黑质网状-束旁核GABA能神经环路在颞叶癫痫形成中的作用研究

发布时间：2018-06-03 10:41

本文选题：颞叶癫痫 + 抑制性神经环路　；参考：《浙江大学》2017年博士论文

【摘要】：黑质网状部(substantia nigra pars reticulata,SNr)位于中脑部位,其主要特征是γ-氨基丁酸(Gamma-aminobutyricacid,GABA)神经元富集,被认为可能与癫痫的形成相关,但是SNr参与调控癫痫形成的相关的神经环路及其机制仍然不清楚。本研究中我们分别使用在体神经元记录和钙信号光纤记录的方式,发现在颞叶癫痫发作过程中,SNr中的GABA能神经元及其主要亚型小清蛋白(Parvalbumin,PV)神经元都出现过度激活的现象。使用光遗传学或者化学遗传学的方式特异性地抑制SNr的GABA能神经元或PV神经元具有延缓颞叶癫痫形成的作用,而使用光遗传学特异性地激活SNr的PV神经元则会加速颞叶癫痫的形成。为了解析SNr的PV神经元的相关神经环路在颞叶癫痫形成中的作用及其功能,我们使用顺向单级突触病毒示踪的方式追踪了 SNr的PV神经元的投射下游核团,并据此进一步使用光遗传学分别特异性地调控SNr的PV神经元投射到丘脑束旁核(parafascular nucleus,PF),丘脑网状核(reticularis nucleus,RT)或者丘脑连结核(reuniens nucleus,RE)的投射轴突末端,发现只有SNr-PF的PV投射环路参与调控了颞叶癫痫的形成过程。此外,结合在体神经元记录,急性脑片离体电生理和逆向跨单突触病毒追踪等实验技术,我们发现SNr的PV神经元直接投射到PF的GABA能神经元,并对其产生抑制作用。最后使用光遗传学的方式调控PF的GABA能神经元,模拟了SNr-PF的PV神经元的投射作用,结果发现激活PF的GABA能神经元可以抑制颞叶癫痫的形成过程,抑制PF的GABA能神经元可以促进颞叶癫痫的形成过程。因此,本研究首次发现SNr的PV神经元可以投射到PF的GABA能神经元形成抑制性神经环路,并且这条抑制性神经环路参与调控了颞叶癫痫的形成过程,抑制这条环路可以有效减缓颞叶癫痫的形成过程。"SNr PV-PF GABA能抑制性神经环路"的发现丰富了对癫痫异常网络形成的认识,对临床精准治疗靶点的选择和药物的研发都具有一定的指导意义。
[Abstract]:The substantia reticulata (SNR) is located in the mesencephalon. Its main feature is the accumulation of Gamma-aminobutyricididine (GABA) neurons, which may be related to the formation of epilepsy. However, it is still unclear that SNr is involved in the neural loop involved in the regulation of epileptogenesis. In this study, we used in vivo neuron recording and calcium signal optical fiber recording respectively. We found that the GABA neurons and their main subtypes of white protein, Parvalbumin GABA, neurons in the temporal lobe epileptic seizures were over-activated. The specific inhibition of SNr GABA or PV neurons by means of photogenetics or chemical genetics has the effect of delaying the formation of temporal lobe epilepsy. PV neurons specifically activated by photogenetics can accelerate the formation of temporal lobe epilepsy. In order to elucidate the role and function of the neural loop associated with PV neurons of SNr in the formation of temporal lobe epilepsy, we tracked the projective downstream nuclei of PV neurons of SNr using a anterograde single-stage synaptic virus tracer. Furthermore, optogenetics was used to specifically regulate the projection of PV neurons of SNr to the end of projective axons of parafvascular nucleus, thalamic reticularis nucleus or thalamic conjunctival tuberculosis, respectively, in the parafascicular nucleus of the thalamus, or in the nucleus reticularis nucleus of the thalamus, or in the thalamic contiguous tuberculosis. It was found that only the PV projection loop of SNr-PF was involved in the process of temporal lobe epilepsy. In addition, in combination with in vivo neuronal recording, in vitro electrophysiology of acute brain slices and reverse transimple-synaptic virus tracing, we found that PV neurons of SNr project directly to PF GABA neurons and have an inhibitory effect on them. Finally, the GABA neurons of PF were regulated by photogenetics, and the projection of PV neurons of SNr-PF was simulated. The results showed that GABA neurons activated PF could inhibit the formation of temporal lobe epilepsy. GABA neurons that inhibit PF can promote the formation of temporal lobe epilepsy. Therefore, this study for the first time found that PV neurons of SNr can project into PF GABA neurons to form an inhibitory neural loop, which is involved in regulating the formation of temporal lobe epilepsy. Inhibition of this loop can effectively slow down the formation of temporal lobe epilepsy. The discovery of "SNr PV-PF GABA can inhibit neural loop" enriches the understanding of the formation of abnormal epileptic networks. It has certain guiding significance for the choice of target and the research and development of drugs.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R742.1

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