inflammation are directly relevant to survival of numerous illnesses. Understanding how biological clocks engage changes in the immune system has implications for the treatment and management of chronic diseases (e.g., cancer, obesity) and acute bacterial and viral infections. The overall goal of the proposed research is to identify the mechanisms by which daily (circadian) and seasonal time information is communicated from the brain to the immune system. Siberian hamsters will be used as a model species specifically because they exhibit robust seasonal and circadian rhythms in innate and adaptive immune function which can be readily driven and synchronized by changes in the light-dark cycle. In this species, the amplitude of the seasonal cycle in several measures of immunity encompasses a range that would be clinically diagnostic of an immunocompromised state, yet hamsters exhibit these changes in immunity in the absence of co-morbid illness and in response to little more than a few hours'change in the light-dark cycle. Understanding the mechanisms by which time information drives changes in immune function will identify novel endogenous mechanisms by which the brain affects the immune system. This is a fundamentally-important issue which will inform treatments for seasonally-recurring illnesses in humans, and the causes of robust circadian rhythms in morbidity. These experiments will assess redistribution of blood leukocyte phenotypes, alterations in adaptive T cell-mediated immune function (DTH reactions), and changes in the magnitude of infection-induced innate inflammatory responses in experiments that seek to: (1) identify the cellular mechanisms by which changes in day length and melatonin control immune cell activity, (2) specify the role of thyroid hormone signaling in the genesis of seasonal changes in the immune system, (3) characterize the influence of the hypothalamic circadian pacemaker on daily rhythms in the immune system and on organismal-level immunocompetence, and (4) identify the output mechanisms that mediate coupling between the circadian clock and the immune system. The proximate causes of human seasonal and circadian rhythms in health and immune function remain largely unknown. Together, the work will afford major and novel biological insights into the mechanisms by which the nervous and endocrine systems guide the activity of the immune system.

Public Health Relevance

Biological clocks in the brain generate high-amplitude daily and seasonal rhythms in immune function and afford direct investigation of mechanisms by which the central nervous system modulates immunity. Daily and seasonal rhythms in morbidity in response to inflammation are directly relevant to survival of numerous illnesses, thus understanding how biological clocks engage changes in the immune system has implications for the treatment and management of chronic diseases and acute bacterial and viral infections. The proposed research seeks to identify the mechanisms by which circadian and seasonal time information is communicated from the brain to the immune system;the work will afford major and novel biological insights into neural and endocrine modulation of immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI067406-06
Application #
8264737
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Nasseri, M Faraz
Project Start
2005-06-01
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
6
Fiscal Year
2012
Total Cost
$390,000
Indirect Cost
$140,000
Name
University of Chicago
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Pyter, Leah M; El Mouatassim Bih, Sarah; Sattar, Husain et al. (2014) Peripheral tumors alter neuroinflammatory responses to lipopolysaccharide in female rats. Brain Res 1552:55-63
Bradley, Sean P; Prendergast, Brian J (2014) Adaptation to short photoperiods augments circadian food anticipatory activity in Siberian hamsters. Horm Behav 66:159-68
Stevenson, Tyler J; Onishi, Kenneth G; Bradley, Sean P et al. (2014) Cell-autonomous iodothyronine deiodinase expression mediates seasonal plasticity in immune function. Brain Behav Immun 36:61-70
Prendergast, Brian J; Onishi, Kenneth G; Patel, Priyesh N et al. (2014) Circadian arrhythmia dysregulates emotional behaviors in aged Siberian hamsters. Behav Brain Res 261:146-57
Stevenson, Tyler J; Prendergast, Brian J (2013) Reversible DNA methylation regulates seasonal photoperiodic time measurement. Proc Natl Acad Sci U S A 110:16651-6
Prendergast, Brian J; Cable, Erin J; Patel, Priyesh N et al. (2013) Impaired leukocyte trafficking and skin inflammatory responses in hamsters lacking a functional circadian system. Brain Behav Immun 32:94-104
Kampf-Lassin, August; Prendergast, Brian J (2013) Acute downregulation of Type II and Type III iodothyronine deiodinases by photoperiod in peripubertal male and female Siberian hamsters. Gen Comp Endocrinol 193:72-8
Prendergast, Brian J; Pyter, Leah M; Kampf-Lassin, August et al. (2013) Rapid induction of hypothalamic iodothyronine deiodinase expression by photoperiod and melatonin in juvenile Siberian hamsters (Phodopus sungorus). Endocrinology 154:831-41
Prendergast, Brian J; Onishi, Kenneth G; Zucker, Irving (2013) Neonatal monosodium glutamate treatment counteracts circadian arrhythmicity induced by phase shifts of the light-dark cycle in female and male Siberian hamsters. Brain Res 1521:51-8
Prendergast, Brian J; Cable, Erin J; Cisse, Yasmine M et al. (2013) Pineal and gonadal influences on ultradian locomotor rhythms of male Siberian hamsters. Horm Behav 63:54-64

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