Verwey Michael, Grant Alanna, Meti Nicholas, Adye-White Lauren, Torres-Berrío Angelica, Rioux Veronique, Lévesque Martin, Charron Frederic, Flores Cecilia
Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada; Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal, Montreal, QC, Canada.
Department of Psychiatry, Douglas Mental Health University Institute, McGill University , Montreal, QC, Canada.
eNeuro. 2016 Jul 13;3(3). doi: 10.1523/ENEURO.0009-16.2016. eCollection 2016 May-Jun.
Motivated behaviors and many psychopathologies typically involve changes in dopamine release from the projections of the ventral tegmental area (VTA) and/or the substantia nigra pars compacta (SNc). The morphogen Sonic Hedgehog (Shh) specifies fates of midbrain dopamine neurons, but VTA-specific effects of Shh signaling are also being uncovered. In this study, we assessed the role of the Shh receptor Cdon in the development of VTA and SNc dopamine neurons. We find that Cdon is expressed in the proliferating progenitor zone of the embryonic ventral midbrain and that the number of proliferating cells in this region is increased in mouse Cdon(-/-) embryos. Consistent with a role of Shh in the regulation of neuronal proliferation in this region, we find that the number of tyrosine hydroxylase (TH)-positive neurons is increased in the VTA of Cdon(-/-) mice at birth and that this effect endures into adulthood. In contrast, the number of TH-positive neurons in the SNc is not altered in Cdon(-/-) mice at either age. Moreover, adult Cdon(-/-) mice have a greater number of medial prefrontal cortex (mPFC) dopamine presynaptic sites, and increased baseline concentrations of dopamine and dopamine metabolites selectively in this region. Finally, consistent with increased dopamine function in the mPFC, we find that adult Cdon(-/-) mice fail to exhibit behavioral plasticity upon repeated amphetamine treatment. Based on these data, we suggest that Cdon plays an important role encoding the diversity of dopamine neurons in the midbrain, influencing both the development of the mesocortical dopamine pathway and behavioral outputs that involve this neural circuitry.
动机性行为和许多精神病理学通常涉及腹侧被盖区（VTA）和/或黑质致密部（SNc）投射的多巴胺释放变化。形态发生素音猬因子（Shh）决定中脑多巴胺神经元的命运，但Shh信号通路对VTA的特异性作用也正在被揭示。在本研究中，我们评估了Shh受体Cdon在VTA和SNc多巴胺神经元发育中的作用。我们发现Cdon在胚胎腹侧中脑的增殖祖细胞区表达，并且在小鼠Cdon基因敲除（Cdon(-/-)）胚胎中该区域的增殖细胞数量增加。与Shh在该区域神经元增殖调节中的作用一致，我们发现出生时Cdon(-/-)小鼠VTA中酪氨酸羟化酶（TH）阳性神经元的数量增加，并且这种效应持续到成年。相比之下，在两个年龄段，Cdon(-/-)小鼠SNc中TH阳性神经元的数量均未改变。此外，成年Cdon(-/-)小鼠内侧前额叶皮质（mPFC）的多巴胺突触前位点数量更多，并且仅在该区域多巴胺及其代谢产物的基线浓度增加。最后，与mPFC中多巴胺功能增强一致，我们发现成年Cdon(-/-)小鼠在反复给予苯丙胺治疗后未能表现出行为可塑性。基于这些数据，我们认为Cdon在编码中脑多巴胺神经元多样性方面发挥重要作用，影响中脑皮质多巴胺通路的发育以及涉及该神经回路的行为输出。
