Summary: A new study reports estrogen fluctuations can alter brain circuit activation in women with a variant of a specific gene.

Source: NIH/NIMH.

Fluctuations in estrogen can trigger atypical functioning in a key brain memory circuit in women with a common version of a gene, NIMH scientists have discovered. Brain scans revealed altered circuit activity linked to changes in the sex hormone in women with the gene variant while they performed a working memory task.

The findings may help to explain individual differences in menstrual cycle and reproductive-related mental disorders linked to fluctuations in the hormone. They may also shed light on mechanisms underlying sex-related differences in onset, severity, and course of mood and anxiety disorders and schizophrenia. The gene-by-hormone interaction’s effect on circuit function was found only with one of two versions of the gene that occurs in about a fourth of white women.

Drs. Karen Berman, Peter Schmidt, Shau-Ming Wei, and colleagues, of the NIMH Intramural Research Program, report on this first such demonstration in women April 18, 2017 in the journal Molecular Psychiatry.

Prior to the study, there was little evidence from research on the human brain that might account for individual differences in cognitive and behavioral effects of sex hormones. For example, why do some women develop postpartum depression and others do not – in response to the same hormone changes? Why do some women report that estrogen replacement improved their memory, whereas large studies of postmenopausal estrogen therapy show no overall improvement in memory performance?

Evidence from humans has also been lacking for the neural basis of stark sex differences in prevalence and course of mental disorders that are likely related to sex hormones. For example, why are there higher rates of mood disorders in females and higher rates of ADHD in males – or later onset of schizophrenia in females?

In seeking answers to these questions, the researchers focused on working memory, a well-researched brain function often disturbed in many of these disorders. It was known that working memory is mediated by a circuit from the brain’s executive hub, the prefrontal cortex, to its memory hub, the hippocampus. Notably, hippocampus activity is typically suppressed during working memory processing.

Following-up on a clue from experiments in mice, the NIMH team hypothesized that estrogen tweaks circuit function by interacting with a uniquely human version of the gene that codes for brain derived neurotrophic factor (BDNF), a pivotal chemical messenger operating in this circuit. To find out, the researchers experimentally manipulated estrogen levels in healthy women with one or the other version of the BDNF gene over a period of months. Researchers periodically scanned the women’s brain activity while they performed a working memory task to see any effects of the gene-hormone interaction on circuit function.

The researchers first scanned 39 women using PET (positron emission tomography) and later confirmed the results in 27 women using fMRI (functional magnetic resonance imaging). Both pegged atypical activity in the hippocampus to the interaction. Turning up the same findings using two types of neuroimaging strengthens the case for the accuracy of their observations, say the researchers. Such gene-hormone interactions affecting thinking and behavior are consistent with findings from animal studies and are suspect mechanisms conferring risk for mental illness, they add.

Source: Jules Asher – NIH/NIMH
Image Source: NeuroscienceNews.com image is credited to Shau-Ming Wei, Ph.D., NIMH Section on Integrative Neuroimaging.
Original Research: Abstract for “Brain-derived neurotrophic factor Val66Met genotype and ovarian steroids interactively modulate working memory-related hippocampal function in women: a multimodal neuroimaging study” by S-M Wei, E B Baller, P D Kohn, J S Kippenhan, B Kolachana, S J Soldin, D R Rubinow, P J Schmidt and K F Berman in Molecular Psychiatry. Published online April 18 2017 doi:10.1038/mp.2017.72

Abstract

Brain-derived neurotrophic factor Val66Met genotype and ovarian steroids interactively modulate working memory-related hippocampal function in women: a multimodal neuroimaging study

Preclinical evidence suggests that the actions of ovarian steroid hormones and brain-derived neurotrophic factor (BDNF) are highly convergent on brain function. Studies in humanized mice document an interaction between estrus cycle-related changes in estradiol secretion and BDNF Val66Met genotype on measures of hippocampal function and anxiety-like behavior. We believe our multimodal imaging data provide the first demonstration in women that the effects of the BDNF Val/Met polymorphism on hippocampal function are selectively modulated by estradiol.

In a 6-month pharmacological hormone manipulation protocol, healthy, regularly menstruating, asymptomatic women completed positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) scans while performing the n-back working memory task during three hormone conditions: ovarian suppression induced by the gonadotropin-releasing hormone agonist, leuprolide acetate; leuprolide plus estradiol; and leuprolide plus progesterone.

For each of the three hormone conditions, a discovery data set was obtained with oxygen-15 water regional cerebral blood flow PET in 39 healthy women genotyped for BDNF Val66Met, and a confirmatory data set was obtained with fMRI in 27 women. Our results, in close agreement across the two imaging platforms, demonstrate an ovarian hormone-by-BDNF interaction on working memory-related hippocampal function (PET: F2,37=9.11, P=0.00026 uncorrected, P=0.05, familywise error corrected with small volume correction; fMRI: F2,25=5.43, P=0.01, uncorrected) that reflects differential hippocampal recruitment in Met carriers but only in the presence of estradiol.

These findings have clinical relevance for understanding the neurobiological basis of individual differences in the cognitive and behavioral effects of ovarian steroids in women, and may provide a neurogenetic framework for understanding neuropsychiatric disorders related to reproductive hormones as well as illnesses with sex differences in disease expression and course.

“Brain-derived neurotrophic factor Val66Met genotype and ovarian steroids interactively modulate working memory-related hippocampal function in women: a multimodal neuroimaging study” by S-M Wei, E B Baller, P D Kohn, J S Kippenhan, B Kolachana, S J Soldin, D R Rubinow, P J Schmidt and K F Berman in Molecular Psychiatry. Published online April 18 2017 doi:10.1038/mp.2017.72