Many women usually say the same thing during pregnancy: they walk into a room and forget why, misplace their keys or struggle to follow a conversation. This phenomenon, often called ‘pregnancy brain’ or ‘momnesia,’ has long lacked a clear biological explanation.
Now, a new study by researchers at Baylor College of Medicine and collaborating institutions and published in Science Bulletin, identifies a specific brain circuit in an animal model that becomes disrupted under the sustained high oestrogen levels present during pregnancy. The findings offer the first biological explanation of how exposure to high-level circulating oestrogen can temporarily impair memory.
A novel brain circuit links high oestrogen levels with memory problems
“We worked with mouse models designed to mimic the sustained, high blood-oestrogen levels of pregnancy. These models showed that elevated oestrogen caused reversible memory impairment without affecting mood or motivation, suggesting a specific cognitive effect rather than a general change in well-being,” said senior author Dr Zheng Sun, associate professor of medicine – endocrinology, diabetes and metabolism and of molecular and cellular biology at Baylor.
Digging into the underlying biology, the team found that oestrogen receptor alpha, the protein that transmits oestrogen’s signals into cells, is the dominant oestrogen receptor in the brain region called the lateral hypothalamus. Furthermore, this region has abundant GABAergic neurons – brain cells that normally send calming, inhibitory signals to other parts of the brain. Using single-nucleus RNA sequencing, the researchers discovered that high oestrogen levels suppress signaling in these neurons, leading them to fire more frequently. “When we genetically removed oestrogen receptors from these hypothalamic neurons, both oestrogen-induced and pregnancy-induced memory problems in mice were reversed,” said Sun, a member of Baylor’s Dan L Duncan Comprehensive Cancer Center.
The team also found that these overactive hypothalamic neurons project directly into a region of the hippocampus that is a hub for memory formation. Using chemogenetics, a technique that allows researchers to turn specific neurons on or off, the team showed that silencing this hypothalamus-to-hippocampus pathway protected mice from estrogen-induced memory problems, whereas artificially activating the same pathway was sufficient to impair memory on its own, even without elevated estrogen.
Reconciling mixed evidence
Oestrogen’s relationship with memory has puzzled researchers for decades. For instance, hormone replacement therapy after menopause has been linked to cognitive benefits in some studies, while high oestrogen during pregnancy or with oral contraceptive use has been linked to memory complaints in others. The new findings suggest a possible explanation – it may not simply be a matter of ‘more oestrogen is better’ or ‘worse,’ but rather where in the brain that oestrogen acts, and at what levels.
“Low-level, cyclical oestrogen exposure appears to support cognitive function, which is part of why hormone therapy can help postmenopausal women,” said senior author Dr Yanlin He, associate professor at Pennington Biomedical Research Center. “But sustained, high-level oestrogen exposure seems to engage a different pathway altogether, one centred in the hypothalamus rather than the hippocampus itself. That distinction may help reconcile a lot of conflicting data in the field.”
Confirming the link in pregnant women
To determine whether these findings translate to humans, the researchers assessed memory performance in women across different stages of pregnancy. They found task-specific memory impairments that emerged during late pregnancy, and that correlated with circulating oestrogen levels, even after accounting for other factors that might influence cognition. This human data supports the idea that the hormone-driven circuit identified in mice may underlie the memory changes many pregnant women experience.
“Momnesia is real, it has a defined biological basis and is temporary,” said senior author Dr Xianghua Zhuang, professor at the Second Qilu Hospital of Shandong University. “We hope this work helps validate what many women have described anecdotally for years, and gives researchers a concrete target for future study.”
“The memory changes observed in both mice and women were temporary and task-specific, not a sign of broader cognitive decline,” said senior author Dr Xinguo Hou, professor at the Qilu Hospital of Shandong University. “Nonetheless, understanding the underlying circuit could eventually inform how clinicians counsel patients about the cognitive side effects of pregnancy or hormonal contraceptives, and could open avenues for therapies targeting this specific pathway without disrupting oestrogen’s broader, beneficial roles in the body.”
Source: Baylor College of Medicine, EurekAlert!
