Numerous studies have indicated that interactions between the central nervous system (CNS) and the immune system play an important role in the maintenance of homeostasis and the development of immunologic diseases including infectious diseases, cancer and autoimmune disorders. One of the most well established findings in the area of CNS-immune interactions is the profound impact of acute and chronic stress on the immune response. Relevant pathways mediating these effects of stress on the immune system include the pothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). Given that HPA axis and SNS outflow pathways during stress are regulated by corticotropin releasing factor (CRF), a number of studies have focused on the impact of CRF on the immune system. Interestingly, in addition to causing suppression of both cell-mediated and humoral immune function, CRF has been found to induce the release of several cytokines including (IL) interleukin-1 and -6. These cytokines in turn have been shown to stimulate CRF production/release and mediate a host of behavioral responses that include """"""""sickness behavior"""""""" with features that overlap with major depression. Early life stress in humans and laboratory animals has been shown to increase CRF synthesis and secretion and moreover, that CRF pathways are sensitized to subsequent stressor exposure in adulthood. In view of the effect of CRF on the immune system and the potential impact of the immune system on the CNS and CRF, in particular, examination of the potential consequences and contributions of CRF-immune interactions to physical and emotional health in individuals exposed to early life stress is of paramount importance. The long term objectives of this proposed project are to further understand 1) how early life stress impacts upon the adult immune system, 2) whether CRF is the major mediator of the observed effects and 3) whether proinflammatory cytokines contribute to the neurobiologic and immunologic features of early life stress. The hypotheses are that 1) early life stress in laboratory animals (rats and rhesus monkeys) and humans will potentiate stress-induced suppression of cellular and humoral immune responses, 2) early life stress will enhance stress-induced activation of proinflammatory cytokines and their signaling pathways, including NFkB and MAP kinase, 3) enhanced suppression of cellular and humoral immune responses and increased activation of proinflammatory signaling pathways secondary to early life stress will be mediated by CRF and its effects on the HPA axis and/or SNS, and 4) activation of proinflammatory signaling pathways by IL-1 and IL-6 will contribute to the neuroendocrine, behavioral and immunologic manifestations of early life stress. Taken together, these studies will provide new insights into the pathophysiology of early life stress and provide a foundation for the development of novel treatment strategies for the neurobiologic and immunologic consequences of early life stress.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
2P50MH058922-06
Application #
6850629
Study Section
Special Emphasis Panel (ZMH1-BRB-S (06))
Project Start
2004-09-01
Project End
2009-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
6
Fiscal Year
2004
Total Cost
$153,000
Indirect Cost
Name
Emory University
Department
Type
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Goodman, Sherryl H; Bakeman, Roger; McCallum, Meaghan et al. (2017) Extending Models of Sensitive Parenting of Infants to Women at Risk for Perinatal Depression. Parent Sci Pract 17:30-50
Schechter, Julia C; Brennan, Patricia A; Smith, Alicia K et al. (2017) Maternal Prenatal Psychological Distress and Preschool Cognitive Functioning: the Protective Role of Positive Parental Engagement. J Abnorm Child Psychol 45:249-260
Houtepen, Lotte C; Vinkers, Christiaan H; Carrillo-Roa, Tania et al. (2016) Genome-wide DNA methylation levels and altered cortisol stress reactivity following childhood trauma in humans. Nat Commun 7:10967
Zannas, Anthony S; Arloth, Janine; Carrillo-Roa, Tania et al. (2015) Lifetime stress accelerates epigenetic aging in an urban, African American cohort: relevance of glucocorticoid signaling. Genome Biol 16:266
Klengel, Torsten; Binder, Elisabeth B (2015) FKBP5 allele-specific epigenetic modification in gene by environment interaction. Neuropsychopharmacology 40:244-6
Johnson, Katrina C; Brennan, Patricia A; Stowe, Zachary N et al. (2014) Physiological regulation in infants of women with a mood disorder: examining associations with maternal symptoms and stress. J Child Psychol Psychiatry 55:191-8
Rouse, Matthew H; Goodman, Sherryl H (2014) Perinatal depression influences on infant negative affectivity: timing, severity, and co-morbid anxiety. Infant Behav Dev 37:739-51
Hecht, Erin E; Murphy, Lauren E; Gutman, David A et al. (2013) Differences in neural activation for object-directed grasping in chimpanzees and humans. J Neurosci 33:14117-34
Heim, Christine M; Mayberg, Helen S; Mletzko, Tanja et al. (2013) Decreased cortical representation of genital somatosensory field after childhood sexual abuse. Am J Psychiatry 170:616-23
Miller, Andrew H; Haroon, Ebrahim; Raison, Charles L et al. (2013) Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress Anxiety 30:297-306

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