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 estrogen levels present during pregnancy. The findings offer the first biological explanation of how exposure to high-level circulating estrogen can temporarily impair memory.
A novel brain circuit links high estrogen levels with memory problems
"We worked with mouse models designed to mimic the sustained, high blood-estrogen levels of pregnancy. This models showed that elevated estrogen 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 estrogen receptor alpha, the protein that transmits estrogen's signals into cells, is the dominant estrogen receptor in the brain reagion 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 estrogen levels suppress signaling in these neurons, leading them to fire more frequently. "When we genetically removed estrogen receptors from these hypothalamic neurons, both estrogen-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
Estrogen'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 estrogen 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 estrogen is better' or 'worse,' but rather where in the brain that estrogen acts, and at what levels.
"Low-level, cyclical estrogen 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 estrogen exposure seems to engage a different pathway altogether, one centered 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 estrogen 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 estrogen's broader, beneficial roles in the body."
Other contributors to this work include Xin Li, Nan Zang, Qianru Zhao, Yuxiang Sun, Udhaya Kumar Siva Kumar, Mengyu Hu, Wenjun Zhou, Yanyan Qi, Hu Chen, Longqing Xia, Jun Qin, Lei Sun, Chaitra Rai, Chao Cheng, Zhandong Liu, Li Chen, Yong Xu, Zhaoyong Hu and Hongjie Li. The authors are affiliated with Baylor College of Medicine, Shandong University or Louisiana State University.
The researchers were supported by the National Key Research and Development Program of China (grants 2023YFA1801100 and 2023YFA1801104), the Taishan Scholars Program of Shandong Province, NIH (grants AG069966 and ES034758), John S. Dunn Foundation, the Texas Medical Center Digestive Diseases Center (P30DK056338), the Gulf Coast Center for Precision Environmental Health (GC-CPEH, P30ES030285), a Frank Belton Kimmel and Sandra Kimmel Endowed Post-doctoral Fellowship and a training fellowship from the Gulf Coast Consortia on the Training in Precision Environmental Health Sciences Program (T32ES027801).
