Sex differences in conditioned stimulus discrimination during context-dependent fear learning and its retrieval in humans: the role of biological sex, contraceptives and menstrual cycle phases

Lonsdorf, Tina B.; Haaker, Jan; Schümann, Dirk; Sommer, Tobias; Bayer, Janine; Brassen, Stefanie; Bunzeck, Nico; Gamer, Matthias; Kalisc, Raffael

doi:10.1503/jpn.140336

Cited by 52 publications

(39 citation statements)

References 48 publications

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“…Our findings are consistent with human studies where females show less discrimination between the fear and safety signals than males (Gamwell et al, 2015; Lonsdorf et al, 2015), which may reflect underlying mechanisms of increased prevalence for anxiety and stress-related disorders in women. For example, a deficiency in effective safety signal processing has been linked to Post-traumatic Stress Disorder (Jovanovic et al, 2009, 2010), panic disorder (Gorka et al, 2014), and anxiety (Lissek et al, 2005), all disorders with a higher incidence in women than men (Mclean et al, 2011).…”

Section: Discussionsupporting

confidence: 91%

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Sex differences in fear regulation and reward seeking behaviors in a fear-safety-reward discrimination task

Greiner

Norris

Müller

et al. 2018

Preprint

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Reward availability and the potential for danger or safety potently regulates emotion. Despite women being more likely than men to develop emotion dysregulation disorders, there are comparatively few studies investigating fear, safety and reward regulation in females. Here, we show that female Long Evans rats do not suppress conditioned freezing in the presence of a safety cue, nor do they extinguish their freezing response, whereas males do both. Females were also more reward responsive during the reward cue until the first footshock exposure, at which point there were no sex differences in reward seeking to the reward cue. Darting analyses indicate females might be able to regulate this behavior in response to the safety cue, suggesting they might be able to discriminate between fear and safety cues but do not demonstrate this with conditioned suppression of the freezing behavior. However, levels of darting in this study were too low to make any clear conclusions. In summary, females showed a significantly different behavioral profile than males in a task that tests the ability to discriminate among fear, safety and reward cues. This paradigm offers a great opportunity to test for mechanisms that are generating these behavioral sex differences in learned safety and reward seeking.

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Section: Discussionsupporting

confidence: 91%

“…Altogether, the data paints a consistent picture of females showing heightened fear responses to cues signaling safety, mimicking the clinical picture in women (Gamwell et al, 2015; Lonsdorf et al, 2015). The presentation of a safety signal not only decreases fear, but also stimulates opposing neuronal activity.…”

Section: Discussionsupporting

confidence: 62%

Sex differences in fear regulation and reward seeking behaviors in a fear-safety-reward discrimination task

Greiner

Norris

Müller

et al. 2018

Preprint

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“…Clear conclusions are hampered by complexities related to prior or concurrent stressors, social factors, choice of unconditioned responses, and whether sex differences are attributable to acquisition, retention, and/or extinction of the memory. In one study of conditioned fear using electric shock, for example, women gave higher subjective ratings of fear on day 2 of testing but lower skin conductance responses [46].…”

Section: Discussionmentioning

confidence: 99%

Male-Specific Conditioned Pain Hypersensitivity in Mice and Humans

et al. 2019

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Highlights d Re-exposure to a context associated with pain results in pain hypersensitivity d Conditioned pain sensitivity is only present in males via testosterone d The phenomenon can be demonstrated in both mice and humans d The phenomenon is dependent on stress and blocked by zeta inhibitory peptide (ZIP) SUMMARYPain memories are hypothesized to be critically involved in the transition of pain from an acute to a chronic state. To help elucidate the underlying neurobiological mechanisms of pain memory, we developed novel paradigms to study context-dependent pain hypersensitivity in mouse and human subjects, respectively. We find that both mice and people become hypersensitive to acute, thermal nociception when tested in an environment previously associated with an aversive tonic pain experience. This sensitization persisted for at least 24 hr and was only present in males of both species. In mice, context-dependent pain hypersensitivity was abolished by castrating male mice, pharmacological blockade of the hypothalamic-pituitary-adrenal axis, or intracerebral or intrathecal injections of zeta inhibitory peptide (ZIP) known to block atypical protein kinase C (including the protein kinase Mz isoform). In humans, men, but not women, self-reported higher levels of stress when tested in a room previously associated with tonic pain. These models provide a new, completely translatable means for studying the relationship between memory, pain, and stress.Detailed methods are provided in the online version of this paper and include the following:TABLE d CONTACT FOR REAGENT AND RESOURCE SHARING d EXPERIMENTAL MODEL AND SUBJECT DETAILS B Animal Subjects B Human Participants d METHOD DETAILS B Animal Experiments B Human Experiments d QUANTIFICATION AND STATISTICAL ANALYSIS SUPPLEMENTAL INFORMATION Supplemental Information includes one data file and five figures and can be found with this article online at https://doi.

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“…Furthermore, fear discrimination and safety signaling both depended on estrogen receptor signaling in females. Evidence indicates that sex differences in contextual fear discrimination also depend on estrogen (Lonsdorf et al, 2015, Lynch et al, 2013). A limitation of our study is that we did not account for variations in the estrous cycle phase of females, yet we still replicated our finding of fear generalization with extended training in a separate cohort of naturally cycling females.…”

Section: Discussionmentioning

confidence: 99%

“…Although a failure to discriminate between cues predicting threat and safety has been proposed as a biomarker of PTSD, little is known about sex differences in fear discrimination. Recent human and animal studies have demonstrated impaired contextual fear discrimination in females (Lonsdorf et al, 2015, Lynch et al, 2013, Reppucci et al, 2013). However, sex differences in fear discrimination involving discrete cues, and the role of altered safety signaling in mediating these differences, are poorly understood.…”

Section: Introductionmentioning

confidence: 99%