ESTROGEN AND MONKEY HIPPOCAMPAL NEUROGENESIS

雌激素与猴海马神经发生

• 批准号: 7409670
• 负责人: Jeffrey H Kordower
• 金额: $ 32.69万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7409670
• 关键词: Adult; Advisory Committees; Area; Biochemical; Biological; Brain; Bromodeoxyuridine; Cells; Chemicals; Cholinergic Agents; Cholinesterases; Chronic; Clinical; Condition; Confocal Microscopy; Count; Data; Development; Dose; Estrogen Replacement Therapy; Estrogens; Failure; Fiber; Foundations; Fruit; Funding; Genes; Glial Fibrillary Acidic Protein; Hippocampus (Brain); Hormonal; Hormones; Human; Injection of therapeutic agent; Label; Limb structure; Menopause; Midbrain structure; Minor; Modeling; Molecular; Molecular Profiling; Monkeys; Neurons; Pattern; Phenotype; Primates; Process; Progesterone; Property; Rattus; Rodent; Role; Schedule; Series; Site Visit; Synapses; System; Testing; Time; Treatment Protocols; United States National Institutes of Health; Ursidae Family; Vertebral column; Vimentin; Woman; aged; basal forebrain; cell type; cholinergic; clinically relevant; cognitive function; day; density; nerve supply; nestin protein; neurogenesis; nonhuman primate; programs; research study; response; species difference; toad; young adult

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.

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的各种标志物以及多巴胺能中皮质和黑质纹状体回路的影响。影响很小。这些影响仅限于斜角带垂直支(VLDB)和皮质胆碱能神经的轻微改变。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。未能在猴子身上复制以前在啮齿动物身上发现的结果，也可能是由于物种对ERT的反应存在差异，并突显了研究物种中雌激素相关过程的必要性。 离人类很近。然而，在目前的建议中，我们选择改变方向，而不是追求ERT在灵长类系统中的影响，对于这些系统，我们的模型无法证明可靠的发现。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，我们知道猴子一生中都有神经发生，然而，没有关于ERT对非人类灵长类神经发生影响的数据。因此，测试ERT在改变非人类灵长类动物神经发生方面的效力是合乎逻辑的，此外，我们将有机会在服用ERT+孕酮(P)的平行猴子组中进行这些研究，从而能够确定P是否与任何阳性反应相反 ERT对神经发生的影响。我们还将确定激素的释放模式，即周期性或慢性的E和P释放是否会影响非人类灵长类动物的神经发生。最后，神经解剖分析的多个标记和单细胞基因阵列将被用来详细描述新分化的神经元，以揭示它们的功能和电路特性。鉴于这一方向的彻底改变，我们认为目前只要求3年的支持是合适的。如果在这个资助期内的实验取得成果，我们将在补充中要求额外的两年资金。