BDNF Val66Met Polymorphism and Gonadal Hormones Modulate Basal and Working Memory-Related Neural Functions in Humans

Wei, Shau-Ming NMN

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Year:: 2013
Contributor:: Wei, Shau-Ming NMN (creator); Berman, Karen (Director); Schmidt, Peter (Reader); Burwell, Rebecca (Reader); Smith, Gwenn (Reader); Brown University. Neuroscience (sponsor)
Genre:: theses
Subject:: BDNF; ovarian steroids; PET; rest; working memory; Estradiol; Progesterone; Short-term memory
Extent:: 13, 87 p.
DOI: https://doi.org/10.7301/Z0S46Q84

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Abstract:: Ovarian steroids have been shown to modulate cognitive functions in both animals and humans, but results are inconsistent. The variability of the findings suggests that the response to ovarian hormones may be modulated by a number of yet-to-be identified contextual factors. In this thesis, I demonstrate that brain derived neurotrophic factor (BDNF) and ovarian hormones interactively affect human brain function. <br/> In the absence of direct in vivo measures of BDNF in human brain, the functional BDNF Val66Met polymorphism offers a window on how BDNF influences human cognition. Using positron emission tomography (PET) to study healthy subjects genotyped for the BDNF Val66Met SNP, I found that, compared to Val homozygotes, Met carriers had higher resting regional cerebral blood flow (rCBF) in prefrontal and hippocampal/parahippocampal areas. Moreover, there were significant sex-by-genotype interactions in these regions: Val homozygotes had higher rCBF in females than males, whereas Met carriers showed the opposite relationship. Functional correlations of BA25, hippocampus, and parahippocampus with frontal and temporal networks were positive for Val homozygotes, but negative for Met carriers. In addition, sex-by-genotype analysis of functional connectivity revealed that genotype affected the direction of the interregional correlations differently in men than women. These results demonstrate that BDNF allelic variation and sex interactively affect basal prefrontal and hippocampal function as well as functional connectivity between these regions.<br/> Next, to determine whether the observed sex-by-genotype interaction is mediated by ovarian steroids, I used PET in concert with a six-month hormone manipulation protocol to investigate the interaction between BDNF polymorphism and ovarian steroids, estrogen and progesterone, on working memory-related hippocampal function in healthy women. I demonstrated a hormone-by-genotype interaction in working memory-related hippocampal function that reflected abnormal hippocampal recruitment in Met carriers but only in the presence of estradiol, suggesting a BDNF genotype-mediated sensitivity to ovarian steroids. Collectively, these data emphasize that interpreting the effects of genotype on brain function in women requires knowledge of the ovarian steroid hormone milieu, and that, conversely, it is crucial to consider BDNF genotype when investigating the effects of ovarian steroids.
Notes:: Thesis (Ph.D. -- Brown University (2013)

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Wei, Shau-Ming NMN, "BDNF Val66Met Polymorphism and Gonadal Hormones Modulate Basal and Working Memory-Related Neural Functions in Humans" (2013). Neuroscience Theses and Dissertations. Brown Digital Repository. Brown University Library. https://doi.org/10.7301/Z0S46Q84

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Neuroscience Theses and Dissertations

Theses and Dissertations for the Neuroscience department.
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