Biomedical Sciences ETDs

Author

Lauren Topper

Publication Date

12-1-2015

Abstract

Drinking during pregnancy can result in fetal alcohol spectrum disorders (FASD), an umbrella term that encompasses a wide array of symptoms ranging from neurocognitive deficits to physical malformations. The mechanism for FASD is not yet fully understood, however recently, activation of the neuroimmune system has been suggested to play a role. Neuroinflammation, characterized by increased pro-inflammatory cytokine production and glial cell activation, has been observed following exposure to alcohol during the neonatal period. Furthermore, neuroimmune activation has been implicated in alcohol-induced neuronal death and/or damage. The studies herein investigate several components of the relationship between neuronal damage following developmental alcohol exposure and neuroimmune system activation. This dissertation is broken down into two main studies. In the first study, we focus on the relatively uncharacterized effects of moderate exposure to alcohol during development. Specifically, re-programming of neuroimmune cells has been demonstrated following exposure to insult during the neonatal period. This "primed" neuroimmune system then over-reacts to subsequent insults and results in exaggerated production of pro-inflammatory molecules, which can cause behavioral deficits. We hypothesized that exposure to alcohol could elicit similar effects and lead to neuroimmune system priming. In the second study we used a high dose, binge-like exposure paradigm during the neonatal period. While this type of exposure has been shown to result in robust increases in pro-inflammatory cytokine production and microglial activation, evidence for an anti-inflammatory component also exists. Neuroimmune system activation has recently been shown to consist of multiple pathways, known as M1 and M2. M1 activation is considered pro-inflammatory and can be neurotoxic, while M2 is generally anti-inflammatory and neuroprotective. This study sought to test the hypothesis that alcohol exposure in the neonatal period would initially produce a M1-type response followed by a regenerative M2 period. The overall findings suggest that high dose, binge-like exposures are much more disruptive to neuroimmune cells than more moderate, yet longer-term exposures. This dissertation reports that withdrawal periods may be more detrimental to neurons than the alcohol exposure itself, and that there is an important role of astrocytes in mediating this response that is distinct from microglia.

Keywords

Microglia, Alcohol, Fetal, Astrocytes, Cytokines, Ethanol, Postnatal

Sponsors

This work was supported by NIH and NIAAA grants R37-AA015614, T32-AA014127, and P50AA022534

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Advisor

Valenzuela, C. Fernando

First Committee Member (Chair)

Milligan, Erin

Second Committee Member

Bhaskar, Kiran

Third Committee Member

Caldwell, Kevin

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