Sex differences in discriminating between cues predicting threat and safety

Day, Harriet Laura Lavinia; Reed, M.; Stevenson, Carl W.

doi:10.1016/j.nlm.2016.07.014

Cited by 69 publications

(68 citation statements)

References 49 publications

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“…First, our experiments only used male rats. 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.…”

Section: Discussionsupporting

confidence: 56%

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

Ray

Russ

Walker

et al. 2020

Preprint

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AbstractFear is adaptive when the level of the response rapidly scales to degree of threat. Using a discrimination procedure consisting of danger, uncertainty and safety cues, we have found rapid fear scaling (within two seconds of cue presentation) in male rats. Here we examined a possible role for the nucleus accumbens core (NAcc) in the acquisition and expression of fear scaling. In experiment 1, male Long Evans rats received bilateral sham or neurotoxic NAcc lesions, recovered and underwent fear discrimination. NAcc-lesioned rats were generally impaired in scaling fear to degree of threat, and specifically impaired in rapid uncertainty-safety discrimination. In experiment 2, male Long Evans rats received NAcc transduction with halorhodopsin or a control fluorophore. After fear scaling was established, the NAcc was illuminated during cue or control periods. NAcc-halorhodopsin rats receiving cue illumination were specifically impaired in rapid uncertainty-safety discrimination. The results reveal a general role for the NAcc in scaling fear to degree of threat, and a specific role in rapid discrimination of uncertain threat and safety.Significance StatementRapidly discriminating cues for threat and safety is essential for survival and impaired threat-safety discrimination is a hallmark of stress and anxiety disorders. In two experiments, we induced nucleus accumbens core (NAcc) dysfunction in rats receiving fear discrimination consisting of cues for danger, uncertainty and safety. Permanent NAcc dysfunction, via neurotoxic lesion, generally disrupted the ability to scale fear to degree of threat, and specifically impaired one component of scaling: rapid discrimination of uncertain threat and safety. Reversible NAcc dysfunction, via optogenetic inhibition, specifically impaired rapid discrimination of uncertain threat and safety. The results reveal that the NAcc is essential to scale fear to degree of threat, and is a plausible source of dysfunction in stress and anxiety disorders.

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Section: Discussionsupporting

confidence: 56%

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

Ray

Russ

Walker

et al. 2020

Preprint

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“…Considering these findings in interpreting our current results, it is possible that males experienced more aversive motivation after re-exposure in our AAT, and this could explain why (1) a subset of males exhibited learned helplessness-like behavior, and (2) the males in the full task were more motivated to avoid the shock on all avoidance trials. The second hypothesis is consistent with the findings of Day et al, who showed that females demonstrate greater discrimination than males after limited training, and generalization after extended training on a fear discrimination task (Day, Reed, & Stevenson, 2016) . Together with our current findings, these results are consistent with the idea that women's vulnerability to anxiety disorders stems from accumulating experience of aversive contexts Finally, we investigated potential sex differences in reward-motivated actions within a context of high cognitive load, requiring flexible shifts between dynamic cue-action-reward contingencies.…”

Section: The Study Of Sex Differences Relevant To Psychiatric Diseasesupporting

confidence: 90%

Sex differences in reward- and punishment-guided actions

Chowdhury

Wallin-Miller

Rear

et al. 2019

Preprint

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Differences in the prevalence and presentation of psychiatric illnesses in men and women suggest that neurobiological sex differences confer vulnerability or resilience in these disorders.Rodent behavioral models are critical for understanding the mechanisms of these differences.Reward processing and punishment avoidance are fundamental dimensions of the symptoms of psychiatric disorders. Here we explored sex differences along these dimensions using multiple and distinct behavioral paradigms. We found no sex difference in reward-guided associative learning but a faster punishment-avoidance learning in females. After learning, females were more sensitive than males to probabilistic punishment but less sensitive when punishment could be avoided with certainty. No sex differences were found in reward-guided cognitive flexibility.Thus, sex differences in goal-directed behaviors emerged selectively when there was an aversive context. These differences were critically sensitive to whether the punishment was certain or unpredictable. Our findings with these new paradigms provide conceptual and practical tools for investigating brain mechanisms that account for sex differences in susceptibility to anxiety and impulsivity. They may also provide insight for understanding the evolution of sex-specific optimal behavioral strategies in dynamic environments.

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“…The inability to effectively inhibit fear is a phenotype of PTSD and is involved in its neurocircuitry and clinical symptoms (Jovanovic, Kazama, Bachevalier, & Davis, ; Jovanovic & Norrholm, ). Generally, fear inhibition includes three processes: (a) fear extinction refers to learning previous threat cues are no longer dangerous (Milad & Quirk, ); (b) safety learning occurs when one learns that environmental stimuli predict safety (Marshall, Acheson, Risbrough, Straus, & Drummond, ); and (c) fear–safety discrimination is the process of distinguishing between “threat” and “safety” cues when simultaneously presented (Day, Reed, & Stevenson, ). Animal models of fear inhibition have been developed to advance understanding of these phenomena (Bowers & Ressler, ; Pollak, Monje, & Lubec, ).…”

Section: Introductionmentioning

confidence: 99%

Sex differences in mouse models of fear inhibition: Fear extinction, safety learning, and fear–safety discrimination

Clark

Drummond

Hoyer

et al. 2019

British J Pharmacology

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Background and Purpose:Women are overrepresented in post-traumatic stress disorder (PTSD), a mental disorder characterised by ineffective inhibition of fear.The use of male animals dominates preclinical studies, which may contribute to a lack of understanding as to why this disparity exists. Thus, the current study explores sex differences in three mouse models of fear inhibition.Experimental Approach: All experiments tested male and female C57Bl/6J mice.Experiment 1 employed two fear conditioning protocols, in which tones were paired with footshocks of differing intensity (moderate or intense). Fear recall and extinction were tested subsequently. In Experiment 2, safety learning was investigated. Tones were explicitly unpaired with footshocks during safety conditioning. Recall of safety learning was tested 24 hr later. Experiment 3 assessed a model of fear-safety discrimination.Cued stimuli were paired or never paired with footshocks during fear and safety conditioning, respectively. Discrimination between stimuli was assessed 24 hr later.Key Results: In fear extinction, males, compared to females, responded with greater fear in sessions most proximal to conditioning but subsequently showed a more rapid fear extinction over time. Sex differences were not observed during safety learning. During fear-safety discrimination, both males and females discriminated between stimuli; however, males revealed a greater level of freezing to stimuli. Conclusion and Implications:The current study provides evidence that sex differences influence fear but not safety-based behaviour in C57Bl/6J mice. These findings indicate that processing of fear, but not safety, may play a greater role in sex differences observed for PTSD.

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Sex differences in discriminating between cues predicting threat and safety

Cited by 69 publications

References 49 publications

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

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

Sex differences in reward- and punishment-guided actions

Sex differences in mouse models of fear inhibition: Fear extinction, safety learning, and fear–safety discrimination

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