RT Journal Article SR Electronic T1 Brain-Derived Neurotrophic Factor Val66Met Polymorphism Affects Resting Regional Cerebral Blood Flow and Functional Connectivity Differentially in Women Versus Men JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 7074 OP 7081 DO 10.1523/JNEUROSCI.5375-11.2012 VO 32 IS 20 A1 Shau-Ming Wei A1 Daniel P. Eisenberg A1 Philip D. Kohn A1 Jonathan S. Kippenhan A1 Bhaskar S. Kolachana A1 Daniel R. Weinberger A1 Karen F. Berman YR 2012 UL http://www.jneurosci.org/content/32/20/7074.abstract AB The human Val66Met single nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene impacts BDNF signaling at the cellular level. At the neural-systems level, it is associated with differences in prefrontal cortex (PFC) and hippocampal function during performance of cognitive and affective tasks. Because the impact of this variant on basal prefrontal and hippocampal activity is not known but may be relevant to understanding the function of this gene in health and disease, we studied 94 healthy individuals with H215O PET to assess regional cerebral blood flow (rCBF) during rest and tested for between-genotype differences. Because BDNF and gonadal steroid hormones conjointly influence neuronal growth, survival, and plasticity in hippocampus and PFC, we also tested for sex × genotype interactions. Finally, in light of the known impact of BDNF on plasticity and dendritic arborization, we complimented direct rCBF comparisons with connectivity analyses to determine how activity in hippocampal and prefrontal regions showing between-genotype group differences covaries with rCBF in other nodes throughout the brain in a genotype- or sex-dependent manner. Compared with Val homozygotes, Met carriers had higher rCBF in prefrontal (BA25 extending into BA10) and hippocampal/parahippocampal regions. Moreover, there were significant sex × genotype interactions in regions (including frontal, parahippocampal, and lateral temporal cortex) in which Val homozygotes showed higher rCBF in females than males, but Met carriers showed the opposite relationship. Functional connectivity analysis demonstrated that correlations of BA25, hippocampus, and parahippocampus with frontal and temporal networks were positive for Val homozygotes and negative for Met carriers. In addition, sex × genotype analysis of functional connectivity revealed that genotype affected directionality of the inter-regional correlations differentially in men versus women. Our data indicate that BDNF allelic variation and sex interactively affect basal prefrontal and hippocampal function.