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"Cellular, molecular and behavioral consequences of neuroinflammation on the developing mouse hippocampus"

by
Stephanie Veerasammy
Cell Biology, Neuroscience and Physiology Track
MBS, 2012, Rutgers Graduate School of Biomedical Sciences
BS, 2006, Rutgers School of Environmental and Biological Sciences



Thesis Advisor: Steven W. Levison, PhD
Professor
Department of Pharmacology, Physiology and Neuroscience

1:00 PM
Cancer Center, G-1196

Thursday, March 2, 2017
1:00 P.M., Cancer Center, G-1196


Abstract

Meta-analyses have revealed associations between the incidence of maternal infections during pregnancy, premature birth, smaller brain volumes and subsequent cognitive, motor and behavioral deficits as these children mature. Inflammation during pregnancy in rodents produces cognitive and behavioral deficits in the offspring that are similar to those reported in human clinical studies. These deficits are accompanied by decreased neurogenesis and proliferation in the subgranular zone of the dentate gyrus of the hippocampus, one of two regions of the brain that harbor neural stem cells and progenitors. As systemic administration of IL-1 to neonatal mice recapitulates many of the brain abnormalities seen in premature babies with developmental delay, the goal of this thesis was to determine whether IL-1 mediated neuroinflammation affects hippocampal growth during development, resulting in cognitive and behavioral abnormalities as adolescents.
The studies in this thesis show that systemic inflammation induced by daily administration of IL-1 during the first 5 days of life increased hippocampal levels of IL-1 and acutely reduced the proliferation of Tbr2+ neural progenitors in the subgranular zone of mice. In vitro, both IL-1 and IL-1 produced G1/S cell cycle arrest that resulted in reduced progenitor cell proliferation within the transient amplifying progenitor cell cohort. By contrast, IL-1 treatment increased neural stem cell frequency. Upon termination of IL-1 treatment, the progenitor cell pool regained its proliferative capacity.
An earlier study that used this in vivo model of perinatal inflammation has shown that mice that received IL-1 as neonates displayed memory deficits which suggested abnormal hippocampal function. To evaluate whether other cognitive and behavioral traits associated with hippocampal function would also be altered in these mice, the mice were tested in tasks designed to assess exploratory and anxiety behavior and working and spatial memory. Interestingly, mice that received IL-1 as neonates showed signs of anxiety in several behavioral assays during adolescence that were also evident in adulthood. However, these mice did not display memory deficits in adulthood. Altogether, the data in this thesis support the view that perinatal inflammation negatively affects the developing hippocampus and results in behavioral problems that persist into adulthood. These data provide a new perspective into the origin of the cognitive and behavioral impairments observed in prematurely born sick infants.


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