Selective Prenatal Dopamine Damage in Non Human Primates

几种在成年前发病的大脑疾病被认为是 涉及中脑多巴胺神经元发育的不规则性。 这些包括一些肌张力障碍，LeschNyhan病，精神分裂症， 发育性缺氧缺血性损伤由于人们对这一点知之甚少， 灵长类多巴胺神经元的个体发生，这项建议的目标是推进 了解这些神经元的早期发育， 这些补偿是对它们的选择性损害的反应。初步研究 将使用正常的非洲绿色猴胎儿，其年龄跨度为 多巴胺神经元分化后的时间到分化前的时间 出生进行的测定将提供关于可能的关键时间的数据 在发育过程中，多巴胺系统的损伤可能会持续很长时间， 有害影响，包括自然细胞死亡（凋亡）的时期， 多巴胺神经元和多巴胺神经元的突触发生与突触后 目标的随后，神经化学特异性原毒素M11rP将被释放。 给怀孕的猴子服用暴露于MPTP的胎儿 在程序性细胞死亡的高峰期间，可以模拟夸大或 异常的自然细胞死亡发生在多巴胺神经元中。其他的胎儿 在妊娠期的相当大一部分时间内暴露于MPTP的影响 时期，包括延长的突触发生期，这可能模拟 在这种情况下，多巴胺神经元比正常的少，或者 是生长或突触形成的缺陷。在人类中， 异常可能是由于遗传、药物滥用、环境 毒素身体创伤缺氧或感染猴尸检测量 胎儿将包括多巴胺神经元数量，完整性， 和功能，并将在出生前制造。随后，我们计划 检查在子宫内暴露于MPTP的新生儿的大脑， 已经到了6个月大。在后一组中，行为观察和 一个挑战与左旋多巴，也将进行，以表明是否 婴儿表现出危及其生存的缺陷， 更详细的行为和心理研究， 之后需要跟进。 我们希望这些研究将提供对正常的 灵长类多巴胺神经元的发育，以及它们对损伤的反应， 个体发育的关键时期因此，拟议的工作可能最终导致 用于一种或多种儿科脑部疾病的动物模型。

Several brains disorders with onset before adulthood are thought to involve irregularities in the development of midbrain dopamine neurons. These include some dystonias, LeschNyhan disease, schizophrenia, and developmental hypoxicischemic injury. As relatively little is known about the ontogeny of primate dopamine neurons, the goal of this proposal is to advance understanding of the early development of these neurons, and the effects and compensations that occur in response to their selective damage. Initial studies will use normal African green monkey fetuses which will span in age from the time just after differentiation of dopamine neurons to the time just before birth. The assays performed will provide data regarding possible critical times in development in which damage to dopamine systems might have longlasting deleterious effects, including periods of natural cell death (apoptosis) in dopamine neurons and synaptogenesis of dopamine neurons with postsynaptic targets. Subsequently, the neurochemically specific protoxin, M11rP, will be given to pregnant monkeys at these times. Fetuses that are exposed to MPTP during a peak of programmed cell death may mimic situation where exaggerated or abnormal natural cell death occurs in dopamine neurons. Other fetuses will be exposed to the effects of MPTP over a substantial proportion of the gestation period, incorporating an extended period of synaptogenesis, which may mimic situations where there are fewer than normal dopamine neurons, or where there are deficits in outgrowth or synapse formation. In humans such developmental abnormalities may occur as a result of genetics, drug abuse, environmental toxins, physical trauma, anoxia or infection. Postmortem measurements in monkey fetuses will include biochemical assays of dopamine neuron number, integrity and function, and will be made just prior to birth. Subsequently we plan to examine the brains of neonates which have been exposed to MPTP in utero, when have reached 6 months of age. In the latter group, behavioral observations and a challenge with Ldopa, will also be carried out to indicate whether the infants show deficits that compromise their survival, and identify potential abnormalities for more detailed behavioral and psychological studies which would need to follow later. We are hopeful that these studies will provide insight into both the normal development of primate dopamine neurons, and their response to injury at critical times in ontogeny. Thus, the proposed work may lead ultimately to an animal model for one or more pediatric brain disorders.