Early adolescent adversity inflates threat estimation in females and promotes alcohol use initiation in both sexes.

Abstract

Childhood adversity is associated with exaggerated threat processing and earlier alcohol use initiation. Conclusive links remain elusive, as childhood adversity typically co-occurs with detrimental socioeconomic factors, and its impact is likely moderated by biological sex. To unravel the complex relationships among childhood adversity, sex, threat estimation, and alcohol use initiation, we exposed female and male Long-Evans rats to early adolescent adversity (EAA). In adulthood, >50 days following the last adverse experience, threat estimation was assessed using a novel fear discrimination procedure in which cues predict a unique probability of footshock: danger (p = 1.00), uncertainty (p = .25), and safety (p = .00). Alcohol use initiation was assessed using voluntary access to 20% ethanol, >90 days following the last adverse experience. During development, EAA slowed body weight gain in both females and males. In adulthood, EAA selectively inflated female threat estimation, exaggerating fear to uncertainty and safety, but promoted alcohol use initiation across sexes. Meaningful relationships between threat estimation and alcohol use initiation were not observed, underscoring the independent effects of EAA. Results isolate the contribution of EAA to adult threat estimation, alcohol use initiation, and reveal moderation by biological sex. (PsycINFO Database Record

The ventrolateral periaqueductal grey updates fear via positive prediction error

“…Previous experiments related to aversive prediction error signalling using rodents have been conducted using only males (Assareh et al., ; Cole & McNally, ; Groessl et al., ; Johansen et al., ; McNally & Cole, ; Ozawa et al., ), and one study in humans used both males and females but did not consider sex as a factor in their analyses (Roy et al., ). Sex differences in baseline behaviour (i.e., nose poke rate and absolute fear levels) in the optogenetics results are consistent with previous findings in the same behavioural task (Walker et al., ). While the effect of optogenetic inhibition to decrease fear to uncertainty was observed across sexes, subtle interactions with sex and the pattern of fear to uncertainty and safety were observed.…”

“…In the procedure, three auditory cues predict unique foot shock probabilities: danger ( p = 1.00), uncertainty ( p = .375) and safety ( p = .00). Using conditioned suppression of rewarded nose poking as our dependent measure, we have previously found excellent discriminative fear in male and female rats: high to danger, intermediate to uncertainty, and low to safety (Berg et al., ; DiLeo, Wright, & McDannald, ; Ray, Hanlon, & McDannald, ; Walker et al., ; Wright et al., ). Theoretically, +PEs provide an updating mechanism that would permit fear to uncertainty to remain at an intermediate level.…”

“…Nevertheless, excessive threat processing is not limited to disorders of anxiety. Adults maltreated as children show exaggerated neural responses to threatening stimuli despite the lack of any clinical diagnosis (Dannlowski et al., ), and our laboratory has shown that early adolescent adversity inflates fear to uncertainty in rodents (Walker et al., ; Wright et al., ). While speculative, the current results offer a potential mechanism by which exaggerated +PE activity in vlPAG neurons could drive excessive fear to ambiguous, threatening cues.…”

“…In two experiments, we sought to uncover a relationship between vlPAG +PE activity and fear updating. We employed a fear discrimination procedure in which a danger cue predicted shock deterministically and an uncertainty cue predicted shock probabilistically (Berg, Schoenbaum, & McDannald, 2014;Walker, Andreansky, Ray, & McDannald, 2018;Wright, DiLeo, & McDannald, 2015). In experiment 1, we recorded vlPAG single-units during ongoing fear discrimination, focusing on activity around predicted (danger) and surprising (uncertainty) foot shock delivery.…”

The nucleus accumbens core is necessary to scale fear to degree of threat

“…Several studies have reported sex differences in danger-safety discrimination (Day et al, 2016;Foilb et al, 2018;Greiner et al, 2019). We find only modest sex differences in our fear procedure (Walker et al, 2018;Walker et al, 2019), suggesting similar neural circuits may be utilized across sexes. Of course, females and males may achieve similar performance through differing neural mechanisms.…”