Date Available

4-21-2018

Year of Publication

2017

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Arts and Sciences

Department/School/Program

Psychology

First Advisor

Dr. Susan Barron

Abstract

Fetal Alcohol Spectrum Disorders (FASD) are a spectrum of anatomical, developmental and neurobehavioral impairments resulting from ethanol (ETOH) exposure during fetal development. Efforts to develop and screen novel pharmacotherapies against fetal ETOH effects depend heavily upon rodent models to provide indicators of the safety and efficacy of such compounds, in addition to helping better understand the underlying mechanisms to develop and test these pharmacotherapies. The following experiments describe the development of a novel mouse model of FASD using behavioral batteries to assess behavioral or cognitive deficits in juvenile and adolescent offspring (Experiment 1, Experiment 2) and whether deficits with this model extend into adulthood (Experiment 3). In Exp 1, three ETOH exposure paradigms were generated to model ETOH exposure during periods of mouse development analogous to the three trimesters of human central nervous system (CNS) development. These included a prenatal (first-second trimester) model, a neonatal (third trimester) model, and a combined prenatal-neonatal (3-trimester) model. Exploratory behavior and learning performance were assessed in juvenile and adolescent development through a behavioral test battery that included open-field (OF), elevated plus maze (EPM) and Morris water maze (MWM). These tasks were selected to model deficits in behavior regulation that are reported in humans with FASD, including hyperactivity, impulse control deficits and learning impairments. The results of this study showed that the neonatal ETOH exposure paradigm produced hyperactivity, inhibitory failures and impaired learning. These effects were not altered by pre-exposure to the present prenatal exposure paradigm. Based on these findings, the neonatal ETOH exposure model was selected for a follow-up study (Experiment 2-3) to provide additional data on the behavioral profile of this model using two novel tasks and a wider testing window extending into adulthood. Testing was conducted in the juvenile, adolescent and early adult stages in the hole-board test (HB), open-field (OF), and attentional set shifting task (ASST) respectively. These tasks and ages were selected to provide additional data on various aspects of the behavioral profile in this model, including distinguishing between enhanced locomotion or investigation in hyperactivity, the potential for OF effects to persist into adolescence, and to determine whether these mice show cognitive inflexibility in adulthood. Results showed that neonatal ETOH exposure led to increased investigation that may be related to both hyperactivity and inhibitory failures, persistent effects on OF activity and exploration in adolescence, and learning deficits in adulthood. It was concluded that the neonatal ETOH exposure model shows substantial face validity for behavioral symptoms in FASD and is a strong rodent model for future use in neurogenetic studies and drug development.

Digital Object Identifier (DOI)

https://doi.org/10.13023/ETD.2017.071

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