Estrogens and Memory Loss in Women
女性雌性激素与记忆减退
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2019-08-12 11:15
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As you read this article, your brain has begun a series of complicated chemical steps in order to form a memory. How long you keep this memory may well depend on whether you are a man or a woman.  

当你在读这篇文章时,大脑为了形成记忆,开始了一系列复杂的化学过程。你能保持多久的记忆很有可能取决于你的性别。

Some scientists think that the reason for this difference may be estrogens. Women are disproportionately affected by Alzheimer’s disease, dementia and memory loss. In fact, almost two thirds of Americans living with Alzheimer’s are women. While researchers across the globe are still working to uncover the basic mechanisms of learning and memory, it is now known that estrogens help to regulate memory formation in both males and females. From a cultural and societal standpoint, when people think of estrogen they probably imagine pregnancy, periods and woman-fueled rage. Most people probably don’t consider memory; but maybe it’s time we all start thinking about estrogens’ role in memory a little more.  

部分科学家认为对于这种差别的解释可能是雌激素。女性更容易患阿尔兹海默症、痴呆症和记忆减退,事实上,美国二分之三的阿尔兹海默症患者为女性。全球研究者一直在调查学习与记忆的基本机制,目前已知的是雌激素有助于调节男性和女性的记忆形成。站在文化与社会的角度上来说,当人们一提到雌激素就会想到怀孕、月经以及更年期,许多人可能想不到记忆。但是时候我们要开始考虑雌激素在记忆中的作用了。

Karyn Frick, a professor of psychology at the University of Wisconsin-Milwaukee, studies the connection between estrogens and memory. She and her students are among the scientists working to uncover the basic cellular and molecular mechanisms underlying memory formation. Part of Frick’s research focuses on how estrogens enhance memory, particularly through their action in the hippocampus.

Karyn Frick是一位研究雌激素与记忆的威斯康星大学的心理学教授,她与她的学生都是研究记忆形成的细胞分子学基本机制的科学家,Frick部分实验主要是通过雌激素对海马体的作用,来研究其如何促进记忆。

The hippocampus is a small, curved region in the brain that plays an important role in the formation of memories. But it wasn’t always known for this role. In fact, so little was known about the brain and memory that, when a young man named Henry Molaison laid down on the surgical table in 1953 in a quest to cure his epilepsy, a skilled surgeon named William Beecher Scoville removed several structures from his brain, including a large portion of his hippocampus.

海马体是大脑中较小、呈弯曲状的一块区域,对于记忆的形成非常重要,但是它不是因为这个功能而闻名的。事实上,我们对于大脑和记忆所知甚少,1953年,一个名叫Henry Molasison的 年轻男子躺在手术台上,想治愈他的癫痫,一名叫William Beecher Scoville的老练医生从颅部摘除了部分结构,包括大部分海马体。

Molaison, although almost entirely cured of his seizures, immediately developed severe amnesia that persisted for the rest of his life; in short, he was unable to form new memories. However, the work surrounding Molaison and his memory impairments set the stage for decades of research into how the hippocampus is able to transform a short-term memory into a long-lasting and persistent one.

尽管Molaison癫痫几乎痊愈了,但是他立马患上了失忆症,并持续性的影响他往后的生活。总之,他无法形成新的记忆。然而,围绕着Molaison和他的记忆损伤便开启了数十年的研究,关于海马体如何将短期记忆转化为长期记忆或是永久记忆 。

But what does this have to do with estrogens? Estrogens, particularly the most potent estrogen, called estradiol, latch onto structures called estrogen receptors, kind of like a key fitting into a lock. These receptors are abundant in the brain regions that support memory formation, particularly in the hippocampus. Now,brain cells have branch-like extensions (dendrites) that are necessary to communicate with other brain cells. On these dendrites are short protrusions called spines.

但是这与雌激素有什么关系呢?雌激素中最有效的是雌二醇,这是一种固定在雌激素受体上的结构,类似于开锁的钥匙。这些受体大量分布在大脑内促进记忆的形成,特别是海马体区域。目前脑细胞有分支状的延伸(树突),与其他脑细胞交流中占重要地位。这些树突上有短突起,称为棘突。

These spines are where the communication between brain cells really happens.

这些棘突是脑细胞交流的真正区域。

Importantly, these spines change with learning experiences. They grow. They shrink. They change shape. And research shows that estradiol can even increase the number of spines within the hippocampus. Thanks to researchers like Frick, we are beginning to understand the basic molecular mechanisms by which this process happens and how it relates to memory loss in aging women.

重要的是,这些棘突随着学习经历的改变而变化。它们延伸或短缩,形状在也变化。有研究表明雌二醇可以增加海马体中棘突的数量。幸好有像Frick一样的科学家我们才开始了解这一过程的分子学机制以及与老年女性记忆减退的关系。

Frick has been studying rodents for nearly 30 years. Believe it or not, most of what we now know about memory comes from research in mice and rats. Early in her career, she characterized both male and female lab mice in regard to their memory function, as there were shockingly little data on memory in female mice at that time. She tested young, middle-aged and old male and female mice on a number of tasks, including a water maze that forces mice to use their hippocampus. She found that all the young mice performed well on these tasks, and all of the old mice were terrible, but it was in the middle-aged group she observed a striking effect.

Frick研究啮齿动物已经近30年了。不管你信不信,我们对记忆的认知大部分都是来自于大鼠实验。在她职业生涯早期,她对雄性和雌性实验小鼠的记忆功能进行了鉴定,因为当时雌性老鼠的记忆数据少得惊人。她对年轻、中年以及老年的小数都进行了大量的研究,包括一个迫使老鼠使用海马体的水迷宫。她发现所有年轻小鼠都完成的很好,所有老年小鼠都表现的都比较糟糕,然而中年小鼠却产生了惊人的效果。

While the middle-aged males performed like young mice, the middle-aged females performed like the old mice in the water maze. Frick and her colleagues attributed this effect to “estropause,” which, while not identical to menopause, is similar in many respects. Estropause refers to when the rodent estrous cycle (which is kind of like a woman’s menstrual cycle) starts to become irregular and essentially falls apart in middle-aged female rodents.

中年男性就像年轻小鼠,而中年女性就像老年小鼠。Frick跟同事将这种效应归因于“绝经期”,虽然它与绝经期不完全相同,但在许多方面是相似的。绝经期在啮齿动物的动情周期(有点像女性的月经周期)开始变得不规则,并在中年雌性啮齿动物中基本消失。

“These [middle-aged] females are going through a premature memory decline. The males got there eventually, but it happened earlier in females and it seemed to be associated with a loss of [estrous] cycling,” she says. “Over the last decade, or more, we have focused on trying to figure out exactly how, on a molecular level, estradiol enhances memory.”

“那些(中年)女性正在经过早的记忆减退。虽然男性最终也会经历这一阶段,但是女性经历的更早,并且似乎与动情周期的减退有关。”她说道“数十年以来,甚至更久,我们一直致力于搞清楚雌二醇在分子水平到底怎样增强记忆的。”

Frick does this by using two tests called the “object recognition” and “object placement” tasks. Essentially, mice love new things, and they can recognize when a new object has been placed in their environment, as well as if a familiar object has been moved. Frick and her students found that when they infuse estradiol into the hippocampus immediately after the mice first encounter the objects, the mice better remember the identity and location of objects later. This allows them to use these tests as tools for figuring out the molecular mechanisms that create memory enhancements.

Frick通过使用“物体辨认”和“物品放置”两个测试任务来做到这一点。本质上,老鼠喜欢新东西,他们会记住那些摆放在他们区域的新东西和被移动了的熟悉的物品。Frick和她的学生发现当大鼠第一次遇见指定物品时,他们便向其海马体注射雌二醇,大鼠之后就能更好的辨认并且记住物品的位置。他们通过这些测试作为工具来弄清楚创造记忆增强的分子机制。

Recently they have started looking at another brain region, the prefrontal cortex, in addition to the hippocampus. The prefrontal cortex is the front-most part of your brain that is important for planning, complex thinking, and personality. Like the hippocampus, estrogen receptors are found in great number here. Importantly, Frick and her students have shown that infusions of estradiol into the hippocampus affect the dendritic spines in the prefrontal cortex.

最近他们开始研究除了海马体的大脑其他区域,前额叶皮质。前额叶皮质是大脑前部的主要部分,对于计划、深度思考以及人格有重要作用。与海马体相似,此区域的雌激素受体也很多。重要的是,Frick与她的学生发现海马体注射雌二醇会影响到前额叶皮质的树突棘。

“Clearly these two brain regions were communicating together in some meaningful way, but we didn’t know whether those two brain regions both had to be active simultaneously in order for the [hippocampus] infusion to enhance memory. All our interpretations of the hippocampal infusions [were] that it was a hippocampus effect, but maybe not, maybe it’s a circuit effect,” says Frick. The idea of circuits, or the connections between two or more brain regions, has been of great interest to neuroscientists in recent years, particularly among memory researchers. Understanding how infusions of estradiol are helping memory at the level of the circuit is an important next step in the basic research that drives science forward. Even Frick says, “What I’m excited about is the concept of trying to figure out what’s going on in the circuit.”

“大脑的这两个区域很明显正在以某种有意义的方式相互交流,但是我们不知道的是这两个大脑区域是否必须同时兴奋才能使(海马体)输注增强记忆。我们对海马体注射的所有解释为海马体效应,或许不是,也许只是电路影响。”Frick说,“最近几年神经科学家,特别是记忆研究者,对电路的概念或大脑两个或多个区域之间的联系非常感兴趣。”

But she also has another reason to be excited these days. 

但是这些天还有其他让她兴奋地事情。

A team of Wisconsin researchers, including Frick, William Donaldson (a synthetic chemist from Marquette University) and Daniel Sem (a pharmacologist from Concordia University) are working together to create a drug that sticks to a special kind of estrogen receptor for the treatment of menopausal memory dysfunction. By designing the drug in this way, the researchers can avoid the negative consequences of estrogen replacement therapy, such as increased risk for cardiovascular diseases and breast cancer. Last summer, this group even formed a company called Estrigenix Therapeutics to facilitate the research and development of this drug.

包括Frick、William Donaldson(马凯特大学的合成化学家)和Daniel Sem(肯考迪亚大学的药理学家)在内的威斯康星州研究小组正在合作开发一种药物,这是一种治疗绝经后记忆功能障碍的特殊雌激素受体。通过研究这种药物,研究人员可以避免雌激素替代疗法的副作用,如心血管病和乳腺癌的风险增加。去年夏天,这个团队组建了一个叫Estrigenix疗法的公司来资助此研究发明这类药物。

Around that same time, as part of a four week long intensive program, they went out and talked to people, mostly menopausal women, physicians, and people from the pharmaceutical industry, and through that process they discovered that most patients and physicians aren’t really concerned about memory dysfunction or their potential increased risk of Alzheimer’s disease.

同时,作为为期四周的加强实验的一部分,他们告知了人们,多数为绝经后妇女、医生和那些在制药厂工作的人们,经过实验他们发现多数患者和医生对于记忆障碍和增加了阿尔兹海默症潜在风险并不感兴趣。

“Many of them weren’t even aware they were at an increased risk of Alzheimer’s disease. What they were most concerned with were hot flashes, depression and anxiety,” says Frick. So how can we make people, particularly women, more aware of the risk of memory loss as result of menopause?

Frick说道:“很多人都没有意识到他们有阿尔兹海默症的潜在风险,潮热,抑郁和焦虑才是他们最关心的。”我们应该怎么样让人们意识到记忆减退的概率与绝经有关呢?尤其是女人。

“People don’t typically like to talk about menopause. It’s one of these things that women don’t like to admit that they’re going through,” says Frick. She goes on to explain that perhaps if women talk more about menopause and the symptoms of menopause, it can help make this period of a woman’s life more socially acceptable and something we can openly talk about. “Female gender, aside from age, is the greatest risk factor for Alzheimer’s disease, and most women don’t realize that,” says Frick.

Frick说,“人们一般不喜欢聊起绝经,这是一个女性正在经历但又不想承认的一件事。”她解释道可能当女性说道绝经或是绝经前征兆时,便让处在这个时期的妇女更具社交性并且成为我们公开谈论的事情。“除年龄外,女性是阿尔茨海默氏病的最大危险因素,大多数女性没有意识到这一点。”Frick说道。

As the basic science moves forward, not every step will be huge. First, we need to change the conversation so that women are aware of the risk their very gender poses.

基础科学在进步,但并不是突飞猛进。首先,我们需要改变交流方式,使妇女意识到她们的性别因素也是一种风险。

The views expressed are those of the author(s) and are not necessarily those of Scientific American.

本文仅限作者的观点,不代表《科学美国人》的看法。

ABOUT THE AUTHOR(S)

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Brooke N. Dulka

Brooke N. Dulka

Brooke N. Dulka is a postdoctoral research associate at the University of Wisconsin-Milwaukee. She is interested in memory, stress, science communication, and science policy; follow her on Twitter @NeuroDulka.

Brooke N. Dulka是威斯康星大学密尔沃基分校的博士后研究助理,她对记忆、压力、科学交流和科学政策感兴趣,你可以在推特关注她。

@NeuroDulka.

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