Estrogen and hippocampal plasticity

雌激素和海马可塑性

基本信息

批准号：
8257977
负责人：
LORI Lynn MCMAHON
金额：
$ 32.3万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8257977
关键词：
Acute Address Age Aging Alzheimer&apos s Disease Anatomy Animals Area Behavior Binding Biochemistry Biological Assay Cardiovascular system Cell Death Cell physiology Cells Clinical Clinical Data Cognition Cognitive Cognitive deficits Collection Conflict (Psychology)Conjugated Equine Estrogens Conjugated Estrogens Data Dendrites Denervation Development Disease Distal Effectiveness Elderly Electrophysiology (science)Enrollment Epidemiologic Studies Equus caballus Estradiol Estrogen Replacement Therapy Estrogens Event Excitatory Synapse Female H19 gene Health Hippocampus (Brain)Hormone replacement therapy Hormones Intervention Investigation Knowledge Lead Learning Life Link Literature Longevity Mammals Mediating Memory Memory impairment Menopause Messenger RNA Morphology Muscarinic Acetylcholine Receptor Ovarian Ovariectomy Pathway interactions Plasma Plastics Postmenopause Progesterone Psyche structure Publishing Pyramidal Cells Rattus Replacement Therapy Reporting Research Risk Role Short-Term Memory Slice Structure of superior cervical ganglion Synapses System Techniques Testing Time Vertebral column Woman Women&apos s Health age related aged base cholinergic cholinergic neuron cognitive function critical period density deprivation effective intervention entorhinal cortex extracellular falls hormone deficiency improved functioning insight memory process men middle age nerve supply neural circuit new growth normal aging object recognition patch clamp prevent receptor synaptic function transmission process young adult

项目摘要

DESCRIPTION (provided by applicant): The Women's Health Initiative (WHI) reported in 2003-2004 that hormone replacement therapy, either progesterone and estrogen in combination or estrogen alone, provided no cardiovascular or cognitive benefit in postmenopausal women. These conclusions lead millions of women to withdraw from hormone replacement therapy. However, clear benefits observed in epidemiological studies have initiated a critical reevaluation of the WHI study. Potential conflicts include the use of equine conjugated hormones, the duration of hormone deficiency, and the advanced age of the subjects. It is becoming increasingly obvious that there is a "window of opportunity" in which hormone replacement is beneficial for maintaining both cardiovascular and cognitive health. Unfortunately, our understanding of why E2 replacement may or may not rescue cognitive deficit is hindered by insufficient mechanistic information at the cellular level regarding how E2 modulates synaptic function. Thus, the discrepancy in the clinical data will only be resolved by further investigation into the basic mechanisms through which E2 acts. Because all women undergo menopause and spend nearly 1/3 of their life in this state, intensive research effort must be dedicated to obtaining new knowledge that will provide insight for interventions to sustain mental and cognitive health. At hippocampal CA3-CA1 synapses, estradiol (E2) increases spine density, NMDAR transmission, and LTP5-8, mechanisms believed to underlie the enhanced memory. However, it remains unknown whether there is a functional relationship between the increased spine density and LTP. This is important because in aged animals, E2 increases NMDAR expression but not spine density, which may explain the age related decrease in cognitive benefit of E2 replacement therapy. On the other hand, aged animals may be able to increase plasticity without the growth of new synapse. It is also not known whether the cortical input onto CA1 cells from the entorhinal cortex is modulated by E2 similarly to CA3 Schaffer collateral synapses. This is critical to know because these synapses drive CA1 cells during spatial exploration and estradiol increases spatial memory. It is known that E2 requires cholinergic innervation to enhance memory, but is it not known whether the same is true for the increase in synaptic function. Because E2 protects cholinergic cells from degeneration, loss of E2 in menopause could lead to increased cholinergic cell death. This is significant because post menopausal women are at greater risk of developing Alzheimer's disease than men and E2 replacement decreases this risk. Therefore insufficient cholinergic transmission would limit the ability of E2 to cause cognitive benefit. Finally, no study has investigated the impact of prolonged hormone loss on the ability of E2 to induce changes in synaptic function. Only one study has investigated potential alterations in NMDAR mRNA levels, but no significant results were observed. This is of high clinical importance because determining the window of opportunity and how this relates to chronological age is absolutely essential to further our understanding of the effectiveness of hormone replacement therapy. In this proposal, we will use extracellular dendritic field potential and whole-cell patch clamp recording techniques in area CA1 of acute slices from young adult, middle aged and aged ovariectomized (OVX) female rats treated with estradiol or vehicle to pursue the following Specific Aims: AIM 1 will test the hypothesis that E2 increases the magnitude of LTP by increasing the density of silent synapses which express NMDARs containing NR2B subunits; AIM 2 will test the hypothesis that E2 mediated effects on spine density and synaptic function are not limited to the Schaffer collateral pathway but also include synapses between the entorhinal cortex and the distal dendrites of CA1 pyramidal cells; AIM3 will test the hypothesis that cholinergic denervation will prevent the E2 induced increase in spine density, NMDAR transmission, and LTP magnitude but that sympathetic sprouting from the superior cervical ganglia will rescue these deficits; AIM 4 will test the hypothesis that prolonged hormone loss combined with normal aging prevents the ability of E2 replacement to induce morphological and functional changes at CA3-CA1 synapses.

描述（由申请人提供）：妇女健康计划（WHI）在2003 - 2004年报道说，仅在联合或雌激素中，孕酮和雌激素替代疗法都没有提供绝经后妇女的心血管或认知益处。这些结论导致数百万妇女退出激素替代疗法。但是，在流行病学研究中观察到的明显好处已开始对WHI研究的重新评估。潜在的冲突包括使用马共轭激素，激素缺乏症的持续时间以及受试者的高龄。越来越明显的是，有一个“机会之窗”，其中激素替代对维持心血管和认知健康是有益的。不幸的是，我们对为什么替换E2可能会或可能不会挽救认知缺陷的理解受到有关E2的方式的机械信息的不足而阻碍调节突触功能。因此，仅通过对E2采取的基本机制进行进一步研究，才能解决临床数据中的差异。由于所有妇女都会更年期并在这种州度过近1/3的生命，因此必须致力于获得新知识，以提供干预措施以维持心理和认知健康。在海马CA3-CA1突触下，雌二醇（E2）增加了脊柱密度，NMDAR传播和LTP5-8，被认为是增强记忆力的基础的机制。但是，尚不清楚脊柱密度和LTP之间是否存在功能关系。这很重要，因为在老年动物中，E2增加了NMDAR的表达，但不能增加脊柱密度，这可能解释了E2替代疗法的认知益处相关的降低。另一方面，老年动物可能能够提高可塑性，而不会增长新的突触。也不知道是否从内嗅皮层上的CA1细胞上的皮质输入与CA3 Schaffer侧支突触相似。这是至关重要的，因为这些突触在空间探索过程中驱动CA1细胞，而雌二醇会增加空间记忆。众所周知，E2需要胆碱能神经才能增强记忆，但是不知道突触功能的增加是否正确。由于E2保护胆碱能细胞免受变性，因此更年期E2的丧失可能导致胆碱能细胞死亡增加。这很重要，因为更年期后妇女比男性更大的风险患阿尔茨海默氏病的风险更大，而E2替代降低了这种风险。因此，胆碱能传播不足将限制E2引起认知益处的能力。最后，尚无研究研究长期激素损失对E2诱导突触功能变化能力的影响。只有一项研究研究了NMDAR mRNA水平的潜在变化，但未观察到显着的结果。这具有很高的临床重要性，因为确定机会窗口以及与年代年龄有关，对于进一步了解激素替代疗法的有效性绝对至关重要。在这项建议中，我们将使用细胞外树突状野外潜力和全细胞斑块夹记录技术在年轻人，中年和年龄卵巢型（OVX）的急性切片区域中的CA1区域中，用雌二醇或雌二醇或工具处理的雌性大鼠以下特定目标：AIM 1的反应测试e2 silties nisters niste e2 cann s and senters nister niste nign Mans niste and niste nign sy nign Mans nign Manges nign Manges nign Manges nign Manges Ins Ins Ins Ins Ins Ins Ins Ins Ins Ins Ins Ins Ins Ins Ins Ins Mantive Ltp增强LTP。 NMDARS 包含NR2B亚基； AIM 2将检验以下假设：E2介导对脊柱密度的影响和突触功能不仅限于Schaffer侧支途径，还包括内嗅皮层和Ca1锥体细胞的远端树突之间的突触； AIM3将检验以下假设：胆碱能神经支配将防止E2诱导的脊柱密度，NMDAR传播和LTP幅度的增加，但从上颈神经节中产生的交感神经发芽将挽救这些缺陷。 AIM 4将检验以下假设：延长的激素损失与正常老化相结合可以防止E2替代诱导CA3-CA1突触时形态和功能变化的能力。