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Title: 基于转录因子Lmx1b条件性敲除来研究中枢5-HT神经元的功能
Author: 戴金霞
Degree Level: 博士
Issued Date: 2008-05-16
Degree Grantor: 中国科学院上海生命科学研究院
Place of Degree Grantor: 上海生命科学研究院
Supervisor: 丁玉强
Keyword: 5-HT ; 恐惧记忆 ; 焦虑 ; 长时程增强 ; 长时程抑制 ; 海马
Alternative Title: Research on the function of central 5-HT neuron by Lmx1b conditional konckout
Major: 神经生物学
Abstract: 中枢5-HT是调节许多生理活动和行为的重要调质,它的不足导致多种精神类疾病如焦虑、抑郁和创伤后应激综合症(以异常的恐惧记忆为特征),但是真正的机理并不清楚。同时近来的研究对于5-HT在这些疾病中的作用存在很多争议。为了研究中枢5-HT在生理活动和行为过程中的确切功能,我们利用条件性敲除遗传学策略在中枢5-HT神经元特异敲除转录因子Lmx1b来阻止5-HT神经元的产生,从而得到了中枢5-HT缺乏(CKO)小鼠,进而对其开展了一系列行为学研究包括焦虑和抑郁、空间学习和记忆、环境关联性恐惧记忆、吗啡成瘾等。Morris水迷宫研究结果显示中枢5-HT缺乏小鼠的空间学习正常,但是空间记忆受损。黑白穿梭箱、高平台和新颖环境抑制摄食的行为学研究得到了出乎意料的结果,此小鼠的焦虑水平是下降的。中枢5-HT缺乏小鼠的环境关联性恐惧记忆相对于野生型小鼠是增强的,而且这种增强的恐惧记忆可以通过在体给予5-HT或DPAT而缓解。进一步的电生理研究显示,此小鼠的海马不能产生足部电击抑制LTP和诱导LTD的现象,但是在加入5-HT或DPAT后可以产生足部电击对海马突触可塑性的调控,说明这些突触可塑性的异常是由于缺乏5-HT引起的。此外,中枢5-HT缺乏小鼠的吗啡成瘾行为不仅增强而且持久,且吗啡成瘾引起的海马LTP的诱导强于野生型对照。我们的这些行为学和电生理研究结果表明,中枢5-HT神经元的敲除会导致焦虑水平下降而不是升高,空间记忆受损坏,但是恐惧记忆和吗啡成瘾行为增强。海马在空间记忆和环境关联性恐惧记忆的形成和维持中起着关键的作用,我们推测海马突触可塑性的改变可能是小鼠行为异常的神经学基础之一。
English Abstract: Central serotonin (5-HT) is an important neuromodulator for regulating numerous physiological and behavioural activities. Its deficiency is believed to be responsible for the development of mental disorders such as anxiety, depression and posttraumatic stress disorder (characterized by abnormal fear memories), but the underlying neural mechanisms remain largely unclear. And recent studies have demonstrated contradictory findings on the roles of central 5-HT in these physiological process. To study the function of 5-HT in the physiological and behavioral processes, we generated conditional knockout mice in which transcription factor Lmx1b was inactivated specifically in raphe nuclei to prevent the development of central 5-HT neurons and examined their anxiety, spatial memory, contextual fear memory and morphine addiction behaviour. In the present studies, we found that central 5-HT deficient mice showed normal spatial learning but impaired spatial memory in Morris water maze test. Surprisingly, central 5-HT deficient mice showed reduced anxiety-like behaviours in light-dark choice, elevated-plus maze and novelty-suppressed feeding tests. Contextual fear memory of central 5-HT deficient mice was stronger than that of wild type mice and this enhanced fear memory was attenuated by giving 5-HT or DPAT in vivo. Further electrophysiological studies in hippocampal slices showed that foot-shock-induced suppression of LTP and induction of LTD were not observed in central 5-HT deficient mice, which was rescued by bath application of 5-HT or DPAT in vitro, suggested that the alteration of hippocampal synaptic plasticity is caused by loss of central 5-HT. Moreover, morphine addictive behaviour of central 5-HT deficient mice became markedly endurable and LTP induction in hippocampal slices of central 5-HT deficient mice was more enhanced than that of WT mice after morphine sensitization. Our findings indicate that genetic removal of central 5-HT neurons in mice results in a reduction of anxiety-like behaviour and impaired spatial memory but an increase of contextual fear memory and morphine addictive behaviour. As hippocampus has a key role in the formation and maintenance of spatial memory and contextual fear memory, we propose that the altered hippocampal synaptic plasticity may contribute to these aberrant behaviours.
Language: 中文
Content Type: 学位论文
URI: http://ir.sibs.ac.cn/handle/331001/2360
Appears in Collections:神经所(总)_学位论文

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Recommended Citation:
基于转录因子Lmx1b条件性敲除来研究中枢5-HT神经元的功能.戴金霞[d].中国科学院上海生命科学研究院,2008.20-25
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