MECHANISMS UNDERLYING ADRENAL STEROID MODULATION OF LTP

LTP 的肾上腺类固醇调节机制

• 批准号: 2892195
• 负责人: CONSTANTINE PAVLIDES
• 金额: $ 13.33万
• 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/2892195
• 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 齿状回 (DG) 和 CA1 海马区 - MR 激活 增强而 GR 激活抑制 LTP。 在CA3领域，我们 观察到肾上腺类固醇在连合/ 关联输入，为此 LTP 诱导需要激活 N- 甲基-D-天冬氨酸受体（NMDAR），同时对 LTP 感应与 NMDAR 无关的苔藓纤维输入，但是 相反取决于阿片肽。 这一发现表明可能 LTP 的肾上腺类固醇调节的潜在机制。 急性压力还会抑制海马体中的 LTP。 本来， LTP 中应激诱导的抑制与血浆升高相关 然而，皮质酮水平，后来的研究支持了这一假设 这些影响可能是由于阿片肽的升高造成的， 而不是肾上腺类固醇。 然而，由于多种原因，这些 研究结果，存在争议。 根据新证据，包括 我们实验室的初步发现，其背后的机制 必须研究应激诱导的 LTP 抑制。 关于其背后的机制实际上一无所知 LTP 的肾上腺类固醇调节。 我们建议，无论是肾上腺 类固醇和压力调节海马体中的 LTP（至少在某些方面） 海马通路）通过其对谷氨酸能神经的影响 传播。 这一假设得到了近期多项研究的支持 研究结果：1）如上所述，在初步实验中我们发现 肾上腺类固醇仅在 LTP 已知的途径中调节 LTP 依赖于谷氨酸、NMDAR； 2）最近有报道称 在压力期间封锁 NMDAR 消除了压力- 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。 该提案分为三个部分：一是初步建议。 实验，测试 MR 和 GR 激活对 LTP 的影响 CA3场，即将竣工。 其次，我们会测试是否有压力 LTP 诱导的抑制也发生在 NMDA 依赖性和 阿片类药物依赖（NMDA 独立）途径 最后，直接影响 肾上腺类固醇和 NMDA 依赖性神经传递的压力将 被确定。 综合起来，这些实验的结果 应该提供对肾上腺潜在机制的第一个了解 类固醇和应激诱导的突触可塑性调节。 肾上腺 类固醇与学习和记忆、衰老和衰老有关 阿尔茨海默病。 了解其背后的机制 对突触可塑性的影响将大大增强我们的理解 他们如何参与人类疾病。