Sex differences in BNST networks during early abstinence in AUD

Alcohol use disorders (AUDs) are common, disabling conditions. There is a growing awareness of important
sex differences in AUDs; for example, women experience more serious health complications from alcohol use
and also develop negative consequences from alcohol use more quickly. While the rate of AUDs is relatively
stable in men, the rate in women is escalating at an alarming rate. Neurobiological differences between sexes
are thought to underlie the differential impact of AUDs in men and women, but to date relatively few studies on
this topic exist. Animal models of addiction have substantially informed our understanding of the stages of
addiction— binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation—and their underlying
pathophysiology. For example, chronic alcohol exposure causes neuroadaptive brain changes in an attempt to
maintain homeostasis. During the withdrawal/negative affect stage, hyperactive stress systems produce
symptoms including anxiety and depression which are thought to lead to relapse through negative
reinforcement. Women have higher rates of anxiety and stress-related disorders, which may contribute to sex
differences in early abstinence. Animal models of early abstinence from alcohol highlight the involvement the
bed nucleus of the stria terminalis (BNST). The BNST is also one of the most sexually dimorphic brain regions,
suggesting the BNST is involved in sex-related differences seen during early abstinence. We previously
published evidence for sex differences in BNST structural connectivity in humans. In addition, pilot data from
our NIAAA funded R21 provide initial evidence for sex differences: females had stronger structural and
functional connectivity within the BNST network, heightened stress responses, and higher anxiety during early
abstinence. The current study will focus on sex differences in the BNST network during early abstinence from
alcohol by investigating three specific aims: (1) Determine whether there are sex-related differences in BNST
intrinsic functional or structural connectivity during early abstinence; (2) Determine whether there are sex-
related differences in stress-related BNST function and BNST network connectivity during early abstinence; (3)
Investigate sex-related differences in the relationship between BNST function/connectivity, stress response,
and negative affect in early abstinence. Based on findings from animal models and our pilot data in humans,
we predict that during early abstinence, the BNST will show sex-specific differences in patterns of activity and
connectivity “at-rest” and in response to a mildly stressful task. We expect women will show stronger structural
and functional connectivity within the BNST network, heightened stress responses, and higher anxiety during
early abstinence. The successful completion of this study will fill a critical knowledge gap, determining whether
men and women show neurobiological differences in BNST networks underlying negative affect during early
abstinence from alcohol. The results will provide foundational information to inform future studies investigating
mechanisms of relapse and can guide the development of sex-specific or personalized treatments for AUD.

Grant Number: 5R01AA029127-05
NIH Institute/Center: NIH
Principal Investigator: Jennifer Blackford