MECHANISMS UNDERLYING ADRENAL STEROID MODULATION OF LTP

LTP 的肾上腺类固醇调节机制

• 批准号: 2694144
• 负责人: CONSTANTINE PAVLIDES
• 金额: $ 14.05万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2694144
• 关键词: Animalia; NMDA receptors; adrenal medulla hormone; glucocorticoids; hippocampus; hormone regulation /control mechanism; long term potentiation; mineralocorticoids; neural transmission; neuroendocrine system; neuroregulation; steroid hormone receptor; stress

DESCRIPTION: Adrenal steroids modulate long-term potentiation (LTP) in the hippocampus. Further, the two types of adrenal steroid receptors, mineralocorticoid (MR) and glucocorticoid (GR), produce opposite effects in th dentate gyrus (DG) and CA1 hippocampal field-MR activation enhances while GR activation suppresses LTP. In the CA3 field, we observed that adrenal steroids modulate LTP in the commissural/ association input, for which LTP induction requires activation of N- methyl-D-aspartate receptors (NMDAR), while having no effects on the mossy fiber input for which LTP induction is NMDAR-independent, but rather depends on opioid peptides. This finding suggests possible underlying mechanisms for the adrenal steroid modulation of LTP. Acute stress also suppresses LTP in the hippocampus. Originally, the stress induced suppression in LTP was correlated with elevated plasma corticosterone levels, however, later studies supported the hypothesis that these effects wer probably due to elevations in opioid peptides, rather than adrenal steroids. For a number of reasons, however, these findings, are controversial. In light of new evidence, including preliminary findings from our laboratory, the mechanisms underlying stress induced suppression of LTP will have to be investigated. Practically nothing is known, about the mechanisms underlying the adrenal steroid modulation of LTP. We propose that both adrenal steroids and stress modulate LTP in the hippocampus (at least in certain hippocampal pathways) through their effects on glutamatergic neuro- transmission. This hypothesis is supported by a number of recent findings: 1) As stated above, in preliminary experiments we found that adrenal steroids modulate LTP only in pathways in which LTP is known to be dependent on glutamatergic, NMDAR; 2) it has been reported recently that blockade of NMDAR during the stress period eliminates the stress- induced suppression in LTP; 3) we now have preliminary evidence tha MR and GR activation modulate glutamatergic neurotransmission via NMDAR. There are three parts to this proposal: first, the preliminary experiments, testing the effects of MR and GR activation on LTP in the CA3 field, will be completed. Second, we will test whether stress induced suppression in LTP also occurs in both NMDA-dependent and opioid-dependent (NMDA-independent) pathways Finally, the direct effects of adrenal steroids and stress on NMDA dependent neurotransmission will be determined. Taken together, the results from these experiments should provide the first insight of the mechanisms underlying adrenal steroid and stress induced modulation of synaptic plasticity. Adrenal steroids have been implicated in learning and memory, aging and Alzheimer's disease. Understanding the mechanisms underlying their effects on synaptic plasticity will greatly enhance out understanding of how they may be involved in human disease.

描述：肾上腺类固醇调节脑内长时程增强(LTP) 海马体。此外，两种类型的肾上腺类固醇受体， 盐皮质激素(MR)和糖皮质激素(GR)产生相反的作用 海马齿状回(DG)和CA1区MR激活 增强而GR激活抑制LTP。在CA3领域，我们 观察肾上腺类固醇对连合LTP的调节作用 联想输入，其LTP诱导需要激活N- 甲基-D-天冬氨酸受体(NMDAR)，但不影响 苔藓纤维输入，其LTP诱导不依赖NMDAR，但 而是依赖于阿片肽。这一发现表明有可能 肾上腺类固醇调节LTP的潜在机制。 急性应激也会抑制海马体中的LTP。最初， LTP应激诱导抑制与血浆升高相关 然而，后来的研究支持了这一假说 这些效应可能是由于阿片肽的升高， 而不是肾上腺类固醇。然而，出于一些原因，这些 这些发现是有争议的。根据新的证据，包括 我们实验室的初步发现，潜在的机制 应激诱导的对LTP的抑制将不得不进行研究。 几乎什么都不知道，关于潜在的机制 肾上腺类固醇对LTP的调节作用。我们认为这两个肾上腺 类固醇和应激调节海马区的LTP(至少在某些情况下 海马区通路)通过它们对谷氨酸能神经元的影响 变速箱。这一假说得到了最近一系列 发现：1)如上所述，我们在初步实验中发现 肾上腺类固醇仅在LTP已知的途径中调节LTP 依赖谷氨酸，NMDAR；2)最近有报道说 在应激期阻断NMDAR可以消除压力- LTP的诱导抑制；3)我们现在有初步证据表明MR GR激活通过NMDAR调节谷氨酸能神经传递。 这项建议分为三个部分：第一，初步 实验，检测MR和GR激活对小鼠LTP的影响 CA3油田，将完成。第二，我们将测试压力是否 对LTP的诱导抑制也发生在NMDA依赖和 阿片依赖(NMDA非依赖)途径最终，直接作用 肾上腺类固醇和应激对NMDA依赖的神经传递的影响 要下定决心。总而言之，这些实验的结果 应该提供了对肾上腺潜在机制的第一个洞察力 类固醇和应激诱导突触可塑性的调节。肾上腺 类固醇与学习和记忆、衰老和 阿尔茨海默氏症。了解其背后的机制 对突触可塑性的影响将大大提高我们对OUT的理解 它们可能与人类疾病有关。