Biomedical Sciences ETDs

Publication Date

Spring 5-15-2020

Abstract

Background: With a recent meta-analysis indicating that 9.8% of women worldwide consume alcohol during pregnancy, understanding the effects of fetal alcohol spectrum disorder (FASD) is critical for both identifying and treating those afflicted. Traditional preclinical research investigating the behavioral effects of neurodevelopmental disorders, such as FASD, has utilized tasks designed for specific animal models. For this reason, preclinical research into FASD requires a shift into clinically relevant behavioral testing. One such method involves touch-sensitive screens integrated into an operant box to emulate clinical computer-based tasks, such as the Cambridge Neuropsychological Test Automated Battery.

Methods: Here, we utilized a mouse model of moderate prenatal alcohol exposure (PAE) that models alcohol consumption through gestation during the active (dark) phase. This drinking-in-the-dark model of PAE produces BACs of ~80 mg/dL throughout development. In Study 1, we used a previously established touchscreen-based reversal learning task with integrated optogenetic stimulation to activate the orbitofrontal cortex (OFC). In Study 2, we used immunohistochemistry and unbiased stereology to quantify GABAergic subpopulations in the OFC. In Study 3, we implemented a novel touchscreen task for identifying hippocampal deficits after PAE.

Results: Our findings for each study were as follows: 1) Direct stimulation of the OFC one second after correct choices during the first four sessions of reversal reduced the average number of perseverative trials PAE performed during the early and middle stages, 2) unbiased stereology determined a sex-specific increase in the number of calretinin (CR+) disinhibitory interneurons in the OFC, and 3) use of touchscreen trial unique nonmatching-to-location tasks uncovered a sex-specific impairment when training was minimal and trials were unpredictable.

Conclusions: Direct, global activation of the OFC is sufficient to reduce the number of perseverative trials PAE mice make during early and chance performance in a touchscreen reversal learning task. The effects PAE has on touchscreen reversal learning could be due to impaired GABAergic signaling in the OFC. A touchscreen-based visual-spatial discrimination task is capable of revealing hippocampal impairments after PAE. Together, our data demonstrate the ability of touchscreen tasks to inform and guide future experiments using mouse models of PAE.

Keywords

prenatal alcohol exposure, executive function, touchscreen, interneurons, optogenetics, sex differences

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Jonathan L. Brigman

Second Committee Member

C. Fernando Valenzuela

Third Committee Member

Lee Anna Cunningham

Fourth Committee Member

Benjamin Clark

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