QQ客服 官方微博 反馈留言

题名	TRPV1 受体调控海马突触可塑性的机制及其功能意义
作者	李红斌
学位类别	博士
答辩日期	2007-04
授予单位	中国科学院研究生院
授予地点	北京
导师	徐林
关键词	辣椒素 辣椒素受体 长时程增强现象 长时程抑制现象 应激 空间记忆
其他题名	TRPV1 activation-modulated hippocampal synaptic plasticity prevents the stress effects on synaptic plasticity and spatial memory
学位专业	动物学
中文摘要	全世界有四分之一人口的日常饮食中包含辣椒及其相关食品，辣椒素是辣椒里使人产生辛辣和呛感觉的主要成分。辣椒素受体最初是在感觉神经元克隆到的，后来被命名为TRPV1，是因为发现它属于TRP（Transient receptor potential，瞬时受体势）离子通道家族。辣椒素及其受体在疼痛学领域已有广泛的研究，但它们如何调节脑功能却知之甚少。很多报道显示辣椒素受体在脑内广泛表达。在啮齿类动物的海马内，辣椒素受体从齿状回到CA3-CA1区均有表达。在亚细胞层次，辣椒素受体在神经元胞体，树突棘和突触部位均有表达。近年来辣椒素受体的内源性配体也被发现，包括花生四烯酸乙醇胺（anandamide, AEA）、氮磷脂-多巴胺(N-arachidonoyl-dopamine, NADA)、 精胺等。辣椒素在很多脑区（包括海马），可通过其受体调节神经元兴奋性和神经递质释放。 海马双向突触可塑性，长时程增强(LTP)和抑制现象(LTD)被认为是学习与记忆的细胞机制。而LTP/LTD的诱导阈值是由 NMDA受体的激活程度及其引起的突触后胞内钙水平决定的。因此调节NMDA受体和胞内钙信号被认为是调节LTP/LTD诱导阈值最直接有效的方式。考虑到辣椒素受体的突触分布及其对钙离子的高通透性，我们认为辣椒素受体的激活可能参与调节LTP/LTD的诱导阈值 本研究采用离体脑片场电位记录方式，发现辣椒素易化LTP的诱导而损伤了LTD的诱导，并且降低了LTP/LTD的诱导阈值。在给予辣椒素受体的拮抗剂以后，或者是在TRPV1基因敲除小鼠的脑片上，辣椒素对LTP/LTD的诱导均没有影响。我们发现的辣椒素对LTP/LTD的影响与行为学应激对LTP/LTD的影响，两者效应恰恰相反，应激是易化LTD的诱导而损伤LTP的诱导。如期所料，辣椒素使应激损伤的LTP恢复，同时阻断了应激易化的LTD。除了对LTP/LTD有重要的调节作用以外，我们的结果也显示应激严重损伤了动物对空间记忆的提取。所以我们进一步研究辣椒素能否对抗应激对动物空间记忆的损伤。我们发现海马内埋置导管给予辣椒素可以使应激损伤的空间记忆得到恢复，同样，灌胃给予辣椒素也可以对抗应激对动物空间记忆的损伤，进一步提示日常饮食中的辣椒会对应激相关的精神障碍有潜在的正面影响。 从动物实验到临床实验都有广泛的证据表明应激对认知功能，焦虑，创伤后应激综合症等有着深刻的影响。综上所述，我们第一次报道了辣椒素通过激活TRPV1受体可以对抗应激引起的空间记忆损伤，该效应可能是通过调节LTP/LTD的诱导阈值来实现的。我们工作的意义在于揭示了辣椒素受体在应激相关的精神疾病中的潜在作用，为寻找治疗应激相关的精神心理障碍提供了新的靶点，也为辣椒偏好的饮食习惯与精神卫生之间的关系研究提供了新的思路。
英文摘要	Capsaicin is the main pungent ingredient in hot chili peppers, which is consumed by nearly one-fourth of the world’s population on a daily basis. The capsaicin receptor is initially identified in sensory neurons and terms as TRPV1 for transient receptor potential vanilloid type-1 since it belongs to a large family of TRP ion channel. Capsaicin and TRPV1 have been extensively investigated in the pain perception, but their functions in the brain remains unclear. Accumulated evidences show that TRPV1 is expressed throughout the whole brain. In hippocampus, TRPV1 is expressed in many neurons throughout the dentate gyrus and CA3-CA1 subfield. At the subcellular level, TRPV1 can be detected predominantly on postsynaptic dendritic spines and cell soma. Recently, several endogenous ligands of TRPV1 have been characterized, which include anandamide (AEA), N-arachidonoyl-dopamine, and products of lipoxygenases. Capsaicin acting at TRPV1 has been demonstrated to modulate neuronal excitability and transmitter release in various brain regions, including hippocampus. Hippocampal bi-directional synaptic plasticity, long-term potentiation (LTP) and depression (LTD), is believed to underlie certain types of learning and memory. It is well known that the different level of NMDAR activation and the subsequently distinct Ca2+ signals determine the threshold of LTP/LTD. Therefore, changes in Ca2+ signaling are one of the most direct ways to alter the threshold of synaptic plasticity. Given the synaptic location of TRPV1 and its high Ca2+ permeability, we hypothesize that TRPV1 can modulate the threshold of LTP/LTD in the hippocampal CA1 area of rodent brain slice. Consistent with this idea, a recent report shows that TRPV1 knockout mice display decreased hippocampal LTP. However, whether TRPV1 activation by its ligands can modulate the threshold of LTP/LTD is still not known. In the present study we found that capsaicin enhanced LTP but reduced LTD as reflected by a leftward shift of the threshold for synaptic plasticity. In marked contrast, these capsaicin effects were absent after applying the antagonist of TRPV1 or using the TRPV1-KO mice. The behavioral stress is known to impair LTP, facilitate LTD and impair the retrieval of spatial memory, which effect seems opposite that of capsaicin. Therefore, we further investigate whether capsaicin can neutralize the effects of stress on LTP/LTD and on spatial memory retrieval. We found that capsaicin indeed neutralized the stress effects rapidly as indicated by normal LTP and no LTD in the stressed animals. Remarkably, either intra-hippocampal or i.g. application of capsaicin can rapidly overcome the stress effect on impairing spatial memory. This is the first evidence that capsaicin activated-TRPV1 not only modifies the threshold for synaptic plasticity but also effectively overcomes the stress effect on synaptic plasticity and spatial memory. These findings may stimulate the research for a potential therapeutic effect on the stress-associated mental disorders by consuming chili pepper.
语种	中文
公开日期	2010-10-14
内容类型	学位论文
源URL	[http://159.226.149.42:8088/handle/152453/6106]
专题	昆明动物研究所_学习记忆的分子神经机制
推荐引用方式 GB/T 7714	李红斌. TRPV1 受体调控海马突触可塑性的机制及其功能意义[D]. 北京. 中国科学院研究生院. 2007.

个性服务

查看访问统计

相关权益政策

暂无数据

收藏/分享

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。