bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2023.07.31.551219

Social isolation-induced transcriptomic changes in mouse hippocampus impact the synapse and show convergence with human genetic risk for neurodevelopmental phenotypes

Laighneach, A.·Kelly, J. P.·Desbonnet, L.·Holleran, L.·Kerr, D. M.·McKernan, D.·Donohoe, G.·Morris, D. W.
View original source ↗Export metadata ↓

Abstract

Early life stress (ELS) can impact brain development and is a risk factor for neurodevelopmental disorders such as schizophrenia. Post-weaning social isolation (SI) is used to model ELS in animals, using isolation stress to disrupt a normal developmental trajectory. We aimed to investigate how SI affects the expression of genes in mouse hippocampus and to investigate how these changes related to the genetic basis of neurodevelopmental phenotypes. BL/6J mice were exposed to post-weaning SI (PD21-25) or treated as group-housed controls (n = 7-8 per group). RNA sequencing was performed on tissue samples from the hippocampus of adult male and female mice. Four hundred and 1,215 differentially-expressed genes (DEGs) at a false discovery rate of < 0.05 were detected between SI and control samples for males and females respectively. DEGS for both males and females were significantly overrepresented in gene ontologies related to synaptic structure and function, especially the post-synapse. DEGs were enriched for common variant (SNP) heritability in humans that contributes to risk of neuropsychiatric disorders (schizophrenia, bipolar disorder) and to cognitive function. DEGs were also enriched for genes harbouring rare de novo variants that contribute to autism spectrum disorder and other developmental disorders. Finally, cell type analysis revealed populations of hippocampal astrocytes that were enriched for DEGs, indicating effects in these cell types as well as neurons. Overall, these data suggest a convergence between genes dysregulated by the SI stressor in the mouse and genes associated with neurodevelopmental disorders and cognitive phenotypes in humans. Author SummaryEarly life stress increases risk of developing neuropsychiatric and neurodevelopmental disorders. Early life stress can be modelled in animals using social isolation (SI) where animals are separated from others after they have stopped weaning and are housed individually rather than in groups. Here, we investigated the effect of SI on gene expression in the hippocampus, a brain region that regulates stress response and emotion, and how this relates to the known genetic aetiology of neuropsychiatric disorders and traits such as cognitive function. We found that genes altered by SI play a role in how synapses form and function - these are the connection points between nerve cells in the brain. We also found these altered genes are also the genes where common changes in the DNA code can increase risk for schizophrenia, bipolar disorder and influence cognitive ability, and where rare changes in the DNA code increase risk for autism spectrum disorder and developmental disorder. Finally, these genes altered by SI are also highly expressed in astrocytes, cells that help nerve cells to function in the hippocampus. Overall, these data suggest a convergence between genes affected by SI, the environmental stressor, and the genes associated with neurodevelopmental disorders and cognition.

Explore related subjects

genomicsPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Laighneach, A., Kelly, J. P., Desbonnet, L., Holleran, L., Kerr, D. M., McKernan, D., Donohoe, G., Morris, D. W.. 2023-07-31. Social isolation-induced transcriptomic changes in mouse hippocampus impact the synapse and show convergence with human genetic risk for neurodevelopmental phenotypes. https://doi.org/10.1101/2023.07.31.551219

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

MaaD-TAD: an all-atom model of the duplicated PRAMEF/HNRNPCL chromatin domain built from sequence homology

In the nucleus, the placement of genes in the 3D fold of DNA affects how they function. Models of this fold use two kinds of data: contact maps constructed from Hi-C, and nucleosome maps showing where DNA is wound around nucleosomes. Over evolution, sections of the genome were copied, creating near-identical regions. Reads from these regions cannot be assigned to one copy and are discarded, leaving "void regions" in both maps. We tested MaaD-TAD, a pipeline that models topologically associating domains (TADs) at the atomic level, on the PRAMEF/HNRNPCL locus on human chromosome 1. This challenging locus spans 652 kb, with only 15% of its nucleosome positions known and most contact data missing. To test our hypothesis that copies with similar sequence lie close in space, i.e. homology as a surrogate for proximity, we constructed a map of sequence homology in place of Hi-C and used CSynth to fold it into a 3D path. We then lengthened the path to fit a chromatin fibre, and refined the model by adding cohesin complexes, which stabilize chromatin structure. Cohesin is a ring-shaped protein complex through which a loop of chromatin is threaded; the loop is commonly anchored by CTCF proteins bound on either leg. Using known databases, we placed CTCF sites in our model and joined three to their copies with cohesin rings; in each pair the sites face each other, as loop anchors do. The final model holds 3,359 nucleosomes and about 55 million atoms. Micro-C, an advanced, higher-resolution form of Hi-C, provided data on two other duplicated regions that support our hypothesis: matching copies touched 1.2 to 1.9 times more often than expected. Our approach provides a novel method to reconstruct DNA regions with absent contact data and, to our knowledge, the first all-atom model of a complete TAD.

genomics↗
bioRxiv2026

Pseudo-observations of longevity improve detection of resilience-associated genes in the Radiation Late Effects Cohort of rhesus macaques.

Non-human primates are an ideal model for interrogating the genetic basis of human lifespan and resilience due to their long lifespan compared to other model organisms, development of similar age-related chronic conditions, and genetic similarity. However, like humans, statistical methods for modeling survival suffer from the challenges of dealing with non-proportionality of hazards, large numbers of living individuals that must be censored, and loss-to-follow-up over studies that may last a decade or more. Here we overcome these challenges through the use of pseudo-observations of Restricted Mean Survival Time as a measure of resilience to the acute challenge of radiation exposure and chronic challenges of aging and a Western-style diet in rhesus macaques (Macaca mulatta) from the Wake Forest Non-Human Primate Radiation Late Effects Cohort. Our whole-exome analysis used Genome-wide Efficient Mixed Model Association (GEMMA) to identify variants associated with longevity, and a subsequent Gene Set Enrichment Analysis (GSEA) highlighted the cadherin and integrin signaling pathways as central to this resilience. As dysregulation of cell adhesion and extracellular matrix signaling is central to the development of fibrosis, we tested the functional relevance of these signals using a targeted Combined Annotation Dependent Depletion (CADD) score-weighted Sequence Kernel Association Test-Optimal (SKAT-O) analysis of GSEA leading-edge genes from both the cadherin and integrin pathways. This linked variant burden in PCDHGA5, PCDHGA3, PCDHGB2, PCDHA11, and PSENEN to the severity of myocardial fibrosis, and in IBSP, PDGFD, and LAMC2 to the severity of pulmonary fibrosis observed at necropsy. Critically, we note that the genetic variants are not caused by the radiation but rather create an underlying risk for disease that is then exacerbated by the acute and persistent stressors challenging these animals' intrinsic resilience. The success of this method in identifying biologically relevant genetic variants underlying survival in animals undergoing a strong challenge to their resilience highlights not only the role of genes predisposing animals to fibrosis in lifespan, but the overall utility of pseudo-observations in overcoming the limitations of survival analyses in humans and other long-lived species.

genomics↗
bioRxiv2026

Segment-dependent phylogenetic resolution reveals geographic and host sampling gaps in Oropouche virus genomes

Background. Oropouche virus (OROV) has been reported in areas beyond its historical Amazonian range since 2023, accompanied by rapid growth in publicly available genomic data. However, the extent to which these data provide reliable phylogenetic and epidemiological resolution, and whether that resolution differs among genome segments, has not been systematically examined. Methods. Nucleotide sequences annotated under Orthobunyavirus oropoucheense were retrieved from NCBI Virus (accessed 13 May 2025) and filtered to retain records at least 70% of the reference length for each segment, yielding 898 S, 831 M, and 832 L sequences. Segments were aligned independently with MAFFT, and maximum-likelihood phylogenies were inferred with IQ-TREE using ModelFinder and ultrafast bootstrap approximation. Trees were annotated with collection date, country, and host in iTOL. Results. Phylogenetic resolution differed among segments. Contemporary Brazilian sequences formed a largely unresolved region in the S segment tree, whereas the M and L trees resolved recent clusters to differing degrees. Resolution did not track segment length: the M tree resolved contemporary structure more strongly than the longer L tree, and total tree length was approximately 3.5 times greater in the M tree despite near-identical taxon sampling. Sequences collected before 2010 were recovered in supported clusters in all three segment trees, although their configuration differed by segment. These sequences were also predominantly non-Brazilian and non-human, preventing collection date, geographic origin, and host from being separated as explanations for the observed clustering. The species-level query also retained three reassortant viruses, which may influence segment-specific topologies; sequences annotated to the United States were Iquitos virus rather than OROV. Two Italian sequences clustered with Cuban sequences across all three trees, concordant with published travel histories. Conclusions. Publicly available sequences contain phylogenetic structure that differs among the S, M, and L segment trees, but interpretation is constrained by uneven temporal, geographic, and host sampling and by the inclusion of reassortant species in a species-level dataset. The concentration of sequences from Brazil and human hosts, together with limited representation of non-human hosts, restricts inference about OROV diversity and ecology. Broader and more balanced genomic surveillance would improve the ability to resolve OROV evolutionary and transmission patterns.

genomics↗