背外侧前额叶皮层的单核转录组分析：包括 17q21.31 位点在内的神经元基因表达在 PTSD 应激反应中的机制作用。
Single-Nucleus Transcriptome Profiling of Dorsolateral Prefrontal Cortex: Mechanistic Roles for Neuronal Gene Expression, Including the 17q21.31 Locus, in PTSD Stress Response.
机构信息
Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, Mass. (Chatzinakos, Pernia, Iatrou, McCullough, Schuler, Snijders, DiPietro, Soliva Estruch, Anastasopoulos, Bowlby, Hartmann, N.M. Ressler, Carlezon, K.J. Ressler, Daskalakis); Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Mass. (Chatzinakos, Pernia, Iatrou, Schuler, Snijders, DiPietro, Soliva Estruch, Anastasopoulos, Bowlby, Daskalakis); National Center for PTSD, VA Boston Healthcare System, Boston (Morrison, Wolf, Logue, Miller); Department of Psychiatry (Morrison, Wolf, Logue, Miller), Department of Neurology (Huber), and Department of Biomedical Genetics (Logue), Boston University School of Medicine, Boston; Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands (Soliva Estruch, Snijders); RG Neurohomeostasis, Department of Psychiatry and Psychotherapy, Medical Faculty, University of Bonn, Bonn, Germany (Bajaj, Gassen); Department of Radiology, University Hospital Basel, University of Basel, Basel, Switzerland (Anastasopoulos); Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore (Bharadwaj, Kleinman); Department of Psychiatry, University of California San Diego, La Jolla (Maihofer, Nievergelt); Center for Excellence in Stress and Mental Health (Maihofer, Nievergelt) and Research Service (Maihofer, Nievergelt), Veterans Affairs San Diego Healthcare System, San Diego; Department of Psychiatry, Yale University School of Medicine, New Haven, Conn. (Krystal, Girgenti); Psychiatry Service, VA Connecticut Healthcare System, West Haven (Krystal, Girgenti); National Center for PTSD, Clinical Neurosciences Division, U.S. Department of Veterans Affairs, West Haven, Conn. (Krystal, Girgenti); Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore (Kleinman); Pathology and Laboratory Medicine, VA Boston Healthcare System, Boston (Huber); Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, and Broad Institute of MIT and Harvard, Cambridge, Mass. (Kellis); Department of Biostatistics, Boston University School of Public Health, Boston (Logue).
出版信息
Am J Psychiatry. 2023 Oct 1;180(10):739-754. doi: 10.1176/appi.ajp.20220478. Epub 2023 Jul 26.
OBJECTIVE
Multidisciplinary studies of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) implicate the dorsolateral prefrontal cortex (DLPFC) in disease risk and pathophysiology. Postmortem brain studies have relied on bulk-tissue RNA sequencing (RNA-seq), but single-cell RNA-seq is needed to dissect cell-type-specific mechanisms. The authors conducted the first single-nucleus RNA-seq postmortem brain study in PTSD to elucidate disease transcriptomic pathology with cell-type-specific resolution.
METHOD
Profiling of 32 DLPFC samples from 11 individuals with PTSD, 10 with MDD, and 11 control subjects was conducted (∼415K nuclei; >13K cells per sample). A replication sample included 15 DLPFC samples (∼160K nuclei; >11K cells per sample).
RESULTS
Differential gene expression analyses identified significant single-nucleus RNA-seq differentially expressed genes (snDEGs) in excitatory (EX) and inhibitory (IN) neurons and astrocytes, but not in other cell types or bulk tissue. MDD samples had more false discovery rate-corrected significant snDEGs, and PTSD samples had a greater replication rate. In EX and IN neurons, biological pathways that were differentially enriched in PTSD compared with MDD included glucocorticoid signaling. Furthermore, glucocorticoid signaling in induced pluripotent stem cell (iPSC)-derived cortical neurons demonstrated greater relevance in PTSD and opposite direction of regulation compared with MDD, especially in EX neurons. Many snDEGs were from the 17q21.31 locus and are particularly interesting given causal roles in disease pathogenesis and DLPFC-based neuroimaging (PTSD: , , and ; MDD: and ), while others were regulated by glucocorticoids in iPSC-derived neurons (PTSD: , ; MDD: ).
CONCLUSIONS
The study findings point to cell-type-specific mechanisms of brain stress response in PTSD and MDD, highlighting the importance of examining cell-type-specific gene expression and indicating promising novel biomarkers and therapeutic targets.
目的
创伤后应激障碍（PTSD）和重度抑郁症（MDD）的多学科研究表明背外侧前额叶皮层（DLPFC）与疾病风险和病理生理学有关。脑死后的研究依赖于组织 RNA 测序（RNA-seq），但需要单细胞 RNA-seq 来剖析细胞类型特异性机制。作者进行了 PTSD 死后大脑的第一项单细胞 RNA-seq 研究，以阐明具有细胞类型特异性分辨率的疾病转录组病理学。
方法
对 11 名 PTSD 患者、10 名 MDD 患者和 11 名对照者的 32 个 DLPFC 样本进行了分析（415K 个核；每个样本超过 13K 个细胞）。一个复制样本包括 15 个 DLPFC 样本（160K 个核；每个样本超过 11K 个细胞）。
结果
差异基因表达分析确定了兴奋性（EX）和抑制性（IN）神经元和星形胶质细胞中显著的单细胞 RNA-seq 差异表达基因（snDEGs），但在其他细胞类型或组织中没有。MDD 样本有更多的错误发现率校正显著 snDEGs，而 PTSD 样本的复制率更高。在 EX 和 IN 神经元中，与 MDD 相比，PTSD 中差异富集的生物学途径包括糖皮质激素信号。此外，诱导多能干细胞（iPSC）衍生皮质神经元中的糖皮质激素信号显示出与 PTSD 更相关，与 MDD 相反的调节方向，特别是在 EX 神经元中。许多 snDEGs 来自 17q21.31 基因座，鉴于它们在疾病发病机制和 DLPFC 神经影像学中的因果作用（PTSD： ， ， 和 ；MDD： 和 ），以及在 iPSC 衍生神经元中受糖皮质激素调节的其他基因（PTSD： ， ；MDD： ），这些基因特别有趣。
结论
该研究结果表明 PTSD 和 MDD 中大脑应激反应的细胞类型特异性机制，强调了检查细胞类型特异性基因表达的重要性，并指出了有前途的新型生物标志物和治疗靶点。
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