Sex-Specific Regulation of Fear Memory by Targeted Epigenetic Editing of Cdk5

Sase, Ajinkya; Lombroso, Sonia I.; Santhumayor, Brandon A.; Wood, Rozalyn R.; Lim, Carissa J.; Neve, Rachael L.; Heller, Elizabeth A.

doi:10.1016/j.biopsych.2018.11.022

Cited by 30 publications

(23 citation statements)

References 96 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The trajectory of new neuron survival is dramatically different in males compared to females suggesting that the ability to influence neurogenesis within each sex may be due to the existing differences in timing and/or maturation of new neurons. Future studies should target mechanisms of these sex differences in adult neurogenesis as there are likely multiple factors involved that could profoundly affect these sex differences such as genetic (four core genotypes; 66), epigenetic (Sase et al, 2019) and mitochondrial functions (Biala et al, 2011) that differ between the sexes. These findings have profound implications for our understanding of adult neurogenesis in the DG, the use of therapeutics that modulate neurogenesis in the general population, and underscore the need to include both sexes in research on hippocampal neurogenesis.…”

Section: Resultsmentioning

confidence: 99%

Sex Differences in Maturation and Attrition of Adult Neurogenesis in the Hippocampus

Yagi

Splinter

Tai

et al. 2020

eNeuro

View full text Add to dashboard Cite

Sex differences exist in the regulation of adult neurogenesis in the hippocampus in response to hormones and cognitive training. Here we investigated the trajectory and maturation rate of adult-born neurons in the dentate gyrus (DG) of male and female rats. Sprague-Dawley rats were perfused two hours, 24 hours, one, two or three weeks after BrdU injection, a DNA synthesis marker that labels dividing progenitor cells and their progeny. Adult-born neurons (BrdU/NeuN-ir) matured faster in males compared to females. Males had a greater density of neural stem cells (Sox2-ir) in the dorsal, but not in the ventral, DG and had higher levels of cell proliferation (Ki67-ir) than non-proestrous females. However, males showed a greater reduction in neurogenesis between one and two weeks after mitosis, whereas females showed similar levels of neurogenesis throughout the weeks. The faster maturation and greater attrition of new neurons in males compared to females suggests greater potential for neurogenesis to respond to external stimuli in males and emphasizes the importance of studying sex on adult hippocampal neurogenesis. Significance Statement Previously studies examining the characteristics of adult-born neurons in the dentate gyrus have used almost exclusively male subjects. Researchers have assumed the two sexes have a similar maturation and attrition of new neurons in the dentate gyrus of adults. However, this study highlights notable sex differences in the attrition, maturation rate and potential of neurogenesis in the adult hippocampus that has significant implications for the field of neuroplasticity. These findings are important in understanding the relevance of sex differences in the regulation of neurogenesis in the hippocampus in response to stimuli or experience and may have consequences for our understanding of diseases that involve neurodegeneration of the hippocampus, particularly those that involve sex differences, such as Alzheimer's disease and depression.

show abstract

Section: Resultsmentioning

confidence: 99%

Sex Differences in Maturation and Attrition of Adult Neurogenesis in the Hippocampus

Yagi

Splinter

Tai

et al. 2020

eNeuro

View full text Add to dashboard Cite

show abstract

“…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%

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

View full text Add to dashboard Cite

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

show abstract

“…Such tools allow a direct analysis of the role of the epigenome in experience-dependent changes in gene expression and its consequences for behavior. For example, Sase et al (120) used epigenome editing (targeted histone acetylation) to examine how regulation of Cdk5 gene expression functioned in sex-specific fear memory recall following exposure to a foot shock paradigm in mice. The authors show that targeted histone acetylation increases Cdk5 expression in females to levels comparable to males, and abolishes the sex-specific differences observed in fear memory observed between untreated female and male mice (120).…”

Section: Advances In Molecular Profilingmentioning

confidence: 99%

“…For example, Sase et al (120) used epigenome editing (targeted histone acetylation) to examine how regulation of Cdk5 gene expression functioned in sex-specific fear memory recall following exposure to a foot shock paradigm in mice. The authors show that targeted histone acetylation increases Cdk5 expression in females to levels comparable to males, and abolishes the sex-specific differences observed in fear memory observed between untreated female and male mice (120). In an elegant example, Liu et al (121) used epigenetic editing, targeting DNA demethylation of the FMR gene in human neurons derived from fragile X syndrome patients; this reactivated the silenced FMR gene, normalizing neuronal activity within these neurons to levels comparable to those from healthy subjects.…”

Section: Advances In Molecular Profilingmentioning

confidence: 99%

Biological embedding of experience: A primer on epigenetics

Aristizabal

Anreiter

Halldorsdottir

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

170

102

View full text Add to dashboard Cite

Biological embedding occurs when life experience alters biological processes to affect later life health and well-being. Although extensive correlative data exist supporting the notion that epigenetic mechanisms such as DNA methylation underlie biological embedding, causal data are lacking. We describe specific epigenetic mechanisms and their potential roles in the biological embedding of experience. We also consider the nuanced relationships between the genome, the epigenome, and gene expression. Our ability to connect biological embedding to the epigenetic landscape in its complexity is challenging and complicated by the influence of multiple factors. These include cell type, age, the timing of experience, sex, and DNA sequence. Recent advances in molecular profiling and epigenome editing, combined with the use of comparative animal and human longitudinal studies, should enable this field to transition from correlative to causal analyses.

show abstract

Sex-Specific Regulation of Fear Memory by Targeted Epigenetic Editing of Cdk5

Cited by 30 publications

References 96 publications

Sex Differences in Maturation and Attrition of Adult Neurogenesis in the Hippocampus

Sex Differences in Maturation and Attrition of Adult Neurogenesis in the Hippocampus

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

Biological embedding of experience: A primer on epigenetics

Contact Info

Product

Resources

About