Morrow Bret A, Redmond D Eugene, Roth Robert H, Elsworth John D
Neuropsychopharmacology Research Unit, Departments of Psychiatry and Pharmacology, Yale University School of Medicine, New Haven, CN 06511, USA.
J Comp Neurol. 2005 Jul 25;488(2):215-23. doi: 10.1002/cne.20599.
Disruption in the development of dopamine-containing neurons has been postulated to underlie several CNS disorders. However, there have been no quantitative studies on the normal development of primate dopamine neurons. Thus, the fetal maturation of primate midbrain dopamine neurons was examined to establish changes that occur in the A9/A10 groups during the second and third trimesters. Eleven fetal African green monkey midbrains were immunostained for tyrosine hydroxylase (TH-ir) as a marker for dopamine neurons and quantified using stereological techniques (nucleator method). The number and size of defined dopamine neurons and the volume occupied by A9/A10 neurons increased in near linear fashion throughout the term. The estimated number of defined dopamine neurons in each hemisphere rose from approximately 50,000 at embryonic day (E) 70 to 225,000 at birth (E165), similar to the adult population. The size and the area occupied by them at birth were, however, well below the estimated adult levels. Additionally, the younger fetal midbrains had far less diversity in dopamine cell volumes compared with older fetuses and adult brains. Until midway through gestation (E81), clusters of apparently immature midbrain TH-ir cells were observed, but could not be counted. Even though the majority of cells destined to become dopamine neurons are generated in the first trimester, phenotypical maturation of A9 and A10 cell bodies continues steadily throughout gestation and extends well into the postnatal period. These data have relevance to transplantation studies that employ fetal dopaminergic grafts, and to disorders hypothesized to result from damage to developing midbrain dopamine neurons.
多巴胺能神经元发育的破坏被认为是几种中枢神经系统疾病的基础。然而，目前尚无关于灵长类动物多巴胺神经元正常发育的定量研究。因此，研究了灵长类动物中脑多巴胺神经元的胎儿成熟情况，以确定在妊娠中期和晚期A9/A10组中发生的变化。对11个非洲绿猴胎儿中脑进行酪氨酸羟化酶免疫染色（TH免疫反应）作为多巴胺神经元的标志物，并使用体视学技术（核仁法）进行定量分析。整个孕期，特定多巴胺神经元的数量、大小以及A9/A10神经元所占体积几乎呈线性增加。每个半球中特定多巴胺神经元的估计数量从胚胎期（E）70天的约50,000个增加到出生时（E165）的225,000个，与成年群体相似。然而，它们在出生时的大小和所占面积远低于估计的成年水平。此外，与较大胎儿和成年大脑相比，较年轻胎儿中脑的多巴胺细胞体积差异要小得多。直到妊娠中期（E81），可观察到明显未成熟的中脑TH免疫反应细胞簇，但无法计数。尽管大多数注定要成为多巴胺神经元的细胞在妊娠早期产生，但A9和A10细胞体的表型成熟在整个孕期持续稳定进行，并一直延伸到出生后阶段。这些数据与采用胎儿多巴胺能移植的研究以及假设由发育中的中脑多巴胺神经元损伤导致的疾病相关。
