Date of Award

12-12-2022

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience Institute

First Advisor

Dr. Kim Huhman

Abstract

Chronic low-grade inflammation and exposure to stress are key contributing factors in the etiology and progression of many neuropsychiatric disorders. Dietary emulsifiers are commonly added to processed foods and are classified by the Food and Drug Administration (FDA) as generally recognized as safe (GRAS). Recently, however, it has been revealed that these additives at translationally relevant doses can cause low-grade inflammation, gut dysbiosis, and may even increase baseline anxiety-like behavior. The latter finding suggests that dietary emulsifiers impact brain areas that modulate stress responses. We used RNA-Seq to examine whether chronic consumption of either polysorbate 80 (P80) or carboxymethylcellulose (CMC) is associated with changes in gene expression in the amygdala and PVN and used Ingenuity Pathway Analysis to identify enriched molecular pathways that may underlie an anxiety-like phenotype. Emulsifier consumption resulted in alterations in gene expression of various immediate early, stress-related, and immune-related genes in brain regions that are known to be important in the generation of behavioral and neuroendocrine responses to stress-provoking stimuli. We also hypothesized that emulsifier-treated mice exhibit sensitized behavioral, hormonal, and neuronal activity responses to stress. To test this hypothesis, C57Bl6/J mice were subjected to acute defeat conditions after 12 weeks of emulsifier or water consumption. When subjected to social defeat, emulsifier-treated mice showed increases in social avoidance and circulating corticosterone as well as alterations in neuronal activity as measured by c-Fos immunofluorescence. Subsequently, given the observed increased expression of PTGS2 (COX-2) in the amygdala, we tested the hypothesis that increased inflammation through the COX pathway is a mechanism driving emulsifier-induced increases is stress sensitivity. Groups were as described above, but mice were also divided into aspirin (25mg/kg/day) and placebo intervention groups. We found that aspirin, a COX pathway inhibitor, appears to block the increase in social avoidance observed in emulsifier-treated mice. These data demonstrate that ingestion of dietary emulsifiers at concentrations analogous to those ingested by humans increases sensitivity to social stress in mice. Further, it appears that the COX pathway may be a prime mechanistic candidate by which emulsifier-induced increases in sensitivity to social stress occurs.

DOI

https://doi.org/10.57709/32574819

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