Enduring Effects of Early Life Inflammation on Stress-related Microglial, Neuronal and Behavioral phenotypes

Inflammatory early life stressors, including maternal obesity via high-fat diet (mHFD) and neonatal infections, are increasingly recognized as contributing factors to the development of mood and cognition-related disorders. In parallel, rodent models of mHFD and neonatal infection exhibit behaviors associated with these disorders, particularly increased anxiety. These animals also exhibit neuroinflammation and altered stress-related gene expression, including glucocorticoid receptor (GR), potential drivers of their altered behavior. Epidemiological studies indicate that neonates born to mothers with obesity have a higher likelihood of developing neonatal infections, however effects on offspring health resulting from the combination of these stressors have yet to be investigated. GR expression in neurons and microglia regulate anxiety behaviors and their densities can influence this regulation. Microglia, neuro-immune cells, orchestrate neuroinflammation with functions ranging from resting state surveillance to activated state phagocytosis. Whether dysregulated cell-specific GR expression, densities and microglial overactivation, characterizable by morphology, explains the neuroinflammation and heightened anxiety phenotypes found previously also remains to be elucidated. The aims of this thesis were to 1) characterize immediate and persistent phenotypes resulting from the combined and independent effects of mHFD and neonatal lipopolysaccharide (nLPS) exposure and 2) delineate cell-specific contributions to altered GR and immune gene expression in key brain regions regulating anxiety. Firstly, juvenile rats with combined but not independent exposures to mHFD+nLPS exhibited altered stress-related transcript abundances in the ventral hippocampus (vHPC) in a manner conducive to potentiating neural stress responses. Surprisingly, mHFD+nLPS juvenile offspring displayed normalized spatial memory behavior and dorsal hippocampal gene expression in contrast to offspring with independent exposures. Secondly, corresponding with potentiating neural stress responses, independent exposures to mHFD or nLPS decreased neuronal densities, GR colocalization and increased microglial densities, activation and toll-like receptor 4 colocalization in the vHPC and amygdala subregions at adulthood, with similar findings in mHFD+nLPS females. Surprisingly, adult mHFD+nLPS males displayed normalization in behavior and the neural features examined, with effects similar to that of controls. As markers of microglial overactivation have been found in human studies of various neuropsychiatric diseases, these findings suggest that maternal obesity and neonatal infections heighten the risk for their development by way of microglial pathology.

Department dc:contributor.department

Cell and Systems Biology

Year dc:date.issued

2022

Author dc:creator

• Rahman, Mouly Fahrin

Advisor dc:contributor.advisor

• McGowan, Patrick O

Statement dc:rights

• Attribution-NonCommercial-NoDerivatives 4.0 International

Licence dc:rights.uri

• http://creativecommons.org/licenses/by-nc-nd/4.0/

Handle dc:identifier.uri

http://hdl.handle.net/1807/129722

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/129722