Section on Integrative Neuroimaging, National Institute of Mental Health Intramural Research Programs, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Neurosci. 2012 May 16;32(20):7074-81. doi: 10.1523/JNEUROSCI.5375-11.2012.
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 H₂ ¹⁵O 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.
人类脑源性神经营养因子（BDNF）基因中的 Val66Met 单核苷酸多态性会影响细胞水平的 BDNF 信号转导。在神经系统水平上，它与认知和情感任务中前额叶皮层（PFC）和海马功能的差异有关。由于该变体对基础前额叶和海马活动的影响尚不清楚，但可能与理解该基因在健康和疾病中的功能有关，我们使用 H₂¹⁵O PET 研究了 94 名健康个体，以评估休息期间的局部脑血流（rCBF），并测试了基因型之间的差异。由于 BDNF 和性腺类固醇激素共同影响海马体和 PFC 中的神经元生长、存活和可塑性，我们还测试了性别与基因型的相互作用。最后，鉴于 BDNF 对可塑性和树突分支的已知影响，我们用连接分析补充了直接 rCBF 比较，以确定在显示基因型差异的海马体和前额叶区域中，活动如何以基因型或性别依赖的方式与大脑中其他节点的 rCBF 相关。与 Val 纯合子相比，Met 携带者在前额（延伸至 BA10 的 BA25）和海马/旁海马区域的 rCBF 更高。此外，在 Val 纯合子中女性的 rCBF 高于男性的区域（包括额叶、旁海马和外侧颞叶皮质）存在显著的性别与基因型的相互作用，但 Met 携带者则存在相反的关系。功能连接分析表明，BA25、海马体和旁海马体与额叶和颞叶网络的相关性在 Val 纯合子中为正，在 Met 携带者中为负。此外，功能连接的性别与基因型分析表明，基因型以不同的方式影响了男性和女性之间的区域间相关性的方向。我们的数据表明，BDNF 等位基因变异和性别相互作用会影响基础前额叶和海马体的功能。
