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解码神经精神疾病和精神活性药物对额颞叶和细胞类型特异性的脆弱性。

Decoding frontotemporal and cell-type-specific vulnerabilities to neuropsychiatric disorders and psychoactive drugs.

机构信息

Institute for Big Data and Artificial Intelligence in Medicine, School of Science, China Pharmaceutical University (CPU), Nanjing, Jiangsu 211198, People's Republic of China.

Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, People's Republic of China.

出版信息

Open Biol. 2024 Jun;14(6):240063. doi: 10.1098/rsob.240063. Epub 2024 Jun 12.

DOI:10.1098/rsob.240063
PMID:38864245
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11285532/
Abstract

Frontotemporal lobe abnormalities are linked to neuropsychiatric disorders and cognition, but the role of cellular heterogeneity between temporal lobe (TL) and frontal lobe (FL) in the vulnerability to genetic risk factors remains to be elucidated. We integrated single-nucleus transcriptome analysis in 'fresh' human FL and TL with genetic susceptibility, gene dysregulation in neuropsychiatric disease and psychoactive drug response data. We show how intrinsic differences between TL and FL contribute to the vulnerability of specific cell types to both genetic risk factors and psychoactive drugs. Neuronal populations, specifically PVALB neurons, were most highly vulnerable to genetic risk factors for psychiatric disease. These psychiatric disease-associated genes were mostly upregulated in the TL, and dysregulated in the brain of patients with obsessive-compulsive disorder, bipolar disorder and schizophrenia. Among these genes, GRIN2A and SLC12A5, implicated in schizophrenia and bipolar disorder, were significantly upregulated in TL PVALB neurons and in psychiatric disease patients' brain. PVALB neurons from the TL were twofold more vulnerable to psychoactive drugs than to genetic risk factors, showing the influence and specificity of frontotemporal lobe differences on cell vulnerabilities. These studies provide a cell type resolved map of the impact of brain regional differences on cell type vulnerabilities in neuropsychiatric disorders.

摘要

额颞叶异常与神经精神疾病和认知有关，但颞叶 (TL) 和额叶 (FL) 之间细胞异质性在遗传风险因素易感性中的作用仍有待阐明。我们将“新鲜”人类 FL 和 TL 的单细胞转录组分析与遗传易感性、神经精神疾病中的基因失调和精神活性药物反应数据相结合。我们展示了 TL 和 FL 之间的内在差异如何导致特定细胞类型对遗传风险因素和精神活性药物的易感性。神经元群体，特别是 PVALB 神经元，对精神疾病的遗传风险因素最为敏感。这些与精神疾病相关的基因主要在上调 TL 中上调，并在强迫症、双相情感障碍和精神分裂症患者的大脑中失调。在这些基因中，与精神分裂症和双相情感障碍相关的 GRIN2A 和 SLC12A5 在 TL PVALB 神经元和精神疾病患者的大脑中显著上调。来自 TL 的 PVALB 神经元对精神活性药物的敏感性是遗传风险因素的两倍，这表明额叶差异对细胞易感性的影响和特异性。这些研究提供了一个细胞类型分辨率的图谱，说明了大脑区域差异对神经精神疾病中细胞类型易感性的影响。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d9b/11285532/7c0c962952d2/rsob.240063.f006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d9b/11285532/ffefb2d4ec6c/rsob.240063.f001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d9b/11285532/710d710b8070/rsob.240063.f002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d9b/11285532/384e8139997a/rsob.240063.f003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d9b/11285532/3f1d841f5453/rsob.240063.f004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d9b/11285532/077b708ad30e/rsob.240063.f005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d9b/11285532/7c0c962952d2/rsob.240063.f006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d9b/11285532/ffefb2d4ec6c/rsob.240063.f001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d9b/11285532/710d710b8070/rsob.240063.f002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d9b/11285532/384e8139997a/rsob.240063.f003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d9b/11285532/3f1d841f5453/rsob.240063.f004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d9b/11285532/077b708ad30e/rsob.240063.f005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d9b/11285532/7c0c962952d2/rsob.240063.f006.jpg

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