Translational Approach to Social Isolation During a Global Pandemic: Hippocampal Somatic Mutation and Stress
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Objective The coronavirus disease-2019 (COVID-19) pandemic’s social isolation has significantly impacted mental health, increasing depression and anxiety. This study explores the effects of social isolation on both humans and mice, focusing on behavioral changes and hippocampal protein expression. It also investigates genetic alterations through single-cell RNA and whole-genome sequencing (WGS).Methods Here we conducted behavioral studies, protein expression studies, single-nucleus sequencing (snRNAseq), and WGS of the hippocampus of mice that underwent early maternal separation and social isolation, and a demographic study of community populations who had been self-quarantined owing to COVID-19 exposure to investigate the link between somatic mutations and stress due to social isolation.Results The demographic study demonstrated more negative mental health findings among individuals who live alone or are single. Mice subjected to early maternal separation and social isolation demonstrated increased anxiety-like behaviors and stress-related corticotropin-releasing hormone receptor 1, and neurogenesis-related sex-determining region Y-box 2 and doublecortin expression. In snRNA-seq, differences, such as transthyretin increase, were observed in the maternal separation group, and somatic mutations, including insertion in the intron site of Tmem267, were observed in the social isolation group on WGS.Conclusion The results of this study suggest that stress, such as social isolation, can cause changes at the genetic level, as well as behavioral and brain protein changes.
Abstract
Objective The coronavirus disease-2019 (COVID-19) pandemic’s social isolation has significantly impacted mental health, increasing depression and anxiety. This study explores the effects of social isolation on both humans and mice, focusing on behavioral changes and hippocampal protein expression. It also investigates genetic alterations through single-cell RNA and whole-genome sequencing (WGS).Methods Here we conducted behavioral studies, protein expression studies, single-nucleus sequencing (snRNAseq), and WGS of the hippocampus of mice that underwent early maternal separation and social isolation, and a demographic study of community populations who had been self-quarantined owing to COVID-19 exposure to investigate the link between somatic mutations and stress due to social isolation.Results The demographic study demonstrated more negative mental health findings among individuals who live alone or are single. Mice subjected to early maternal separation and social isolation demonstrated increased anxiety-like behaviors and stress-related corticotropin-releasing hormone receptor 1, and neurogenesis-related sex-determining region Y-box 2 and doublecortin expression. In snRNA-seq, differences, such as transthyretin increase, were observed in the maternal separation group, and somatic mutations, including insertion in the intron site of Tmem267, were observed in the social isolation group on WGS.Conclusion The results of this study suggest that stress, such as social isolation, can cause changes at the genetic level, as well as behavioral and brain protein changes.
참고문헌 (57)
- Brandt L, "The effects of social isolation stress and discrimination on mental health", Transl Psychiatry, 12, pp.398~ (2022)
- Brooks SK, "The psychological impact of quarantine and how to reduce it : rapid review of the evidence", Lancet, 395, pp.912~920 (2020)
- Taquet M, "Bidirectional associations between COVID-19 and psychiatric disorder : retrospective cohort studies of 62354 COVID-19 cases in the USA", Lancet Psychiatry, 8, pp.130~140 (2021)
- Penninx BWJH, "How COVID-19shaped mental health : from infection to pandemic effects", Nat Med, 28, pp.2027~2037 (2022)
- COVID-19 Mental Disorders Collaborators, "Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic", Lancet, 398, pp.1700~1712 (2021)
- Robinson E, "A systematic review and meta-analysis of longitudinal cohort studies comparing mental health before versus during the COVID-19 pandemic in 2020", J Affect Disord, 296, pp.567~576 (2022)
- Racine N, "Global prevalence of depressive and anxiety symptoms in children and adolescents during COVID-19 : a meta-analysis", JAMA Pediatr, 175, pp.1142~1150 (2021)
- Luca L, "Covid-19 and the Spanish flu. From suffering to re-silience", Brain(Bacau), 11, pp.1~7 (2021)
- Douglas PK, "Preparing for pandemic influenza and its aftermath : mental health issues considered", Int J Emerg Ment Health, 11, pp.137~144 (2009)
- Ieraci A, "Social isolation stress induces anxiousdepressive-like behavior and alterations of neuroplasticity-related genes in adult male mice", Neural Plast, 2016, pp.6212983~ (2016)
- Cacioppo JT, "Social isolation and health, with an emphasis on underlying mechanisms", Perspect Biol Med, 46, pp.S39~S52 (2003)
- Agorastos A, "The neuroendocrinology of stress : the stress-related continuum of chronic disease development", Mol Psychiatry, 27, pp.502~513 (2022)
- Martincorena I, "Somatic mutation in cancer and normal cells", Science, 349, pp.1483~1489 (2015)
- Greenman C, "Patterns of somatic mutation in human cancer genomes", Nature, 446, pp.153~158 (2007)
- Sherman MA, "Genome-wide mapping of somatic mutation rates uncovers drivers of cancer", Nat Biotechnol, 40, pp.1634~1643 (2022)
- Miller MB, "Somatic genomic changes in single Alzheimer’s disease neurons", Nature, 604, pp.714~722 (2022)
- Bedrosian TA, "Environment-driven somatic mosaicism in brain disorders", Genome Med, 8, pp.58~ (2016)
- Hao Y, "Dictionary learning for integrative, multimodal and scalable single-cell analysis", Nat Biotechnol, 42, pp.293~304 (2024)
- Kolberg L, "gprofiler2--an R package for gene list functional enrichment analysis and namespace conversion toolset g : Profiler", F1000Res, 9, pp.ELIXIR-709~ (2020)
- Li H, "Fast and accurate long-read alignment with Burrows–Wheeler transform", Bioinformatics, 26, pp.589~595 (2010)
- Van der Auwera GA, "Genomics in the cloud: using Docker, GATK, and WDL in Terra" (2020), O’Reilly Media
- Danecek P, "Twelve years of SAMtools and BCFtools", Gigascience, 10, pp.giab008~ (2021)
- Rausch T, "DELLY : structural variant discovery by integrated paired-end and split-read analysis", Bioinformatics, 28, pp.i333~i339 (2012)
- Wang X, "CNVcaller : highly efficient and widely applicable software for detecting copy number variations in large populations", Gigascience, 6, pp.gix115~ (2017)
- Koboldt DC, "VarScan 2 : somatic mutation and copy number alteration discovery in cancer by exome sequencing", Genome Res, 22, pp.568~576 (2012)
- Wang K, "ANNOVAR : functional annotation of genetic variants from high-throughput sequencing data", Nucleic Acids Res, 38, pp.e164~ (2010)
- Bae T, "Analysis of somatic mutations in 131 human brains reveals aging-associated hypermutability", Science, 377, pp.511~517 (2022)
- Lee JH, "Somatic mutations in disorders with disrupted brain connectivity", Exp Mol Med, 48, pp.e239~ (2016)
- Miller MB, "Brain somatic mutation in aging and Alzheimer’s disease", Annu Rev Genomics Hum Genet, 22, pp.239~256 (2021)
- Park JS, "Brain somatic mutations observed in Alzheimer’s disease associated with aging and dysregulation of tau phosphorylation", Nat Commun, 10, pp.3090~ (2019)
- Lodato MA, "Aging and neurodegeneration are associated with increased mutations in single human neurons", Science, 359, pp.555~559 (2018)
- Kim J, "Somatic deletions implicated in functional diversity of brain cells of individuals with schizophrenia and unaffected controls", Sci Rep, 4, pp.3807~ (2014)
- Bundo M, "Increased l1 retrotransposition in the neuronal genome in schizophrenia", Neuron, 81, pp.306~313 (2014)
- Kim MH, "Low-level brain somatic mutations are implicated in schizophrenia", Biol Psychiatry, 90, pp.35~46 (2021)
- Sun X, "microRNA and mRNA profiles in ventral tegmental area relevant to stress-induced depression and resilience", Prog Neuro-Psychopharmacol Biol Psychiatry, 86, pp.150~165 (2018)
- Dai W, "Sex-specific transcriptomic signatures in brain regions critical for neuropathic paininduced depression", Front Mol Neurosci, 15, pp.886916~ (2022)
- Sun M, "NUDT21 regulates 3'-UTR length and microRNA-mediated gene silencing in hepatocellular carcinoma", Cancer Lett, 410, pp.158~168 (2017)
- Reddy RB, "Molecular prognosticators in clinically and pathologically distinct cohorts of head and neck squamous cell carcinoma—a meta-analysis approach", PLoS One, 14, pp.e0218989~ (2019)
- Cuenco KT, "Association of TTR polymorphisms with hippocampal atrophy in Alzheimer disease families", Neurobiol Aging, 32, pp.249~256 (2011)
- Li X, "Neuronal production of transthyretin in human and murine Alzheimer’s disease : is it protective", J Neurosci, 31, pp.12483~12490 (2011)
- Sousa JC, "Transthyretin and Alzheimer’s disease : where in the brain", Neurobiol Aging, 28, pp.713~718 (2007)
- Lin JC, "The netrin-G1 ligand NGL-1promotes the outgrowth of thalamocortical axons", Nat Neurosci, 6, pp.1270~1276 (2003)
- Eastwood SL, "Decreased mRNA expression of netrin-G1and netrin-G2 in the temporal lobe in schizophrenia and bipolar disorder", Neuropsychopharmacolog, 33, pp.933~945 (2008)
- Aoki-Suzuki M, "A family-based association study and gene expression analyses of netrin-G1 and-G2 genes in schizophrenia", Biol Psychiatry, 57, pp.382~393 (2005)
- Kiecolt-Glaser JK, "Slowing of wound healing by psychological stress", Lancet, 346, pp.1194~1196 (1995)
- Glaser R, "Stress-induced immune dysfunction : implications for health", Nat Rev Immunol, 5, pp.243~251 (2005)
- Reiche EMV, "Stress and depression-induced immune dysfunction : implications for the development and progression of cancer", Int Rev Psychiatry, 17, pp.515~527 (2005)
- Sragovich S, "Putative blood somatic mutations in post-traumatic stress disorder-symptomatic soldiers : High impact of cytoskeletal and inflammatory proteins", J Alzheimers Dis, 79, pp.1723~1734 (2021)
- Song L, "Prenatal stress causes oxidative damage to mitochondrial DNA in hippocampus of offspring rats", Neurochem Res, 34, pp.739~745 (2009)
- Sequeira A, "Mitochondrial mutations in subjects with psychiatric disorders", PLoS One, 10, pp.e0127280~ (2015)
- Nishioka M, "Somatic mutations in the human brain : implications for psychiatric research", Mol Psychiatry, 24, pp.839~856 (2019)
- Lavigne MD, "Global unleashing of transcription elongation waves in response to genotoxic stress restricts somatic mutation rate", Nat Commun, 8, pp.2076~ (2017)
- Reiche EMV, "Stress, depression, the immune system, and cancer", Lancet Oncol, 5, pp.617~625 (2004)
- Legge SE, "Associations between schizophrenia polygenic liability, symptom dimensions, and cognitive ability in schizophrenia", JAMA Psychiatry, 78, pp.1143~1151 (2021)
- Scangos KW, "New and emerging approaches to treat psychiatric disorders", Nat Med, pp.317~333 (2023)
- Zylka MJ, "Gene length matters in neurons", Neuron, 86, pp.353~355 (2015)
- Lodato MA, "Somatic mutation in single human neurons tracks developmental and transcriptional history", Science, 350, pp.94~98 (2015)