Department of Neurology and NeuroEpigenetcis Laboratory, MassGeneral Institute for Neurodegenerative Disease, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
J Neurosci. 2011 Sep 21;31(38):13400-11. doi: 10.1523/JNEUROSCI.2944-11.2011.
Prenatal cocaine exposure impairs brain development and produces lasting alterations in cognitive function. In a prenatal cocaine exposure mouse model, we found that tangential migration of GABA neurons from the basal to the dorsal forebrain and radial neuron migration within the dorsal forebrain were significantly decreased during the embryonic period. The decrease in the tangential migration occurred early in gestation and normalized by late gestation, despite ongoing cocaine exposure. The decrease in radial migration was associated with altered laminar positioning of neurons in the medial prefrontal cortex. The cocaine exposure led to transient decreases in the expression of Tbr2 and Tbr1, transcription factors associated with intermediate progenitor cells and newborn neurons of the dorsal forebrain, respectively, although neurogenesis was not significantly altered. Since cocaine can modulate brain derived neurotrophic factor (BDNF) expression in the mature brain, we examined whether cocaine can alter BDNF expression in the embryonic brain. We found a transient decrease in BDNF protein expression in the cocaine-exposed embryonic forebrain early in gestation. By late gestation, the BDNF expression recovered to control levels, despite ongoing cocaine exposure. In basal forebrain explants from cocaine-exposed embryos, cell migration was significantly decreased, corroborating the in vivo data on tangential GABA neuron migration. Since BDNF can influence tangential neuronal migration, we added BDNF to the culture medium and observed increased cell migration. Our data suggest that cocaine can alter tangential and radial neuronal migration as well as BDNF expression in the embryonic brain and that decreased BDNF may mediate cocaine's effects on neuronal migration.
产前可卡因暴露会损害大脑发育，并对认知功能产生持久的改变。在产前可卡因暴露的小鼠模型中，我们发现胚胎期 GABA 神经元从基底到背侧前脑的切线迁移和背侧前脑内的放射状神经元迁移明显减少。尽管持续暴露于可卡因，但切线迁移的减少发生在妊娠早期，并在妊娠晚期恢复正常。放射状迁移的减少与内侧前额叶皮质神经元层状定位的改变有关。可卡因暴露导致背侧前脑的中间祖细胞和新生神经元分别与 Tbr2 和 Tbr1 转录因子的表达短暂下降，尽管神经发生没有明显改变。由于可卡因可以调节成熟大脑中的脑源性神经营养因子 (BDNF) 表达，我们研究了可卡因是否可以改变胚胎大脑中的 BDNF 表达。我们发现，在妊娠早期，可卡因暴露的胚胎前脑的 BDNF 蛋白表达短暂下降。到妊娠晚期，尽管持续暴露于可卡因，BDNF 的表达恢复到对照水平。在可卡因暴露胚胎的基底前脑外植体中，细胞迁移明显减少，这与体内关于 GABA 神经元切线迁移的研究结果一致。由于 BDNF 可以影响切线神经元迁移，我们在培养基中添加了 BDNF，并观察到细胞迁移增加。我们的数据表明，可卡因可以改变胚胎大脑中的切线和放射状神经元迁移以及 BDNF 表达，并且 BDNF 的减少可能介导可卡因对神经元迁移的影响。
