How does the estrous cycle affect gene expression in female rats?

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Florian Duclot is a Research Faculty in the lab of Mohamed Kabbaj in the department of Biomedical Sciences at Florida State University. His work focuses on understanding how individuals, from the same sex or not, differ in emotional and social behaviors, with applications to related disorders.

Mohamed Kabbaj是佛罗里达州立大学的生物医学科学和神经科学教授。他的研究旨在在精神疾病（包括抑郁症和药物滥用）的背景下，了解情感行为，社会行为和吸毒成瘾的个体差异和性别差异的神经生物学。

Can you explain what you set out to investigate and why?

Increasing evidence suggests that men and women differ in cognitive functions and emotional processing, resulting in clear sex differences in vulnerability to multiple neuropsychiatric or mood disorders.

同样重要的是要注意，在月经周期的不同阶段，女性的认知表现和情绪水平各不相同，这表明后者对这种性别差异的程度和性质产生了重大影响。

有趣的是，尽管基因表达变化的观念是充分记录了情绪和认知性别差异的基础，但我们仍然不知道卵巢周期对转录组的影响及其与性别差异的最终相互作用的全部程度。

In this study, we sought to characterize the changes in genes expression across the ovarian cycle and to determine whether these variations impact how females and males differ. To this end, we focused on examining gene expression in the medial prefrontal cortex (mPFC), which is a critical regulator of mood and cognition in male and female rats.

Female rats display an estrous cycle (the name given to the reproductive cycle of non-primate vertebrates) similar to the human menstrual cycle with phases of high and low levels of ovarian hormones (although shorter in rats, 4-5 days, than in humans, which is 28 days).

您报告说，女性在发情周期的不同阶段的大脑比男性和女性之间的差异更大。这是您期望的吗？

Since ovarian hormones and estrogen in particular are known to have widespread effects on gene expression, we expected substantial differences in gene expression between the two stages of the estrous cycles that we focused on.

Since ovarian hormones and estrogen in particular are known to have widespread effects on gene expression, we expected substantial differences in gene expression between the two stages of the estrous cycles that we focused on.

However, our study was the first to investigate these differences in naturally cycling female rats in which a multitude of additional factors (hormonal or not) are at play and were thus likely to interfere with estrogens’ genomic effects.

It was thus with great surprise that we observed such a large number of differences across the estrous cycle, which exceeds 10 to 14 times the amount of differences seen between males and females.

是什么导致女性大脑在发情周期的不同阶段之间的差异？

尽管这些差异可能是由于多种因素之间的复杂相互作用导致的，但卵巢激素作为主要候选者出现，以解释这些变化。确实，我们发现，在女性的不同阶段，大约41％的基因及其相关的生物学功能在女性之间差异表达，已知由雌激素或孕激素直接或间接地调节。因此，这意味着大多数基因在整个发情循环中都不是迄今为止卵巢激素的靶标。

In this context, it is important to note that we observed a variety of transcription factors among the genes varying across the estrous cycle. In particular, the immediate early gene early growth response 1 (Egr1) appeared as a critical candidate in explaining the estrous cycle-specific transcriptomic regulations and we were able to analyze its binding throughout the genome in the same conditions, thus confirming its involvement in controlling the genes varying across the estrous cycle.

What are the implications of your findings?

We first reveal that the mPFC undergoes a profound reorganization of its transcriptome across the estrous cycle, even in intact cycling females, and that the majority of genes between males and females were not the same in the two stages of the estrous cycle we analyzed.

此外，与男性相比，相关的潜在生物学途径在发情周期的两个阶段之间显示出相反的调节。换句话说，与男性相比，根据发情循环阶段，给定的生物学途径在女性中被上调或下调。

我们希望我们的工作将被证明对研究人员有用，以开发更适合女性特异性的实验设计。

This therefore reveals that the estrous cycle critically impacts the mPFC transcriptome, and demonstrates the need to control for the stage of the estrous cycle in research involving females, especially in the context of sex differences.

It is particularly important to note that dysregulations in the genes and biological pathways we found varying across the estrous cycle are recurring features reported upon cognitive decline or neuropsychiatric and mood-related disorders, thereby emphasizing the importance of accounting for the estrous cycle in any research using females.

In the context of an increasing consideration of females in neuroscience research encouraged by major funding agencies such as the National Institute of Mental Health (NIMH), we hope our work will prove useful to investigators for developing experimental designs better suited to females’ specificities.

需要进行什么进一步的研究？

由于这项工作的“先驱”性质，还有很多待研究。例如，尽管我们的分析广泛支持基因表达法规的关联，但我们仍然需要清楚地评估这些法规在多大程度上与情绪和认知表现的变化有关MPFC的控制。

因此，这将有助于洞悉男性和女性在压力方面的差异以及与压力有关的疾病。此外，确定在MPFC中发现的发情周期和性别差异之间的相互作用是否在对认知和情绪调节至关重要的其他大脑区域中观察到。