Grech Adrienne M, Ratnayake Udani, Hannan Anthony J, van den Buuse Maarten, Hill Rachel A
Department of Psychiatry, School of Clinical Sciences, Monash Medical Centre, Monash University, Clayton, VIC, Australia.
The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
Front Behav Neurosci. 2018 Oct 9;12:227. doi: 10.3389/fnbeh.2018.00227. eCollection 2018.
Neurodevelopmental disorders are thought to be caused by a combination of adverse genetic and environmental insults. The "two-hit" hypothesis suggests that an early first "hit" primes the developing brain to be vulnerable to a second "hit" during adolescence which triggers behavioral dysfunction. We have previously modeled this scenario in mice and found that the combined effect of a genetic hapolinsuffuciency in the brain-derived neurotrophic factor (BDNF) gene (1st hit) and chronic corticosterone (CORT) treatment during adolescence (2nd hit), caused spatial memory impairments in adulthood. Environmental enrichment (EE) protocols are designed to stimulate experience-dependent plasticity and have shown therapeutic actions. This study investigated whether EE can reverse these spatial memory impairments. Wild-type (WT) and BDNF heterozygous (HET) mice were treated with corticosterone (CORT) in their drinking water (50 mg/L) from weeks 6 to 8 and exposed to EE from 7 to 9 weeks. Enriched housing included open top cages with additional toys, tunnels, housing, and platforms. Y-maze novel preference testing, to assess short-term spatial memory, was performed at 10 weeks of age. At week 16 dorsal hippocampus tissue was obtained for Western blot analysis of expression levels of BDNF, the BDNF receptor TrkB, and NMDA receptor subunits, GluNR1, 2A and 2B. As in our previous studies, spatial memory was impaired in our two-hit (BDNF HET + CORT) mice. Simultaneous EE prevented these impairments. However, EE appeared to worsen spatial memory performance in WT mice, particularly those exposed to CORT. While BDNF levels were lower in BDNF HET mice as expected, there were no further effects of CORT or EE in males but a close to significant female CORT × EE × genotype interaction which qualitatively corresponded with Y-maze performance. However, EE caused both sex- and genotype-specific effects on phosphorylated TrkB residues and GluNR expression within the dorsal hippocampus, with GluNR2B levels in males changing in parallel with spatial memory performance. In conclusion, beneficial effects of EE on spatial memory emerge only following two developmental disruptions. The mechanisms by which EE exerts its effects are likely via regulation of multiple activity-dependent pathways, including TrkB and NMDA receptor signaling.
神经发育障碍被认为是由不利的遗传和环境因素共同作用引起的。“两次打击”假说表明，早期的第一次“打击”使发育中的大脑在青春期易受第二次“打击”，从而引发行为功能障碍。我们之前在小鼠中模拟了这种情况，发现脑源性神经营养因子（BDNF）基因的遗传单倍剂量不足（第一次打击）与青春期慢性皮质酮（CORT）处理（第二次打击）的联合作用，导致成年后空间记忆受损。环境富集（EE）方案旨在刺激经验依赖性可塑性，并已显示出治疗作用。本研究调查了EE是否能逆转这些空间记忆损伤。野生型（WT）和BDNF杂合子（HET）小鼠在6至8周龄时饮用含皮质酮（CORT）（50 mg/L）的水，并在7至9周龄时暴露于EE环境中。丰富的饲养环境包括带有额外玩具、隧道、栖身之所和平台的开放式笼子。在10周龄时进行Y迷宫新异偏好测试，以评估短期空间记忆。在第16周时获取背侧海马组织，用于蛋白质免疫印迹分析BDNF、BDNF受体TrkB以及NMDA受体亚基GluNR1、2A和2B的表达水平。与我们之前的研究一样，在我们的两次打击（BDNF HET + CORT）小鼠中空间记忆受损。同时进行的EE预防了这些损伤。然而，EE似乎使WT小鼠的空间记忆表现恶化，尤其是那些暴露于CORT的小鼠。虽然正如预期的那样，BDNF HET小鼠中的BDNF水平较低，但CORT或EE对雄性小鼠没有进一步影响，但在雌性小鼠中存在接近显著的CORT×EE×基因型相互作用，这与Y迷宫表现定性相符。然而，EE对背侧海马内磷酸化TrkB残基和GluNR表达产生了性别和基因型特异性影响，雄性小鼠中的GluNR2B水平变化与空间记忆表现平行。总之，EE对空间记忆的有益作用仅在两次发育干扰后才出现。EE发挥作用的机制可能是通过调节多种活动依赖性途径，包括TrkB和NMDA受体信号传导。
