单细胞转录组测序在药物成瘾研究中的应用

Application of Single Cell Transcriptome Sequencing in Drug Addiction Research

药物成瘾是复杂的中枢神经系统疾病,相关基础与临床研究均证实药物成瘾的神经机制及神经环路在成瘾行为形成的不同阶段逐渐发生改变。利用全基因组关联研究、全基因组测序、全外显子测序或高通量转录组测序等技术的组学研究对包括药物成瘾在内的精神疾病遗传的脆弱性进行了深入研究。上述单核苷酸多态性检测技术或测序技术主要预测疾病的遗传风险位点。然而,许多中枢神经系统疾病的发生与环境因素密切相关,而且在疾病发展的不同阶段,相关基因的表达存在脑区特异性的细胞异质性信息。因此,传统研究对发病机制的解释存在一定的局限性。单细胞转录组测序技术是针对单个细胞进行转录水平的测定,规避了传统测序对细胞群体平均转录水平检测的缺点,可以定量描述细胞异质性。近年来,单细胞转录测序技术在神经精神科学研究中的应用逐渐受到关注,本文总结了该技术在神经科学研究中的重要应用,并以药物成瘾为例,重点阐述说明其在中枢神经系统疾病中的应用价值。

Drug addiction is a complicated central nervous system(CNS)disorder.Both basic and clinical studies have confirmed that the neural mechanisms of drug addiction are progressively altered at different stages of the development of addictive behaviors.Genomic studies using technologies such as whole-genome association studies,whole-genome sequencing,whole-exome sequencing or high-throughput transcriptome sequencing have provided insight into the genetic vulnerability of mental disorders,including drug addiction.The single nucleotide polymorphism detection techniques or sequencing technologies mainly predict genetic risk loci for diseases.However,the occurrence of many CNS disorders is closely related to environmental factors and there is brain region-specific cellular heterogeneity information on the expression of relevant genes at different stages of disease development.Therefore,traditional molecular genetic studies have limitations in explaining the pathogenesis of CNS disorder.Single-cell RNA sequencing(ScRNA-seq)technologies,which target individual cells for transcript level determination,avoid the disadvantages of traditional sequencing for detecting the average transcript level of cell populations and can quantitatively describe cellular heterogeneity.In recent years,single-cell transcriptional sequencing technology has been applied to the study of drug addiction.The cortico-mesolimbic system,corticostriatal-thalamo-cortical pathway and the hippocampus are important brain regions associated with drug addiction.It was found that more neuronal subtypes exist in both the striatum and hippocampus than previously known.In the cortex,pyramidal neurons exhibit a projection-specific gene expression profile.In rodent models experiencing from cocaine,morphine,and tetrahydrocannabinol,recent studies have identified single-cell transcriptome alterations in the nucleus accumbens and prefrontal cortex,the key brain regions for rewarding.These studies have advanced the mechanisms of drug addiction and drug development to the level of cellular resolution in specific brain regions.This review summarizes the important applications of single-cell RNA-Seq in neuroscience research and uses drug addiction as an example to illustrate its value in the study of CNS disorders.