ESTROGEN AND MONKEY HIPPOCAMPAL NEUROGENESIS

在目前的资助期间，我们详细研究了ERT对胆碱能基底前脑系统以及多巴胺能中皮层和黑质纹状体回路的各种标志物的影响。效果甚微。这些影响仅限于斜角带垂直支（VLDB）和皮质胆碱能神经支配的适度改变。这些系统的许多差异可能是由于所采用的特定参数，如雌激素替代疗法（ERT）的剂量和时间表。未能在猴子中复制先前在啮齿动物中观察到的结果也可能是由于对ERT反应的物种差异，并强调了在物种中研究雌激素相关过程的必要性 接近人类。然而，在本提案中，我们选择改变方向，而不是追求ERT在灵长类动物系统中的影响，因为我们的模型无法证明这些系统具有强大的发现。相反，这个新的方向集中在ERT对猴子神经发生的影响上，这是一个在低等物种中看到的令人兴奋的发现。我们知道ERT影响大鼠的神经发生，我们知道神经发生在猴子的一生中，但是，没有关于ERT对非人灵长类动物神经发生影响的数据。因此，在非人灵长类动物中测试ERT改变神经发生的效力是合乎逻辑的，此外，我们将有机会在具有ERT+孕酮（P）的平行猴组中进行这些研究，因此将能够确定P是否对抗任何阳性反应。 ERT对神经发生的影响。我们还将确定是否激素的交付模式，即周期性或慢性E和P的交付影响非人类灵长类动物的神经发生。最后，神经解剖学分析和单细胞基因阵列的多个标志物将被用来表征新分化的神经元的非常详细，以揭示其功能和电路特性。鉴于方向的彻底改变，我们认为目前只要求3年的支持是适当的。如果在这段资助期内的试验取得成果，我们将要求额外两年的补充资助。

During the current funding period, we examined in detail the effects of ERT on a variety of markers of the cholinergic basal forebrain system as well as dopaminergic mesocortical and nigrostriatal circuits. Effects were few. The effects that were limited to modest alterations in the vertical limb of the diagonal band (VLDB) and cholinergic innervation of cortex. Many of the discrepancies with respect to these systems could be due to the specific parameters employed such as the dose and schedule of estrogen replacement therapy (ERT). The failure to replicate findings in monkeys previously seen in rodents could also be due to species differences in response to ERT and highlights the need to study estrogen-related processes in a species close to humans. However, in the present proposal, we chose to change directions rather than pursue effects of ERT in primate systems for which robust findings cannot be demonstrated in our model. Instead this new direction focuses on ERT's effects of neurogenesis in monkeys, an exciting finding seen in lower species. We know that ERT influences neurogenesis in rats and we know that neurogenesis occurs in monkeys throughout their lifetime, however, there are no data available on the effect of ERT on neurogenesis in nonhuman primates. Thus it is logical to test the potency of ERT in altering neurogenesis in nonhuman primates, in addition, we will have the opportunity to pursue these studies in a parallel group of monkeys that have ERT+progesterone (P), and thus will be able to determine if P counters any positive effects of ERT on neurogenesis. We will also determine whether the pattern of hormone delivery, that being cyclic or chronic E and P delivery influences neurogenesis in nonhuman primates. Finally, multiple markers for neuroanatomic analyses and single cell gene arrays will be used to characterize the newly differentiated neurons in great detail to reveal their functional and circuitry properties. Given this total change of direction, we feel it is appropriate to request only 3 years of support at this time. Should the experiments in this funding period bear fruit, we will ask for an additional 2 years of funding in a supplement.