Procurement and Characterization of Postmortem Brain Tissue

目前，HBCC资源包括患有以下诊断的个人的大脑(括号中列出的受试者数量)：躁郁症(153例)、非精神病对照(307例)、精神分裂症和分裂情感障碍(202例)、药物滥用(59例)、严重抑郁症(237例)、其他精神/神经学诊断136例(未诊断)(79例)。 数据库中的主题总数为1580个。从2017年10月1日到2018年7月31日，我们通过华盛顿特区和退伍军人管理局北部和中部验尸官办公室收集了78个大脑。 诊断病例数 1焦虑症 2双相情感障碍 4控制 2未确定的抑郁障碍 5种严重抑郁障碍 1神经科 1例强迫症 其他2个 48个待定 1例创伤后应激障碍 10种物质使用障碍 1个未确定 1例因脓毒症被排除 其他资源包括： -从数百名精神障碍患者和对照组的背侧前额叶皮质(DLPFC)、海马体、前扣带回皮质(ACC)和膝下前扣带回皮质(SgACC)以及硬脑膜构建的cDNA库 -来自DLPFC、海马体和硬脑膜的微阵列表达和基因分型数据(可在DBGaP Access ID：phs000979.v1.p1上公开获得) -放在载玻片上的冰冻切片(14微米厚)(来自32名精神分裂症患者和63名对照的DLPFC)， -福尔马林固定的单侧大脑半球冠状切片(约15毫米厚)，来自15名对照组，10名精神分裂症患者，5名重度抑郁症患者，4名双相情感障碍患者。 -来源于死后硬脑膜的成纤维细胞：450 -400名受试者的全基因组测序、RNA测序和芯片测序数据即将公开提供 -来自亚属ACC的200人的RNA测序数据可能在明年提供。 我们与神经生物库(NBB)和HBCC资源共享信息。我们从NMS获得了数百个样本的详细定量电子毒理学数据，并与NBB分享。我们实施了向DSM5/ICD10代码的转换，使我们的诊断定义可以轻松地与NBB共享。我们已经统一了HBCC中可用大脑区域/标本的命名和报告，目标是使NBB和研究人员能够轻松获得这些字段(工作正在进行中，因为我们有超过53,700个条形码生物显微镜可用)。 与去年同期相比，去年索取组织/数据的请求数量有所增加。自HBCC成立以来，我们已经为125个已获批准的项目向调查人员分发了样本和数据，其中大多数是在过去两年内。 仍在进行中或已在去年启动的项目/协作包括： 1.成人脑内未成熟神经元的定性和定量分析 2.人丘脑标记基因的荧光原位杂交 3.双相情感障碍患者Na+、K+ATPase与内源性心脏类固醇激素的关系 4.人脑中胰岛素的产生。 5.扣带回前皮质和背外侧前额叶皮质的单核RNA测序 6.正常志愿者和ADHD患者(血液、尾状核粉末状组织、黑质DNA和RNA)中多巴胺转运体基因甲基化作为多巴胺转运体结合的生物标志物 7.催产素受体在背外侧前额叶皮质和海马区的表达 8.神经退行性疾病和精神分裂症小胶质细胞的体细胞嵌合体 9.精神疾病中的转座因子 10.用RNA测序鉴定人类前岛在情感性障碍中的死后基因组表达 11.双相情感障碍的表观遗传老化加速和线粒体DNA拷贝数 12.尾状回和内侧前额叶皮质中ADHD的RNA-SEQ 13.催产素受体的放射性配基研究进展 14.严重精神病患者的全基因组基因分型。 15.开发与精神相关的短串联重复序列(STR)基因分型小组，该小组调节大脑中的基因表达。 16.精神分裂症患者眼眶-额叶皮质铁失调的作用。 17.抗精神病药物在D2-多巴胺受体上的药盒活性。 18.精神分裂症和双相情感障碍患者多巴胺神经元的转录组和表观基因组图谱。 19.人脑室下区的犬尿氨酸通路。 20.根据神经炎症对精神分裂症患者进行分层。 21.突触后密度和突触小体准备的蛋白质组学。 22.严重精神疾病患者海马区Ghrelin受体的表达 23.MIR137宿主基因的生理学与精神分裂症 24.与GABA相关的转录：衰老和遗传学。 25.定量聚合酶链式反应对来自sgACC的RNAseq结果的验证。 26.人脑在衰老过程中背外侧前额叶和后扣带回皮质转录组的变化。 27.重症精神病患者颞上回和背侧前扣带回的RNA序列分析 28.精神分裂症的分子图谱(单细胞+ATAC-seq)。 去年使用HBCC资源发表的手稿： 尔本·L、何明贤、莱曼斯·A、帕克·E、博南诺·A(2017)。一种新的细胞分辨率超灵敏的原位杂交方法检测短序列和剪接变异体。摩尔·神经比奥尔。55(7)：6169-6181 Hoffman GE，Hartley BJ，Flaherty E，Ladran I，Gochman P，Ruderfer DM等(2017)。精神分裂症在HiPSC来源的神经前体细胞和神经元中的转录特征与死后的成人大脑一致。NAT Commun 8(1)：2225。 LaPaglia DM，Sapio MR，Burbelo PD，Thierry-Mieg J，Thierry-Mieg D，Raithel SJ等人(2017)。人死后三叉神经节的RNA-Seq研究。头痛症：333102417720216。

Currently, the HBCC resources include brains from individuals with the following diagnoses (numbers of subjects listed in parentheses): Bipolar disorder (153), Non-psychiatric controls (307), Schizophrenia and schizoaffective disorder (202), Substance Abuse (59), Major depressive disorder (237), Other psychiatric/neurological diagnoses 136, Not diagnosed (79). A total number of subjects in the database is 1580. From Oct 1, 2017, until July 31, 2018 we collected 78 brains through the DC and Northern and Central VA Medical Examiners Offices. Number of cases Diagnosis 1 Anxiety Disorder 2 Bipolar Disorder 4 Control 2 Undetermined depressive disorder 5 Major depressive disorder 1 Neurological 1 Obsessive Compulsive Disorder 2 Other 48 pending 1 Post-traumatic stress disorder 10 Substance use disorder 1 Undetermined 1 was excluded due to sepsis Other resources include: -cDNA libraries constructed from dorsolateral prefrontal cortex (DLPFC), hippocampus, anterior cingulate cortex (ACC) and subgenual anterior cingulate cortex (sgACC), and dura from hundreds of subjects with mental disorders and controls -microarray expression and genotyping data (publicly available at dbGAP accession ID: phs000979.v1.p1) from DLPFC, hippocampus and dura -frozen sections (14 um thick) mounted on slides (DLPFC from 32 patients with schizophrenia and 63 controls), -formalin-fixed coronal slices (approximately 15 mm thick) of a single hemisphere from 15 controls, 10 patients with schizophrenia, 5 with major depression, 4 with bipolar disorder. -Fibroblasts derived from postmortem dura: 450 -Whole genome sequencing, RNA sequencing, and Chip-sequencing data for 400 subjects, to become publicly available soon -RNA sequencing data from 200 individuals from the subgenual ACC will become available probably in the next year. We share information with Neurobiobank (NBB) and HBCC resources. We obtain detailed quantitative electronic toxicological data from NMS on hundreds of our specimens and share them with NBB. We implemented a transition to DSM5/ICD10 codes that makes our diagnostic definitions easily sharable with NBB. We have unified the naming and reporting of brain regions/specimens available in HBCC with the goal of making these fields easily available to NBB and investigators (work in progress as we have over 53,700 barcoded biospecimens available). The number of requests for tissue/data in the last year increased compared to the same period last year. We have distributed samples and data to investigators for 125 approved projects since the inception of the HBCC, most in the last 2 years. The projects/collaborations that are still in progress or have been initiated in the last year are: 1. Qualitative and quantitative analysis of immature neurons in adult human brain 2. Fluorescent in situ hybridization for marker genes in human thalamus 3. Na+ and K+ ATPases and endogenous cardiac steroids in bipolar disorder 4. Insulin production in the human brain. 5. Single nucleus RNA sequencing in the subgenual anterior cingulate and dorsolateral prefrontal cortex 6. Methylation of the dopamine transporter gene as a biomarker for dopamine transporter binding in normal volunteers and patients with ADHD (blood, pulverized tissue of caudate, DNA and RNA from substantia nigra) 7. Oxytocin receptor expression in the dorsolateral prefrontal cortex and hippocampus 8. Somatic mosaicism in microglia in neurodegenerative disorders and schizophrenia 9. Transposable elements in psychiatric disorders 10. Characterization of human anterior insula postmortem genome expression in affective disorders using RNA-Sequencing 11. Accelerated epigenetic aging and mitochondrial DNA copy number in bipolar disorder 12. RNA-seq in ADHD in caudate and medial prefrontal cortex 13. Radioligand development for oxytocin receptors. 14. Whole genome genotyping of individuals with serious mental illness. 15. Development of a psychiatrically relevant genotyping panel of Short Tandem Repeats (STRs) that regulate gene expression in brain. 16. The role of iron dysregulation in the orbito-frontal cortex of individuals with schizophrenia. 17. Pharmacochaperone activity of antipsychotics at D2-Dopamine receptors. 18. Transcriptome and epigenome mapping in dopamine neurons from individuals with schizophrenia and bipolar disorder. 19. The kynurenine pathway in the human subventricular zone. 20. Stratifying people with schizophrenia based on neuroinflammation. 21. Proteomics of postsynaptic density and synaptosomal preparations. 22. Expression of Ghrelin receptors in hippocampus of individuals with serious mental illness. 23. Physiology of mir137 host gene and schizophrenia. 24. GABA related transcripts: aging and genetics. 25. qPCR validation of RNAseq findings from sgACC. 26. Human brain transcriptome changes during aging in the dorsolateral prefrontal and posterior cingulate cortices. 27. RNA-seq of the superior temporal gyrus and dorsal anterior cingulate cortex in serious mental illness 28. Molecular profiling (single cell + ATAC-seq) of schizophrenia. Manuscripts published in the last year using HBCC resources: Erben L, He MX, Laeremans A, Park E, Buonanno A (2017). A Novel Ultrasensitive In Situ Hybridization Approach to Detect Short Sequences and Splice Variants with Cellular Resolution. Mol Neurobiol. 55(7):6169-6181 Hoffman GE, Hartley BJ, Flaherty E, Ladran I, Gochman P, Ruderfer DM, et al (2017). Transcriptional signatures of schizophrenia in hiPSC-derived NPCs and neurons are concordant with post-mortem adult brains. Nat Commun 8(1): 2225. LaPaglia DM, Sapio MR, Burbelo PD, Thierry-Mieg J, Thierry-Mieg D, Raithel SJ, et al (2017). RNA-Seq investigations of human post-mortem trigeminal ganglia. Cephalalgia: 333102417720216.