ESTROGEN IN CHOLINERGIC BASAL FOREBRAIN AND MESOCORTICAL DOPAMINERGIC SYSTEMS

卵巢类固醇可能影响额外的下丘脑大脑，并影响认知等多种功能。啮齿类动物的胆碱能基底前脑（CBF）和多巴胺能中皮层（DA）系统对循环雌激素水平敏感。这些皮层投射系统也完整地参与高阶认知功能，当这些系统被实验性病变或退行性疾病破坏时，就会发生认知缺陷。雌激素可以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亚群上，表明其作用机制具有基因组性。相比之下，在同一种群的猴子中没有发现这样的受体，这表明雌性激素在灵长类动物中通过非基因组机制起作用。出于这个原因，以及其他原因，研究雌激素在认知过程中的作用可能会受益于使用非人类灵长类动物作为动物模型。本研究采用四个具体目标。在所有实验中，循环雌激素将通过卵巢切除术（OVX）和雌激素替代（OVX + ERT）在年轻和老年恒河猴中进行调节。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，并对胆碱能基因表达和胆碱能酶的蛋白质测量进行定量评估，并对胆碱能基因表达和蛋白质进行定量评估。脑血流是一个对营养因子的营养影响非常敏感的系统。因此，第二个特异性目标将确定通过OVX和OVX + ERT调节循环雌激素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）的基因表达和蛋白质。第三个特异性目的将确定通过OVX和OVX + ERT调节循环雌激素是否会改变DA中皮层神经元的数量，这些细胞中酪氨酸羟化酶和多巴胺转运蛋白的蛋白质和基因表达，以及前额皮质靶区域内的多巴胺水平。在Specific Aim 4中，在Specific Aims 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，这些猴子已经具有行为特征。建立雌激素介导的分子、形态和神经化学改变与猴子认知状态的关系。

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.