ESTROGEN IN CHOLINERGIC BASAL FOREBRAIN AND MESOCORTICAL DOPAMINERGIC SYSTEMS

卵巢类固醇可以有效地影响下丘脑以外的脑区，并能影响认知等多种功能。在啮齿动物中，胆碱能基底前脑(CBF)和多巴胺能(DA)中皮层系统对循环雌激素水平很敏感。这些皮质投射系统也完整地参与了更高级别的认知功能，当这些系统被实验性损伤或退行性疾病破坏时，就会出现认知缺陷。雌激素可通过基因组或非基因组机制影响大脑功能。关于CBF，雌激素受体位于大鼠胆碱能神经元的一个亚群上，这表明其作用机制是基因组的。相比之下，在同一种群的猴子中没有发现这样的受体，这表明雌激素在灵长类动物中通过非基因组机制发挥作用。由于这一点，以及其他原因，研究雌激素在认知过程中的作用的研究可能会受益于使用非人类灵长类动物作为动物模型。本研究采用了四个具体目标。在所有实验中，幼年和老年恒河猴的循环雌激素都将通过卵巢切除(OVX)和雌激素替代(OVX+ERT)进行调节。我们将首先研究OVX和OVX+ERT对胆碱能酶的分子、形态和神经化学测量的影响，以及胆碱能基因表达和蛋白质测量的定量评估，以及胆碱能基因表达和蛋白质的定量评估。CBF是一个对营养因子的营养影响非常敏感的系统。因此，第二个特定目标将确定OVX和OVX+ERT对循环雌激素的调节是否会改变神经营养因子(NGF和BDNF)和神经营养因子受体(TrkA和p75NTR)的基因表达和蛋白。第三个具体目标将确定OVX和OVX+ERT对循环雌激素的调节是否会改变DA中皮质神经元的数量、这些细胞内酪氨酸羟基酶和多巴胺转运体的蛋白质和基因表达，以及前额叶皮质靶区内的多巴胺水平。在特定目标4中，在特定目标1-3中观察到的最一致和最有效的变化将在OVX和OVX-ERT治疗的猴子中进行评估，这些猴子已经被表现出行为特征。雌激素介导的分子、形态和神经化学改变与猴子的认知状态之间的关系将被建立。

Ovarian steroids potently influence extra hypothalamic brain sties and can effect diverse functions as cognition. The cholinergic basal forebrain (CBF) and dopaminergic (DA) mesocortical systems are sensitive to levels of circulating estrogen in rodents. These cortically projecting systems are also integrally involved in higher order cognitive functions such that cognitive deficits occur when these systems are destroyed by experimental lesions or degenerative disease. Estrogen can influence brain function through genomic or non-genomic mechanisms. With regards to the CBF, estrogen receptors are located upon a sub-population of cholinergic neurons in rats suggesting a genomic mechanism of action. In contrast, such receptors are not found within the same population in monkey, suggesting that estrogen functions via non-genomic mechanisms in primates. For this, as well as other reasons, studies investigating the role of estrogen in cognitive processes may benefit by using non-human primates as an animal model. The present study employs four Specific Aims. In all experiments, circulating estrogens will be modulated via ovariectomy (OVX) followed by estrogen replacement (OVX + ERT) in both young and aged Rhesus monkeys. We will first examine the effects of OVX and OVX + ERT upon molecular, morphological, and neurochemical measurements of cholinergic enzymes, and a quantitative assessment of cholinergic gene expression and protein measurements of cholinergic enzymes, and a quantitative assessment of cholinergic gene expression and protein. The CBF is a system which is exquisitely sensitive to the trophic influences of trophic factors. Thus, the second Specific Aim will establish whether modulation of circulating estrogens via OVX and OVX + ERT will alter the gene expression and protein for neurotrophins (NGF and BDNF) and neurotrophin receptors (trkA and P75NTR). The third Specific Aim will establish whether modulation of circulating estrogens via OVX and OVX + ERT alters the number of DA mesocortical neurons, the protein and gene expression for tyrosine hydroxylase and dopamine transporter within these cells, as well as dopamine levels within the target regions within the prefrontal cortex. In Specific Aim 4, the most consistent and potent changes observed in Specific Aims 1-3 will be evaluated in OVX and OVX-ERT treated monkeys which have been behaviorally characterized. The relationship between the molecular, morphological, and neurochemical alterations mediated by estrogen and the cognitive status of the monkeys will be established.