Neuroendocrine or immune events occurring within the perinatal environment often produce effects on brain and behavior that endure throughout an organism's life span. An estimated 1/3 of pregnancies suffer complications involving infection or trauma of the uterus, fetus, or newborn, and one of the most common consequences of infection or inflammation during the perinatal period is cognitive dysfunction, including learning, memory, and attention disorders. Systemic infection with bacteria (Escherichia coli) on postnatal day 4 in rats is associated with dramatic memory impairments in conjunction with a peripheral immune challenge (lipopolysaccharide;LPS) in adulthood. The current proposal is designed to address two related questions: (1) What changes occur in the neonatal brain in response to the infection that render the brain vulnerable to a later challenge? and (2) What changes occur in the brains of neonatally-infected adult rats in response to the LPS challenge, which produce the memory impairments? The proposed experiments will test the hypothesis that long-term changes in brain microglia, the primary immune cells of the brain, occur in response to infection early in life, which then contribute to altered brain function (e.g., cytokine production, neurogenesis) and memory impairment in adulthood. This hypothesis will be tested by examining the following questions, using gene expression, protein expression, and behavioral techniques: (1) Does neonatal E. coli infection result in increased microglial reactivity in adulthood? (2) Do neonatal E. coli infection-induced changes in microglia underlie exaggerated brain cytokine responses and memory impairments in adulthood? and (3) Why does postnatal day 4 appear to be during a sensitive period for neonatal infection- induced vulnerabilities later in life? These collective data will provide novel insight into the influence of early immune activation on neural and immune system development, the role that the brain's immune response plays in cognition, and ultimate treatment decisions.

Public Health Relevance

An estimated 1/3 of pregnancies suffer complications involving infection or trauma of the uterus, fetus, or newborn, and one of the most common consequences of infection or inflammation during the perinatal period is cognitive dysfunction, including learning, memory, and attention disorders. The data collected from this proposal will provide novel insight into the influence of early immune activation on neural and immune system development, the role that the brain's immune response plays in cognition, and ultimately treatment decisions aimed at preventing the negative consequences of early infection or trauma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH083698-02
Application #
7862323
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Desmond, Nancy L
Project Start
2009-06-08
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
2
Fiscal Year
2010
Total Cost
$452,400
Indirect Cost
Name
Duke University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Hanamsagar, Richa; Bilbo, Staci D (2017) Environment matters: microglia function and dysfunction in a changing world. Curr Opin Neurobiol 47:146-155
Williamson, Lauren L; Bilbo, Staci D (2014) Neonatal infection modulates behavioral flexibility and hippocampal activation on a Morris Water Maze task. Physiol Behav 129:152-9
Bilbo, Staci D (2013) Frank A. Beach award: programming of neuroendocrine function by early-life experience: a critical role for the immune system. Horm Behav 63:684-91
Bilbo, Staci D; Schwarz, Jaclyn M (2012) The immune system and developmental programming of brain and behavior. Front Neuroendocrinol 33:267-86
Bilbo, Staci D; Smith, Susan H; Schwarz, Jaclyn M (2012) A lifespan approach to neuroinflammatory and cognitive disorders: a critical role for glia. J Neuroimmune Pharmacol 7:24-41
Schwarz, Jaclyn M; Sholar, Paige W; Bilbo, Staci D (2012) Sex differences in microglial colonization of the developing rat brain. J Neurochem 120:948-63
Williamson, Lauren L; Chao, Agnes; Bilbo, Staci D (2012) Environmental enrichment alters glial antigen expression and neuroimmune function in the adult rat hippocampus. Brain Behav Immun 26:500-10
Schwarz, Jaclyn M; Bilbo, Staci D (2011) LPS elicits a much larger and broader inflammatory response than Escherichia coli infection within the hippocampus of neonatal rats. Neurosci Lett 497:110-5
Williamson, Lauren L; Sholar, Paige W; Mistry, Rishi S et al. (2011) Microglia and memory: modulation by early-life infection. J Neurosci 31:15511-21
Bland, Sondra T; Beckley, Jacob T; Young, Sarah et al. (2010) Enduring consequences of early-life infection on glial and neural cell genesis within cognitive regions of the brain. Brain Behav Immun 24:329-38

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