Dong Brittany E, Chen Hao, Sakata Kazuko
Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN, USA.
J Neurochem. 2020 Jul;154(1):41-55. doi: 10.1111/jnc.15017. Epub 2020 Jun 12.
Deficiency of activity-induced expression of brain-derived neurotrophic factor (BDNF) disturbs neurotransmitter gene expression. Enriched environment treatment (EET) ameliorates the defects. However, how BDNF deficiency and EET affect the neurotransmitter gene expression differently across ages remains unclear. We addressed this question by determining the neurotransmitter gene expression across three life stages in wild-type and activity-dependent BDNF-deficient (KIV) mice. Mice received 2-months of standard control treatment (SCT) or EET at early-life development (ED: 0-2 months), young adulthood (2-4 months), and old adulthood (12-14 months) (N = 16/group). Half of these mice received additional 1-month SCT to examine persisting EET effects. High-throughput quantitative reverse transcription polymerase chain reaction measured expression of 81 genes for dopamine, adrenaline, serotonin, gamma aminobutyric acid, glutamate, acetylcholine, and BDNF systems in the frontal cortex (FC) and hippocampus. Results revealed that BDNF deficiency mostly reduced neurotransmitter gene expression, greatest at ED in the FC. EET increased expression of a larger number of genes at ED than adulthood, particularly in the KIV FC. Many genes down-regulated in KIV mice were up-regulated by EET, which persisted when EET was provided at ED (e.g., 5-hydroxytryptamine (serotonin) transporter [5HTT], ADRA1D, GRIA3, GABRA5, GABBR2). In both the regions, BDNF deficiency decreased the density of gene co-expression network specifically at ED, while EET increased the density and hub genes (e.g., GAT1, GABRG3, GRIN1, CHRNA7). These results suggest that BDNF deficiency, which occurs under chronic stress, causes neurotransmitter dysregulations prominently at ED, particularly in the FC. EET at ED may be most effective to normalize the dysregulations, providing persisting effects later in life. OPEN SCIENCE BADGES: This article has received a badge for Open Materials because it provided all relevant information to reproduce the study in the manuscript. More information about the Open Science badges can be found at https://cos.io/our-services/open-science-badges/.
脑源性神经营养因子（BDNF）活性诱导表达的缺乏会干扰神经递质基因的表达。丰富环境处理（EET）可改善这些缺陷。然而，BDNF缺乏和EET如何在不同年龄段对神经递质基因表达产生不同影响仍不清楚。我们通过测定野生型和活性依赖性BDNF缺陷（KIV）小鼠三个生命阶段的神经递质基因表达来解决这个问题。小鼠在生命早期发育阶段（ED：0 - 2个月）、成年早期（2 - 4个月）和成年晚期（12 - 14个月）接受2个月的标准对照处理（SCT）或EET（每组N = 16只）。其中一半小鼠接受额外1个月的SCT以检查EET的持续影响。通过高通量定量逆转录聚合酶链反应测量额叶皮质（FC）和海马体中多巴胺、肾上腺素、血清素、γ-氨基丁酸、谷氨酸、乙酰胆碱和BDNF系统的81个基因的表达。结果显示，BDNF缺乏主要降低神经递质基因表达，在FC的ED阶段最为明显。EET在ED阶段比成年期增加了更多基因的表达，特别是在KIV的FC中。许多在KIV小鼠中下调的基因通过EET上调，当在ED阶段给予EET时这种上调持续存在（例如5-羟色胺（血清素）转运体[5HTT]、ADRA1D、GRIA3、GABRA5、GABBR）。在这两个区域中，BDNF缺乏特别是在ED阶段降低了基因共表达网络的密度，而EET增加了密度和中心基因（例如GAT1、GABRG3、GRIN1、CHRNA7）。这些结果表明，在慢性应激下发生的BDNF缺乏在ED阶段尤其是在FC中显著导致神经递质失调。ED阶段的EET可能最有效地使失调正常化，并在生命后期产生持续影响。开放科学徽章：本文已获得“开放材料”徽章，因为它提供了重现手稿中研究的所有相关信息。有关开放科学徽章的更多信息可在https://cos.io/our-services/open-science-badges/上找到。
