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Chronic exposure to low-dose ethanol impacts flexible behavioral responding in a sex-selective manner
Dissertation

Chronic exposure to low-dose ethanol impacts flexible behavioral responding in a sex-selective manner

Christina Marie Curran-Alfaro
Doctor of Philosophy (Ph.D.), Drexel University
Jun 2026
DOI:
https://doi.org/10.17918/00011462
pdf
Curran-Alfaro_Christina_20264.28 MB
PDF Embargoed Access, Embargo ends: 30 Jun 2028

Abstract

Alcohol use disorder Basolateral amgydala Behavior Ethanol Flexible behavior Motivation
In 2023, the World Health Organization released a statement indicating that there is no safe level of alcohol exposure. However, a majority of adults in the US consume alcohol at casual drinking levels, with reports indicating an increase of daily consumption from 6.3% in 2019 to 9.6% in 2021 amongst men and women (Kerr et al., 2022). Despite this, the effects of chronic exposure to low-dose ethanol on the brain and behavior, and the potential risk for ethanol-associated negative outcomes, are understudied. A characteristic of alcohol use disorder (AUD) includes impaired behavioral and cognitive flexibility, which contributes to the maintenance of ethanol seeking despite negative consequences. Factors which promote flexible behavior include the ability to track and use changes in reward value, valence, and contingency. The basolateral amygdala (BLA) plays a large role in flexible behavior by encoding changes in reward value or valence outcomes, thus influencing future actions, such as reward seeking and decision-making. The BLA is further particularly vulnerable to the effects of chronic ethanol exposure, making it a potential mediator of low-dose ethanol effects on behavioral flexibility. Thus, the broad objective of this thesis work was to identify the effects of chronic low-low dose ethanol exposure on flexible reward seeking and limbic corticostriatal correlates such as the BLA. Behavioral findings revealed sex selective effects of low-dose ethanol on multiple factors impacting behavioral flexibility - changes in reward value, valence, and contingency. In a progressive ratio (PR) task, female mice exposed to low-dose ethanol showed altered sucrose motivation in response to changes in reward magnitude. Furthermore, a history of low-dose ethanol exposure blocked expression of lithium chloride (LiCl) conditioned taste aversion in females. These effects were not observed in male mice. In contrast, chronic exposure to low-dose ethanol impaired reversal learning during an effort-guided decision-making task in male, but not female, mice. This revealed that chronic low-dose ethanol exposure impacts behavior in a sex specific manner. However, the impacts of chronic low-dose ethanol on the brain during reward seeking was not selective to sex. Chronic low-dose ethanol altered cFos expression within cortical structures during sucrose reward seeking in female and male mice. To determine the role of the BLA in the ability of male mice to use reversal of effort requirements to guide decision-making, the BLA was inhibited during the effort-guided decision-making task when effort requirements were reversed. This did not impair reversal learning. These results suggest that chronic exposure to low-dose ethanol leads to enduring sex-selective effects on flexible behavioral responding. An increase in understanding in how chronic low-dose ethanol impacts the brain and behavior may potentially inform risk of casual drinking in the development of alcohol-associated comorbidities and the transition to AUD.

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