Marwarha Gurdeep, Claycombe-Larson Kate, Schommer Jared, Ghribi Othman
Department of Biomedical Sciences, School of Medicine & Health Sciences, University of North Dakota, Grand Forks, ND 58203, USA.
U.S. Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58203, USA.
J Nutr Biochem. 2017 Jul;45:54-66. doi: 10.1016/j.jnutbio.2017.03.005. Epub 2017 Apr 6.
Prenatal exposure to a maternal low-protein (LP) diet has been known to cause cognitive impairment, learning and memory deficits. However, the underlying mechanisms have not been identified. Herein, we demonstrate that a maternal LP diet causes, in the brains of the neonatal rat offspring, an attenuation in the basal expression of the brain-derived neurotrophic factor (BDNF), a neurotrophin indispensable for learning and memory. Female rats were fed either a 20% normal protein (NP) diet or an 8% LP 3 weeks before breeding and during the gestation period. Maternal LP diet caused a significant reduction in the Bdnf expression in the brains of the neonatal rats. We further found that the maternal LP diet reduced the activation of the cAMP/protein kinase A/cAMP response element binding protein (CREB) signaling pathway. This reduction was associated with a significant decrease in CREB binding to the Bdnf promoters. We also show that prenatal exposure to the maternal LP diet results in an inactive or repressed exon I and exon IV promoter of the Bdnf gene in the brain, as evidenced by fluxes in signatory hallmarks in the enrichment of acetylated and trimethylated histones in the nucleosomes that envelop the exon I and exon IV promoters, causing the Bdnf gene to be refractory to transactivation. Our study is the first to determine the impact of a maternal LP diet on the basal expression of BDNF in the brains of the neonatal rats exposed prenatally to an LP diet.
已知产前暴露于母体低蛋白（LP）饮食会导致认知障碍、学习和记忆缺陷。然而，其潜在机制尚未明确。在此，我们证明母体LP饮食会使新生大鼠后代大脑中脑源性神经营养因子（BDNF）的基础表达减弱，BDNF是学习和记忆所必需的一种神经营养因子。在受孕前3周及妊娠期，给雌性大鼠喂食20%正常蛋白（NP）饮食或8%LP饮食。母体LP饮食导致新生大鼠大脑中Bdnf表达显著降低。我们进一步发现，母体LP饮食会降低cAMP/蛋白激酶A/cAMP反应元件结合蛋白（CREB）信号通路的激活。这种降低与CREB与Bdnf启动子结合的显著减少有关。我们还表明，产前暴露于母体LP饮食会导致大脑中Bdnf基因的外显子I和外显子IV启动子处于无活性或受抑制状态，这通过包裹外显子I和外显子IV启动子的核小体中乙酰化和三甲基化组蛋白富集的标志性通量得以证明，导致Bdnf基因难以被反式激活。我们的研究首次确定了母体LP饮食对产前暴露于LP饮食的新生大鼠大脑中BDNF基础表达的影响。
