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 ValMet 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 ValMet, 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: F=9.11, P=0.00026 uncorrected, P=0.05, familywise error corrected with small volume correction; fMRI: F=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.

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Functional genetic variation in BDNF (brain-derived neurotrophic factor) is posited to impact neural activity in the hippocampus in a manner relevant to schizophrenic pathophysiology. To test this hypothesis, 47 medication-free patients with schizophrenia or schizoaffective disorder and 74 healthy control individuals underwent genotyping for the BDNF Val66Met single-nucleotide polymorphism and [15O]H2O positron emission tomography during rest, sensorimotor (0 bk) and working memory (2 bk) conditions. When compared with their genotype-matched control cohort, only patients carrying the BDNF Met variant showed diminished mean whole-hippocampus perfusion, regardless of scanning condition (bar graphs; Bonferroni-corrected post-hoc tests: P ¼ 0.0004 (rest), P ¼ 0.004 (0 bk), P ¼ 0.02 (2 bk)). Mean voxel-wise resting perfusion maps rendered to hippocampal surfaces are likewise shown for each group with warmer colors (color bar), indicating greater normalized regional cerebral blood flow values. This research was supported by the