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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）：妇女健康倡议（WHI）在2003-2004年报告称，激素替代疗法，无论是黄体酮和雌激素联合使用还是单独使用雌激素，对绝经后妇女的心血管或认知没有益处。这些结论导致数百万妇女退出激素替代疗法。然而，在流行病学研究中观察到的明显益处引发了对WHI研究的关键性重新评估。潜在的冲突包括马结合激素的使用、激素缺乏的持续时间和受试者的高龄。越来越明显的是，有一个“机会之窗”，其中激素替代有利于维持心血管和认知健康。不幸的是，我们对为什么E2替代可能会或可能不会挽救认知缺陷的理解受到细胞水平上关于E2如何调节突触功能。因此，临床数据的差异只能通过进一步研究E2作用的基本机制来解决。由于所有女性都会经历更年期，并且一生中有近1/3的时间处于这种状态，因此必须致力于深入研究，以获得新的知识，为维持心理和认知健康的干预措施提供见解。在海马CA 3-CA 1突触，雌二醇（E2）增加棘密度，NMDAR传输，和LTP 5 -8，被认为是增强记忆的基础机制。然而，它仍然是未知的，是否有增加的棘密度和LTP之间的功能关系。这一点很重要，因为在老年动物中，E2增加NMDAR表达，但不增加脊柱密度，这可以解释E2替代疗法的认知益处的年龄相关性降低。另一方面，老年动物可能能够增加可塑性，而不需要新突触的生长。也不知道从内嗅皮质到CA 1细胞的皮质输入是否类似于CA 3 Schaffer侧支突触被E2调制。这是至关重要的，因为这些突触在空间探索过程中驱动CA 1细胞，而雌二醇增加了空间记忆。已知E2需要胆碱能神经支配来增强记忆，但不知道突触功能的增加是否也是如此。由于E2保护胆碱能细胞免于退化，因此绝经期E2的丧失可能导致胆碱能细胞死亡增加。这一点很重要，因为绝经后妇女患阿尔茨海默病的风险比男性更大，而E2替代可以降低这种风险。因此，胆碱能传递不足将限制E2产生认知益处的能力。最后，没有研究调查的影响，长期的激素损失的能力E2诱导突触功能的变化。只有一项研究调查了NMDAR mRNA水平的潜在变化，但未观察到显著结果。这具有很高的临床重要性，因为确定机会窗口以及这与实际年龄的关系对于进一步了解激素替代疗法的有效性是绝对必要的。在本研究中，我们将采用细胞外树突状场电位和全细胞膜片钳记录技术，在年轻、中年和老年去卵巢（OVX）雌性大鼠的急性脑片CA 1区进行雌二醇或溶媒处理，以实现以下具体目的：AIM 1将检验E2通过增加表达NMDAR的沉默突触的密度来增加LTP幅度的假设 AIM 2将检验E2介导的对棘密度的影响的假设，突触功能不限于Schaffer侧支通路，还包括内嗅皮层和CA 1锥体细胞的远端树突之间的突触; AIM 3将检验以下假设：胆碱能去神经支配将阻止E2诱导的棘密度、NMDAR传递和LTP幅度的增加，但来自上级颈神经节的交感神经萌芽将挽救这些缺陷;目的4将检验这一假设，即长期的激素损失与正常衰老相结合，阻止了E2替代诱导CA 3-CA 1突触形态和功能变化的能力。