【作者】 张俊然；

【导师】 胡三觉；

【作者基本信息】 第四军医大学 ， 神经生物学， 2008， 博士

【摘要】 背根节神经元是感觉传入的第一级神经元,其胞体发出的轴突分为两支:外周突伸向外周组织其末梢结构接受外界感觉信息;中枢突负责将已编码的刺激信息传入中枢。除了末梢结构以外的外周突部分与背根节神经元的中枢突一起称为初级传入纤维。脊髓背角是源于DRG神经元的初级传入纤维终止并与位于脊髓背角的中枢神经元形成突触的区域。这一区域在躯体感觉系统中起着重要的中继及处理感觉信息的作用,故透彻地研究初级传入纤维与脊髓背角神经元之间的突触传递过程具有重要的生物学意义。神经元接受刺激后产生动作电位,是神经元最主要的功能反应之一。以往对神经元电生理基本性质的研究中,发现了神经元产生动作电位具有多种不同排列组合的时间模式,也称为放电模式。并且证实这种组成序列的动作电位会通过突触向其它神经元进行传递,也即是说,神经元的放电模式很可能携带了要传递的信息。但是对于不同放电模式如何参与信息的传递还了解得很少。突触传递是中枢神经系统神经元之间信息传递的基本方式。突触前神经元接受刺激后产生具有一定时间排列特征动作电位,形成某种放电模式,该放电模式通过轴突传递到纤维末梢,引起末梢释放神经递质,完成电信号向化学信号的转换,达到信息传递的目的。神经元放电模式和神经递质释放之间、电信号与化学信号之间究竟存在什么相互关系的问题至今尚不清楚。突触传递效率是指突触对神经信息传递能力的大小。目前关于判定突触传递效率的指标,主要是对单个脉冲刺激诱发兴奋性和抑制性突触后电位(EPSPs和IPSPs)的幅度和斜率,兴奋性和抑制性突触后电流(EPSCs和IPSCs)的幅度和面积。传递效率的另一个直观指标是突触前/后序列的互信息值,突触传递互信息简单来说就是突触后信号保留突触前信息的能力。按照目前的观点,一系列动作电位才可能真正携带信息,所以应该综合考察不同排列组合的多个刺激脉冲引起突触后神经元产生EPSC和突触前后放电序列互信息的情况,以此检验突触前神经元不同放电模式对突触传递效率的影响。我们认为通过对不同模式放电序列的突触后EPSC和突触前后互信息的综合分析比较能够真实地反映突触传递效率。在本课题中,我们的主要研究内容包括以下三方面:(1)以实验数据为基础建立了脊髓背角无髓鞘纤维初级传入突触的计算机仿真模型,(2)分析模型中产生突触前不同放电模式的动力学机制(3)结合实验和模型,研究由短簇脉冲与单个脉冲所构成的两种不同时间结构的突触前放电模式的突触传递规律及其突触机制。主要结果:1.建立了脊髓背角无髓鞘纤维初级传入突触的仿真模型a.参考Scriven的工作建立了突触前无髓鞘纤维的放电模型。b.在Destexhe建立的突触模型基础上,结合脊髓背角初级传入突触的实验数据建立了此突触的传递模型。c.将突触前的放电模型和突触传递模型结合起来拟合实验数据建立脊髓背角无髓鞘纤维初级传入突触的仿真模型d.此模型可以修改成突触短时程可塑性模型而进行相关研究。作为一个双室模型,模型的适应范围很广,如可以修改模型的突触前部分使之成为脊髓背角有髓鞘纤维初级传入突触模型。2.突触前不同放电模式的动力学机制分析a.连续和簇这两种不同的放电模式是由不同的动力学机制决定的。b.这种动力学机制不同可以由Na-K泵的活动和刺激电流共同引起。3.脊髓背角初级传入突触不同突触前模式的突触传递-实验和模型的对比a.两种不同序列的突触前刺激时,总的说来,低频连续刺激(0.5~4Hz)更容易引起突触后的EPSC反应,其变异系数更小。b.突触后EPSC变异系数分析表明,连续刺激在只有AMPA受体介导的情况下更小、更稳定。簇刺激在AMPA+NMDA共同介导的情况下突触后EPSC变异系数更小、更稳定。c.通过计算突触前与突触后序列的互信息,他人实验证实短簇脉冲序列突触前后的互信息值显着地大于连续连续单个脉冲序列时的情况,但在模型中去掉NMDA受体成分后,我们发现短簇脉冲序列情况下的互信息值显著下降。结论:在本课题中,我们首次建立了脊髓背角无髓鞘纤维初级传入突触的仿真模型来研究不同动作电位模式通过此突触的传递过程。动力学分析表明:突触前产生不同放电模式是由于不同的动力学机制引起的。低频连续刺激(0.5~4Hz)更容易引起突触后的EPSC反应,其变异系数更小。簇刺激在AMPA+NMDA共同介导的情况下突触后EPSC变异系数更小、更稳定。通过计算突触前/后序列的互信息,发现在短簇脉冲序列刺激下,突触前脉冲序列所包含的信息可以更为可靠地通过突触传递。在模型中对突触前的释放概率进行扰动,发现突触前释放概率变异的增大对两种模式的突触传递过程没有明显的影响。在仿真模型和实验中都阻断NMDA受体成分后,发现短簇脉冲突触传递可靠性明显下降,提示短簇脉冲突触传递的可靠性主要是突触后机制,并且和NMDA受体成分关系密切。脊髓背角无髓鞘纤维初级传入突触的仿真模型可以较好地拟合在不同条件下所记录到的关于突触传递的实验数据,并分析在不同放电模式下突触传递效率差异的机制;此外,做为双室模型,模型可以方便的改动来进行其他方面的研究。更多还原

【Abstract】 Neurons in dorsal root ganglion are primary sensory neurons, whose axon has two branches: one projecting to the periphery and one prejecting to the central nervous system. The terminal of the peripheral branch of the axon is the only portion of the dorsal root ganlion neuron that is sensitive to natural stimuli. The properties of the nerve terminal determine the sensory function of each dorsal root ganglion neuron. The remainder of the peripheral branch, together with the central branch, is called the primary afferent fiber; it transmits the encoded stimulus information to the spinal cord or brain stem. Spinal dorsal horn is the region where the primary afferent fibers terminate and form synaptic contacts with the central neurons. In somatosensory system, spinal dorsal horn plays an important role in relaying and processing the sensory information. So it is of great biological significance to comprehensively study the syanptic transmission bentween primary afferent fiber and spinal dorsal horn neuron.Neurons are able to generate action potentials when the stimulation occurred. This is one of the most important functional responses for neurons. In the past study of basic electrophysiological properties of neurons it is found that action potentials have many types of timing pattern, which is also termed as firing pattern. Moreover, it is confirmed that the timing series of action potentials composed can be transmitted to other neurons via synapses. That is, firing pattern in neurons may contain information which needed to be conveyed. However, it is not confirmed whether firing pattern is coding mode of information transmission in nervous system. In addition, it is not known that whether firing pattern have biological significance. Synapse transmission is basic mode of information transmission in central nervous system. Chemical synapse and electrical synapse have two different structure and function. Presynaptic neurons generate action potentials with certain timing series when stimulated. These action potentials form firing pattern, which are delivered to fiber terminal via axon, thus cause transmitter release. In the end, transformation from electrical signal to chemical signal is completed and information transmission is fulfilled. What is the relationship between firing pattern and transmitter release? How do electrical signal transform to chemical signal?The efficiency of synapse transmission is the capability of neural information transmission between synapses. The assessed indexes of synapse transmission are as follows: the magnitude and slope rate of PSPs evoked by signal pulse stimulus; the magnitude and area of PSCs. The another indicator of synaptic transmission efficiency is mutual information.Mutual information,in a word,is the ability of postsynapse in keeping the presynaptic information completely.According to popular views, information can be carried by a series action potential only.As a result,to evaluate the impact factors of transmission efficiency,we should consider the different postsynaptic EPSCs induced by different presynaptic action potential and the mutual information both.So it is in great need of developing the further study how we establish a set of reasonable indexes of evaluation the efficiency of synapse transmission. The present research includes three objectives: (1) We created the simulational model of primary afferent synapses in unmyelinated nerve fiber based on the electrophysiological experimental data.(2)We analyze the dynamical mechanisms who caused different presynaptic firing patterns.(3)Combining the simulational model and the experimental data,we investigated the rules of synaptic transmission and synaptic mechanisms which dominate the bursting firing pattern and the single firing pattern.Main results:1. We finished the simulational model of primary afferent synapses in unmyelinated nerve fibera.We created the presynaptic C-fiber firing model by referred Sriven’s workb.Based on Destexhe’s model and the experimental data,we created the synaptic transmission model of primary afferent synapses in unmyelinated nerve fiber.c. Based on experimental data,we merge the presynaptic firing model and the synaptic transmission model to our model.d. This model can be modified to short-term plasticity model easily.As a two compartments model,the model can be widely used.For example,it can be modified to the model of primary afferent synapses in myelinated nerve fiber easily.2. We analyzed the dynamical mechanisms of different presynaptic firing patterns.a. Realized repetitive firing and busrting due to different dynamical mechanismb. The different dynamical mechanism can be induced by Na-K pump and inject current jointly.3. Synatpic transmission of different firing pattern on primary afferent synapse-the contrasting between model and experiment. a. In the different presynaptic condition,the low frequency presynaptic firing pattern(0.5~4Hz) can induce the postsynaptic EPSC more easily.And also,the CV is small in the low frequency presynaptic firing pattern condition.b. The CV analyzing show us,in the AMPA ONLY condition,the consecutive stimulus can make the CV stable.At the same , bursing stimulus accommodated the MPA&NMDA condition more.c. By calculating the mutual information between input and output trains, we found that under brief-burst stimulation, the information carried by input trains can be more reliably relayed during synaptic transmission. Conclusion:In the present research, we established our simulation model to study the mechanism of synaptic transmission at primary afferent synapse originally.To analyze the dynamical mechanism,we found the different firing patterns due to different dynamical mechanisms.The low frenquency(0.5~4Hz) repetitive stimulus can indue the EPSC easily and stably. By calculate the mutual information,we found the main temporal structure of presynaptic firing patterns can transfer to the postsynapse,especially in the presynaptic bursting firing patterns.According to distube the presynaptic release function in the model,we found that it has little effect in synaptic transmission process.After cuting off the NMDA component,we found that the reliability of bursting firing pattern transferring slow down sharply.It indicated that the mechanism of reliability of bursting firing pattern transferring is the postsynaptic mechanism,more over,the mechanism is related to NMDA tightly.Experimental data recorded under different conditions were fitted with small errors, using the model of synaptic transmission. This model can also be used to analyze the mechanism of change in transmission synaptic effiency. This method provides a good computational way to study the synaptic transmission in spinal dorsal horn. Our research systematically explored the transmission efficiency at primary afferent synapse and its mechanism. Moreover, the model is a double compartment model,it can be modified to other model easily,just like short-term plasticity model and simulational model of primary afferent synapse in myelinated nerve fiber.更多还原