A Dynamic Memory Systems Framework for Sex Differences in Fear Memory

Tronson, Natalie C.; Keiser, Ashley A.

doi:10.1016/j.tins.2019.07.009

Cited by 26 publications

(16 citation statements)

References 113 publications

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“…Recently, there has been growing interest in understanding sex differences in memory networks critical for fear learning (Tronson and Keiser, 2019). Important sex differences may exist throughout the brain, including at the level of neural circuits.…”

Section: Discussionmentioning

confidence: 99%

Age-Related Memory Impairment and Sex-Specific Alterations in Phosphorylation of the Rpt6 Proteasome Subunit and Polyubiquitination in the Basolateral Amygdala and Medial Prefrontal Cortex

Dulka

Trask

Helmstetter

2021

Front. Aging Neurosci.

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Aging is marked by an accumulation of damaged and modified brain proteins, and the ubiquitin-proteasome system (UPS) is important for cellular protein degradation. Recent work has established a critical role for the UPS in memory and synaptic plasticity, but the role of the UPS in age-related cognitive decline remains poorly understood. We trained young, middle-aged, and aged male and female rats using trace fear conditioning (TFC) to investigate the effects of age and sex on memory. We then measured markers of UPS-related protein degradation (phosphorylation of the Rpt6 proteasome regulatory subunit and K48-linked polyubiquitination) using western blots. We found that aged males, but not aged females, showed behavioral deficits at memory retrieval. Aged males also displayed reduced phosphorylation of the Rpt6 proteasome subunit and accumulation of K48 in the basolateral amygdala, while aged females displayed a similar pattern in the medial prefrontal cortex. These findings suggest that markers of UPS function are differentially affected by age and sex in a brain region-dependent manner. Together these results provide an important step toward understanding the UPS and circuit-level differences in aging males and females.

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Section: Discussionmentioning

confidence: 99%

Age-Related Memory Impairment and Sex-Specific Alterations in Phosphorylation of the Rpt6 Proteasome Subunit and Polyubiquitination in the Basolateral Amygdala and Medial Prefrontal Cortex

Dulka

Trask

Helmstetter

2021

Front. Aging Neurosci.

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“…Other examples of sex-specific mechanisms in behavioral regulation have been reported. For example, knockout of glutamate receptor 1 has sex-specific effects on fear memory despite producing similar effects on spatial memory, and epigenetic editing of Cdk5 selectively regulates fear memory in females and not in males 17,63 . Similar effects were recently reported for stress-mediated adaptations to pain, whereby knocking out the nociception/ orphanin FQ receptor (NOP) is protective against PTSD-potentiated pain sensitivity in males without having an effect in females 16 .…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, sex differences have been described for the cellular and molecular mechanisms of fear memory, stress, and pain responses. For fear circuitry, differences exist in synaptic function, circuit activity, and in the size and volume of hippocampus and amygdala subregions, even when memory performance is similar (reviewed in 17,18 ). Similarly, acute stress exposure results in widely distinct transcriptional responses in males and females 19 and stress exposure may sensitize pain responses through sex-specific mechanisms.…”

mentioning

confidence: 99%

Sex-specific effects of the histone variant H2A.Z on fear memory, stress-enhanced fear learning and hypersensitivity to pain

Ramzan

Creighton

Hall

et al. 2020

Sci Rep

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Emerging evidence suggests that histone variants are novel epigenetic regulators of memory, whereby histone H2A.Z suppresses fear memory. However, it is not clear if altered fear memory can also modify risk for PTSD, and whether these effects differ in males and females. Using conditionalinducible H2A.Z knockout (cKO) mice, we showed that H2A.Z binding is higher in females and that H2A.Z cKO enhanced fear memory only in males. However, H2A.Z cKO improved memory on the non-aversive object-in-place task in both sexes, suggesting that H2A.Z suppresses non-stressful memory irrespective of sex. Given that risk for fear-related disorders, such as PTSD, is biased toward females, we examined whether H2A.Z cKO also has sex-specific effects on fear sensitization in the stress-enhanced fear learning (SEFL) model of PTSD, as well as associated changes in pain sensitivity. We found that H2A.Z cKO reduced stress-induced sensitization of fear learning and pain responses preferentially in female mice, indicating that the effects of H2A.Z depend on sex and the type of task, and are influenced by history of stress. These data suggest that H2A.Z may be a sex-specific epigenetic risk factor for PTSD susceptibility, with implications for developing sex-specific therapeutic interventions. The capacity to remember fear-related cues is an important survival-promoting adaptation, but it can become maladaptive in some psychiatric conditions, such as post-traumatic stress disorder (PTSD). PTSD develops in response to a traumatic experience and is characterised by intrusive memories of the trauma and sensitization to fear, which presents as enhanced formation of new memories for relatively mild fearful stimuli 1-7. PTSD disproportionately affects women, who have twice the risk of developing the disorder 8 , and who are more prone to developing new fear memories compared to men with PTSD 9-11. In rodents, fear sensitization is modeled with stress-enhanced fear learning (SEFL), a paradigm in which exposure to a strong stressor (used to model traumatic experience) results in strengthened acquisition of fear memory compared to mice without prior stress exposure 10. This sensitization effect is observable within 24 h after stress, is long lasting, and is associated with a range of PTSD-like symptoms, including increased anxiety and impaired fear extinction 10. Some evidence suggests that PTSD may also sensitize patients to various forms of painful stimuli. Rates of chronic pain are higher among patients with PTSD compared to the general population, pain onset begins after PTSD symptoms emerge, and intensity of pain positively correlates with the severity of PTSD 12. Although sex differences in pain sensitivity in PTSD patients have not been widely studied, sex differences in pain sensitivity in the general population are widely reported, with women exhibiting higher prevalence of chronic pain and lower pain thresholds compared to men 13-15. One recent study in rodents showed that exposure to a single prolonged

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“…Interestingly, a female-only effect of probiotics was observed in the cue associated fear conditioning, where probiotic-treated females exhibited significantly less freezing time after a fear-associated tone than the control females. Overall, these results may indicate that probiotics modulated anxiolytic behaviors that tend to be higher in females [31,32].…”

Section: Plos Onementioning

confidence: 74%

Prenatal exposure to the probiotic Lactococcus lactis decreases anxiety-like behavior and modulates cortical cytoarchitecture in a sex specific manner.

et al. 2020

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Development of the cerebral cortex may be influenced by the composition of the maternal gut microbiota. To test this possibility, we administered probiotic Lactococcus lactis in drinking water to mouse dams from day 10.5 of gestation until pups reached postnatal day 1 (P1). Pups were assessed in a battery of behavioral tests starting at 10 weeks old. We found that females, but not males, exposed to probiotic during prenatal development spent more time in the center of the open field and displayed decreased freezing time in cue associated learning, compared to controls. Furthermore, we found that probiotic exposure changed the density of cortical neurons and increased the density of blood vessels in the cortical plate of P1 pups. Sex-specific differences were observed in the number of mitotic neural progenitor cells, which were increased in probiotic exposed female pups. In addition, we found that probiotic treatment in the latter half of pregnancy significantly increased plasma oxytocin levels in mouse dams, but not in the offspring. These results suggest that exposure of naïve, unstressed dams to probiotic may exert sex-specific long-term effects on cortical development and anxiety related behavior in the offspring.

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A Dynamic Memory Systems Framework for Sex Differences in Fear Memory

Cited by 26 publications

References 113 publications

Age-Related Memory Impairment and Sex-Specific Alterations in Phosphorylation of the Rpt6 Proteasome Subunit and Polyubiquitination in the Basolateral Amygdala and Medial Prefrontal Cortex

Age-Related Memory Impairment and Sex-Specific Alterations in Phosphorylation of the Rpt6 Proteasome Subunit and Polyubiquitination in the Basolateral Amygdala and Medial Prefrontal Cortex

Sex-specific effects of the histone variant H2A.Z on fear memory, stress-enhanced fear learning and hypersensitivity to pain

Prenatal exposure to the probiotic Lactococcus lactis decreases anxiety-like behavior and modulates cortical cytoarchitecture in a sex specific manner.

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