酒精对线虫作用的分子机理及神经元功能成像研究
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摘要
酒精在现代社会中被广泛使用甚至滥用。酒精能够对神经系统产生严重的影响,长期饮酒能使机体对酒精产生耐受性和依赖性。在对酒精作用机制的研究中,近年来取得了一些重要的成果,但其分子机理仍然需要进一步深入研究。
酒精可以影响很多物种学习行为的发生。在模式生物——秀丽隐杆线虫(Caenorhabditis elegans)中,味觉可塑性是学习行为的一个简单的范例,即在无食物状态下,长时间暴露于吸引浓度的作为化学引诱剂的NaCl溶液之后,线虫会改变它们对NaCl的化学趋向性,最终表现出对NaCl的趋向性降低甚至回避。利用这种简单的模式化的学习行为,我们探讨了酒精对线虫味觉可塑性行为的影响及其作用机制。结果表明,无论是在预处理阶段还是随后的测试阶段加入酒精,都干扰了线虫对NaCl的味觉可塑性行为。此外,通过对酒精作用的效应时间、效应浓度和线虫培养环境的研究,我们发现：酒精这一作用不是状况依赖性的,味觉可塑性并不因酒精加入导致的前后关联条件的改变而丧失；酒精的作用效果也不具有剂量依赖性；酒精的作用与线虫的摄食状况有关,依赖于线虫良好的摄食状况。对神经系统相关的突变体线虫株系的分析表明,复合胺信号途径的关键基因如tph-1、ser-4和ser-7,以及G蛋白基因gpa-3参与了酒精影响线虫味觉可塑性的调控,并且复合胺信号也参与调控了酒精对移动、产卵行为的作用。还进一步发现酒精对于受到食物信号控制的其它行为—辛醇厌恶行为也具有影响。我们的结果揭示出复合胺信号通路在线虫响应急性的酒精作用中的调控作用。
本研究的另外一个重要方面,我们开发了一个带有矩形块状微阀和类Y型微通道的双层微流控芯片装置,用以实现线虫的活体固定和头部的液流刺激。在特异性启动子的控制下,利用钙离子指示探针G-CaMP标记线虫目标神经元,通过成像手段进行活体响应环境刺激时神经元细胞钙离子变化反应的检测。在此平台基础上,我们研究了ASE神经元(ASER和ASEL)感受NaCl刺激时的响应方式,以及受酒精的影响。结果表明,酒精可以直接在活体神经元水平上,影响ASER神经元对NaCl浓度升高产生的失活反应；对NaCl浓度降低产生的激活反应并无明显作用。并且,酒精对ASE神经元响应NaCl重复刺激的适应性具有明显作用。
本研究通过多种技术方法揭示出酒精对于线虫的急性效应以及复合胺信号途径在其中所起的调控作用。酒精作用于线虫学习行为的分子机制的探索以及酒精对于神经元活动的直接影响的研究结果,对于揭示高等动物中酒精影响神经系统的机理具有重要的推动作用。
Alcohol is widely used or even abused in modern society. Alcohol can cause serious problems on nervous system and long-term alcohol consumption is correlated with an increased risk of developing tolerance and alcoholism. Although some important results have been achieved in recent years, the molecular mechanisms underlying the behavioral effects of ethanol still need further study.
Ethanol can affect the formation of learning and memory in many species. In the model organism Caenorhabditis elegans, gustatory plasticity is a simple learning paradigm in which animals after prolonged pre-exposure to a chemo-attractive salt show chemo-aversion to this salt. Here, our results indicated that ethanol administration during pre-exposure or test stage interfered with gustatory plasticity in well-fed worms, in a dose-independent manner. Genetic analysis revealed that genes play important roles in serotonin signaling such as tph-1, ser-4 and ser-7 were involved in ethanol-mediated gustatory plasticity; serotonin signal also participated in behavior responses affected by ethanol such as locomotion and egg laying. In addition, the gpa-3 mutant animal, carrying mutations in the G-protein a subunit, also showed defects in response to ethanol in modulating gustatory plasticity. Further studies revealed that ethanol could affect the aversive response to diluted octanol, which was another behavioral response dependent on feeding status. These results suggested that serotonin signal play important roles in regulating acute intoxicating effects of ethanol in C. elegans.
Another important aspect in this study is that we developed a Y-shaped microfluidic chip for immobilizing and stimulating worms with a one-piece valve for enhanced immobilization of worms. A genetically encoded calcium sensor protein, G-CaMP, was expressed in ASE neurons of C. elegans under the control of specific promoters. Using the well-established interface shifting method, neuronal activities in response to stimuli of immobilized animals could then be monitored by in vivo fluorescence imaging. Results showed that average calcium transients in ASER neurons in response to up-step but not down-step of NaCl concentration were significantly affected by ethanol. ASER and ASEL exhibited different sensitivity in adaptation to NaCl, however ethanol produced significant effect on the adaptation response in ASEL neurons when compared to ASER neurons. Results of calcium imaging indicated that ethanol directly affected the neuronal activity of ASE neuron that plays a dominant role in chemotaxis to salt.
Together, our results demonstrated the distinct role of serotonin pathway in modulation of acute response to ethanol in gustatory plasticity in C. elegans. Investigation of the molecular mechanisms underlying ethanol's effect on learning behaviors in C. elegans as well as the direct impact of ethanol on neuronal activity may make a great contribution to the understanding of ethanol's function manner in higher animals.
酒精可以影响很多物种学习行为的发生。在模式生物——秀丽隐杆线虫(Caenorhabditis elegans)中,味觉可塑性是学习行为的一个简单的范例,即在无食物状态下,长时间暴露于吸引浓度的作为化学引诱剂的NaCl溶液之后,线虫会改变它们对NaCl的化学趋向性,最终表现出对NaCl的趋向性降低甚至回避。利用这种简单的模式化的学习行为,我们探讨了酒精对线虫味觉可塑性行为的影响及其作用机制。结果表明,无论是在预处理阶段还是随后的测试阶段加入酒精,都干扰了线虫对NaCl的味觉可塑性行为。此外,通过对酒精作用的效应时间、效应浓度和线虫培养环境的研究,我们发现：酒精这一作用不是状况依赖性的,味觉可塑性并不因酒精加入导致的前后关联条件的改变而丧失；酒精的作用效果也不具有剂量依赖性；酒精的作用与线虫的摄食状况有关,依赖于线虫良好的摄食状况。对神经系统相关的突变体线虫株系的分析表明,复合胺信号途径的关键基因如tph-1、ser-4和ser-7,以及G蛋白基因gpa-3参与了酒精影响线虫味觉可塑性的调控,并且复合胺信号也参与调控了酒精对移动、产卵行为的作用。还进一步发现酒精对于受到食物信号控制的其它行为—辛醇厌恶行为也具有影响。我们的结果揭示出复合胺信号通路在线虫响应急性的酒精作用中的调控作用。
本研究的另外一个重要方面,我们开发了一个带有矩形块状微阀和类Y型微通道的双层微流控芯片装置,用以实现线虫的活体固定和头部的液流刺激。在特异性启动子的控制下,利用钙离子指示探针G-CaMP标记线虫目标神经元,通过成像手段进行活体响应环境刺激时神经元细胞钙离子变化反应的检测。在此平台基础上,我们研究了ASE神经元(ASER和ASEL)感受NaCl刺激时的响应方式,以及受酒精的影响。结果表明,酒精可以直接在活体神经元水平上,影响ASER神经元对NaCl浓度升高产生的失活反应；对NaCl浓度降低产生的激活反应并无明显作用。并且,酒精对ASE神经元响应NaCl重复刺激的适应性具有明显作用。
本研究通过多种技术方法揭示出酒精对于线虫的急性效应以及复合胺信号途径在其中所起的调控作用。酒精作用于线虫学习行为的分子机制的探索以及酒精对于神经元活动的直接影响的研究结果,对于揭示高等动物中酒精影响神经系统的机理具有重要的推动作用。
Alcohol is widely used or even abused in modern society. Alcohol can cause serious problems on nervous system and long-term alcohol consumption is correlated with an increased risk of developing tolerance and alcoholism. Although some important results have been achieved in recent years, the molecular mechanisms underlying the behavioral effects of ethanol still need further study.
Ethanol can affect the formation of learning and memory in many species. In the model organism Caenorhabditis elegans, gustatory plasticity is a simple learning paradigm in which animals after prolonged pre-exposure to a chemo-attractive salt show chemo-aversion to this salt. Here, our results indicated that ethanol administration during pre-exposure or test stage interfered with gustatory plasticity in well-fed worms, in a dose-independent manner. Genetic analysis revealed that genes play important roles in serotonin signaling such as tph-1, ser-4 and ser-7 were involved in ethanol-mediated gustatory plasticity; serotonin signal also participated in behavior responses affected by ethanol such as locomotion and egg laying. In addition, the gpa-3 mutant animal, carrying mutations in the G-protein a subunit, also showed defects in response to ethanol in modulating gustatory plasticity. Further studies revealed that ethanol could affect the aversive response to diluted octanol, which was another behavioral response dependent on feeding status. These results suggested that serotonin signal play important roles in regulating acute intoxicating effects of ethanol in C. elegans.
Another important aspect in this study is that we developed a Y-shaped microfluidic chip for immobilizing and stimulating worms with a one-piece valve for enhanced immobilization of worms. A genetically encoded calcium sensor protein, G-CaMP, was expressed in ASE neurons of C. elegans under the control of specific promoters. Using the well-established interface shifting method, neuronal activities in response to stimuli of immobilized animals could then be monitored by in vivo fluorescence imaging. Results showed that average calcium transients in ASER neurons in response to up-step but not down-step of NaCl concentration were significantly affected by ethanol. ASER and ASEL exhibited different sensitivity in adaptation to NaCl, however ethanol produced significant effect on the adaptation response in ASEL neurons when compared to ASER neurons. Results of calcium imaging indicated that ethanol directly affected the neuronal activity of ASE neuron that plays a dominant role in chemotaxis to salt.
Together, our results demonstrated the distinct role of serotonin pathway in modulation of acute response to ethanol in gustatory plasticity in C. elegans. Investigation of the molecular mechanisms underlying ethanol's effect on learning behaviors in C. elegans as well as the direct impact of ethanol on neuronal activity may make a great contribution to the understanding of ethanol's function manner in higher animals.
引文
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