Tang Y P, Wang H, Feng R, Kyin M, Tsien J Z
Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544, USA.
Neuropharmacology. 2001 Nov;41(6):779-90. doi: 10.1016/s0028-3908(01)00122-8.
It has been known that environmental enrichment leads to better learning and memory in mice. However, the molecular mechanisms are not known. In this study, we used the 10th-12th of the NR2B transgenic (Tg) lines, in which the NMDA receptor function is enhanced via the NR2B subunit transgene in neurons of the forebrain, to test the hypothesis of the involvement of NMDA receptor function in enrichment-induced better learning and memory. Consistent with our previous results, both larger long-term potentiation (LTP) in the hippocampus and superior learning and memory were observed in naive NR2B Tg mice even after the 10th-12th generation of breeding. After enrichment, wild-type mice exhibited overall improvement in their performances in contextual and cued conditioning, fear extinctions, and novel object recognition tasks. Interestingly, the same enrichment procedures could not further increase the performance of NR2B Tg mice in contextual conditioning, cued conditioning, or fear extinction, thereby indicating that enhanced NMDA receptor function can occlude these enrichment effects. However, we found that in the novel object recognition task enriched NR2B Tg mice exhibited much longer recognition memory (up to 1 week), compared to that (up to 3 days) in naive NR2B Tg mice. Furthermore, our biochemical experiments showed that enrichment significantly increased protein levels of GluR1, NR2B, and NR2A subunits of glutamate receptors in both wild-type and NR2B Tg mice. Therefore, our results suggest an interactive nature of molecular pathways involved in both environmental and genetic NMDA receptor manipulations for enhancing learning and memory.
已知环境丰富化可使小鼠的学习和记忆能力增强。然而，其分子机制尚不清楚。在本研究中，我们使用了第10至12代NR2B转基因（Tg）品系，其中通过前脑神经元中的NR2B亚基转基因增强了NMDA受体功能，以检验NMDA受体功能参与丰富化诱导的更好学习和记忆这一假说。与我们之前的结果一致，即使在繁殖到第10至12代后，未接触过丰富化环境的NR2B Tg小鼠在海马体中仍表现出更强的长时程增强（LTP）以及更优的学习和记忆能力。经过环境丰富化处理后，野生型小鼠在情境性和线索性条件反射、恐惧消退以及新物体识别任务中的表现总体有所改善。有趣的是，相同的丰富化程序并不能进一步提高NR2B Tg小鼠在情境性条件反射、线索性条件反射或恐惧消退任务中的表现，这表明增强的NMDA受体功能可以掩盖这些丰富化效应。然而，我们发现，在新物体识别任务中，经过环境丰富化处理的NR2B Tg小鼠表现出的识别记忆时间长得多（长达1周），而未接触过丰富化环境的NR2B Tg小鼠的识别记忆时间则较短（长达3天）。此外，我们的生化实验表明，环境丰富化显著提高了野生型和NR2B Tg小鼠中谷氨酸受体的GluR1、NR2B和NR2A亚基的蛋白质水平。因此，我们的结果表明，参与环境和基因NMDA受体操纵以增强学习和记忆的分子途径具有相互作用的性质。
