Ren Jia-Qian, Malanga C J, Tabit Eddy, Kosofsky Barry E
Laboratory of Molecular and Developmental Neuroscience, Department of Neurology, Massachusetts General Hospital, Room 2508, 149 13th Street, Charlestown, MA 02129, USA.
Int J Dev Neurosci. 2004 Aug-Oct;22(5-6):309-20. doi: 10.1016/j.ijdevneu.2004.05.003.
We have developed an animal model in Swiss Webster mice to identify mechanisms by which prenatal exposure to cocaine results in persistent alterations in brain structure and function. Clinical data suggests that children who demonstrate the largest impairments in prenatal brain growth, which are positively correlated with the highest level of prenatal cocaine exposure, are more likely to demonstrate selective impairment in postnatal brain growth, as well as postnatal impairments in motor function, attention and language skills. We conducted neuroanatomic studies to identify the postnatal evolution of structural changes in the primary somatosensory (SI) cortex of the developing mouse brain following prenatal exposure to cocaine. Our previous work, and that of others, provides evidence that many of the processes underlying corticogenesis are disrupted by gestational exposure of the developing mouse brain to cocaine, and that from the earliest phases of corticogenesis that there is an imprecision in the development of cortical lamination. We performed morphometric comparisons between the brains of animals prenatally exposed to varying amounts of cocaine with vehicle and malnutrition controls on postnatal (P) days P9 and P50. We found that on P50, but not P9, the relative number of cortical neurons in S1 is significantly less in cocaine exposed animals as compared with controls. The significant decrease in the number of cells in cocaine exposed animals on P50 is evident as a decreased density of cells restricted to the infragranular compartment (layers V and VI). Those changes are not seen in malnourished animals. Taken together our findings support the conclusion that cocaine-induced alterations in SI cortical cytoarchitectonics are in part a consequence of altered postnatal survival of infragranular cortical neurons, which are lost during the interval between P9 and P50. Determining whether a similar process is evident in a subset of humans following in utero cocaine exposure is a high priority for future clinical brain imaging studies, because analogous structural changes could impact the brain function and behavioral repertoire of infants and children following significant prenatal exposures.
我们在瑞士韦伯斯特小鼠中建立了一种动物模型，以确定产前接触可卡因导致大脑结构和功能持续改变的机制。临床数据表明，产前脑生长受损最严重的儿童（与产前可卡因接触水平呈正相关）更有可能在出生后脑生长出现选择性受损，以及出生后运动功能、注意力和语言技能受损。我们进行了神经解剖学研究，以确定产前接触可卡因后发育中小鼠大脑初级体感（SI）皮层结构变化的出生后演变。我们之前的工作以及其他人的工作都表明，许多皮质发生的潜在过程会因发育中的小鼠大脑在孕期接触可卡因而受到干扰，并且从皮质发生的最早阶段起，皮质分层的发育就存在不精确性。我们对产前接触不同剂量可卡因的动物与接受赋形剂和营养不良对照的动物在出生后（P）第9天和第50天的大脑进行了形态计量学比较。我们发现，在出生后第50天而非第9天，与对照组相比，接触可卡因的动物S1区皮质神经元的相对数量显著减少。出生后第50天接触可卡因的动物细胞数量显著减少，表现为仅限于颗粒下层（V层和VI层）的细胞密度降低。这些变化在营养不良的动物中未观察到。综合我们的研究结果支持这样的结论，即可卡因诱导的SI皮质细胞结构改变部分是颗粒下层皮质神经元出生后存活率改变的结果，这些神经元在出生后第9天至第50天之间丢失。确定子宫内接触可卡因的一部分人类是否也存在类似过程是未来临床脑成像研究的高度优先事项，因为类似的结构变化可能会影响产前大量接触可卡因的婴儿和儿童的脑功能和行为表现。
