Unexpected mechanisms of sex-specific memory vulnerabilities to acute traumatic stress

Background

Clinical evidence points out that there are various differences between male and female patients suffering from post-traumatic stress disorder (PTSD), a group of mental symptoms caused by traumatic events that affect daily functioning. For example, there is a difference in the prevalence and types of symptoms experienced including nightmares, amnesia, re-experiencing and memory disturbances relating to the traumatic event. Estrogen is repeatedly mentioned as the mediator in relevant brain regions, especially in the hippocampus¹. However, reports on the influence of hippocampal estrogen levels on memory are contradictory.

In their latest manuscript, Hokenson and colleagues reveal the complicated mechanism explaining how different levels of estrogen can function in opposite ways. Specifically, two types of estrogen receptors, ERα and ERβ, in the hippocampus are shown to underly the different outcomes observed between males and females after acute traumatic stress.

Key findings

In this study, male, proestrous female and estrus female mice were included, respectively representing a group that has high estrogen levels in the male hippocampus, high estrogen levels in the female hippocampus, and low estrogen in the female hippocampus. Hokenson and colleagues tested spatial and temporal order memory after an acute traumatic treatment in these different groups. Furthermore, they identified the role of ERα and ERβ receptors in male and female mice and analyzed chromatin states as well as gene expression. Their key findings show that:

1. Acute traumatic stress causes enhanced traumatic memory and temporal and spatial memory disturbances in mice.
2. High levels of estrogen in the hippocampus – either in male or female mice – failed to protect against memory disturbances and to alleviate traumatic memory
3. Hippocampal ERα receptors in male and ERβ in female mice mediate estrogenic effects after trauma and this is accompanied by altered chromatin states and gene expression profiles compared to females with low estrogen levels.

Importance

Hokenson and colleagues used a remarkable behavioral experiment to evaluate the post-traumatic performance of mice. In addition, they managed to uncover the different roles of the two typical estrogen receptors in male and female mice.Also, a discussion on the role of the G-protein coupled estrogen receptor was added. Overall, Hokenson and colleagues provide important insights into the interplay between traumatic memory, estrogen levels in the hippocampus and sex.

Questions for the authors

1. The design of the acute traumatic stress-cue memory task is quite delicate – my question would be whether different scents could possibly cause unexpected effects? For example, compared to water, mice sniff and stay longer with almond extract odor², and products rich in peppermint oil are used as mice repellents. Can these have an additional impact on fear cues you think?
2. Two kinds of ER antagonists mentioned in the manuscript, MPP and PHTPP, have been shown to have memory-enhancing effects in mice without an ovary³. Does this have any implications for the memory experiments tested in the presence of estrogen?
3. As illustrated in manuscript, ERβ KO female mice show a reversed trend in memory test compared to ERα KO mice. Progesterone levels also change with estrogen in mice, reaching the peak in proestrous and decreasing in estrus⁴. What are your thoughts on the effect of progesterone, and could it explain the differences observed between ERαβ KO and ERβ KO female mice?

Reference

1. Borrow AP, Handa RJ. Estrogen Receptors Modulation of Anxiety-Like Behavior. Vitam Horm. 2017;103:27-52. doi: 10.1016/bs.vh.2016.08.004. Epub 2016 Oct 13. PMID: 28061972; PMCID: PMC5815294.
2. Islam S, Ueda M, Nishida E, Wang MX, Osawa M, Lee D, Itoh M, Nakagawa K, Tana, Nakagawa T. Odor preference and olfactory memory are impaired in Olfaxin-deficient mice. Brain Res. 2018 Jun 1;1688:81-90. doi: 10.1016/j.brainres.2018.03.025. Epub 2018 Mar 20. PMID: 29571668.
3. Kim J, Frick KM. Distinct effects of estrogen receptor antagonism on object recognition and spatial memory consolidation in ovariectomized mice. Psychoneuroendocrinology. 2017 Nov;85:110-114. doi: 10.1016/j.psyneuen.2017.08.013. Epub 2017 Aug 14. PMID: 28846921.
4. Pestana JE, Graham BM. The impact of estrous cycle on anxiety-like behaviour during unlearned fear tests in female rats and mice: A systematic review and meta-analysis. Neurosci Biobehav Rev. 2024 Sep;164:105789. doi: 10.1016/j.neubiorev.2024.105789. Epub 2024 Jul 14. PMID: 39002829.

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