Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, Canada.
PLoS One. 2010 Jul 8;5(7):e11463. doi: 10.1371/journal.pone.0011463.
Puberty is a critical period in mesocorticolimbic dopamine (DA) system development, particularly for the medial prefrontal cortex (mPFC) projection which achieves maturity in early adulthood. The guidance cue netrin-1 organizes neuronal networks by attracting or repelling cellular processes through DCC (deleted in colorectal cancer) and UNC-5 homologue (UNC5H) receptors, respectively. We have shown that variations in netrin-1 receptor levels lead to selective reorganization of mPFC DA circuitry, and changes in DA-related behaviors, in transgenic mice and in rats. Significantly, these effects are only observed after puberty, suggesting that netrin-1 mediated effects on DA systems vary across development. Here we report on the normal expression of DCC and UNC5H in the ventral tegmental area (VTA) by DA neurons from embryonic life to adulthood, in both mice and rats. We show a dramatic and enduring pubertal change in the ratio of DCC:UNC5H receptors, reflecting a shift toward predominant UNC5H function. This shift in DCC:UNC5H ratio coincides with the pubertal emergence of UNC5H expression by VTA DA neurons. Although the distribution of DCC and UNC5H by VTA DA neurons changes during puberty, the pattern of netrin-1 immunoreactivity in these cells does not. Together, our findings suggest that DCC:UNC5H ratios in DA neurons at critical periods may have important consequences for the organization and function of mesocorticolimbic DA systems.
青春期是中脑边缘多巴胺（DA）系统发育的关键时期，特别是对于内侧前额叶皮层（mPFC）投射，其在成年早期达到成熟。导向分子 netrin-1 通过分别吸引或排斥 DCC（结直肠癌缺失）和 UNC-5 同源物（UNC5H）受体来组织神经元网络。我们已经表明，netrin-1 受体水平的变化会导致 mPFC DA 回路的选择性重组，并导致 DA 相关行为发生变化，这在转基因小鼠和大鼠中都得到了证实。重要的是，这些影响仅在青春期后观察到，这表明 netrin-1 对 DA 系统的影响在发育过程中是不同的。在这里，我们报告了 DCC 和 UNC5H 在腹侧被盖区（VTA）中的正常表达，从胚胎生命到成年，在小鼠和大鼠中均如此。我们发现 DCC：UNC5H 受体的比例在青春期发生了显著而持久的变化，反映出 UNC5H 功能的主导地位。这种 DCC：UNC5H 比率的转变与 VTA DA 神经元中 UNC5H 表达的青春期出现相吻合。尽管 VTA DA 神经元中的 DCC 和 UNC5H 分布在青春期发生变化，但这些细胞中 netrin-1 免疫反应性的模式没有变化。总之，我们的研究结果表明，DA 神经元在关键时期的 DCC：UNC5H 比值可能对中脑边缘 DA 系统的组织和功能具有重要意义。
