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Single-Cell Transcriptomics of hypothalamic CRH-expressing neurons informs mechanisms by which Early-Life Adversity sculpts stress-responses enduringly

ABSTRACT: Mental and cognitive health, as well as vulnerability to neuropsychiatric disorders, involve the interplay of genes with the environment during sensitive developmental periods. Genetic and environmental factors contribute to the development and maturation of neurons, synapses, and the resulting brain circuits. Within the hypothalamus, early-life experiences cause changes in the number of excitatory synapses onto corticotropin-releasing hormone (CRH)-expressing neurons in the paraventricular nucleus (PVN). Further, such synaptic changes suffice to induce enduring epigenomic changes within these cells, influencing programs of gene expression. However, the epigenetic mechanisms by which early-life experiences orchestrate transcriptional programs within individual CRH-expressing neurons, with enduring functional consequences, remain unknown. We utilize animal models of an impoverished environment and unpredictable maternal care (in a limited bedding and nesting [LBN] paradigm), which provokes major alterations in cognitive and emotional outcomes. We are focused on the change in gene expression profiles of stress-sensitive CRH-neurons in the PVN following early-life adversity (ELA). Because of the known heterogeneity of CRH-expressing neuronal populations, we are using single-cell RNA sequencing (RNA-seq) to determine differential gene expression associated with early-life adversity and establish the upstream mechanisms and downstream consequences. We found that CRH-expressing populations of neurons in the PVN can be clustered by both their gene expression profiles as well as by their neurotransmitter phenotype. ELA significantly modified gene expression programs in some neuronal clusters more than others, reducing programs of neuronal development and differentiation and enhancing gene families involved in responses to stress and inflammation. The use of single-cell transcriptomics revealed that ELA impacts gene expression profiles in a cell-type specific manner, with distinctive influence on the different clusters and subpopulations of CRH neurons.

ORGANISM(S): Mus musculus

PROVIDER: GSE174085 | GEO | 2022/05/06

REPOSITORIES: GEO

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Project description:In a systemic effort to survive environmental stress, organ systems fluctuate and adapt to overcome external pressures. The evolutionary drive back towards homeostasis, makes it difficult to determine if an organism experienced a toxic exposure to stress, especially in early prenatal and neonatal periods of development. Previous studies indicate that primary human teeth may provide historical records of experiences related to stressors during that early time window. To assess the molecular effects of early life adversity on enamel formation, we used a limited bedding and nesting (LBN) mouse model of early life adversity (ELA), to assess changes in enamel organ gene expression and enamel mineralization. Enamel of postnatal day 12 (P12) weight-matched ELA mice was more mineralized as compared control enamel. RNAseq showed 724 genes significantly upregulated in ELA enamel organs as compared to controls, and 574 significantly downregulated genes (DESeq2 p-value <= 0.05). Transcripts expressing the enamel matrix proteins amelogenin (Amelx) and enamelin (Enam) were among the top 4 most differentially expressed genes. The most significantly enriched GO and Reactome pathway was Extracellular Matrix Organization, while the most significantly enriched KEGG Pathways were Butanoate metabolism and Synthesis and Degradation of Ketone Bodies. qPCR analysis of weight-matched ELA and control enamel organs confirmed that expression of the ameloblast-specific proteins Amelx and Enam were highly upregulated in ELA mice. When evaluating molecular mechanisms for amelogenin upregulation, we found significantly increased expression of Dlx3, while transcripts for clock genes Per1 and Nrd1, which have also positively associated with amelogenin expression, were downregulated. These findings suggest that the developing enamel organs are sensitive to the pressures of early life adversity and produce structural biomarkers in tooth enamel mineral to reflect these changes. Together these results support the possibility that tooth enamel may contain biomarkers of cellular effects associated with systemic early life adversity.

Project description:Social anxiety disorder (SAD) is a psychiatric disorder characterized by severe fear in social situations and avoidance of these. Multiple genetic as well as environmental factors contribute to the etiopathology of SAD. One of the main risk factors for SAD is stress, especially during early periods of life (early life adversity; ELA). ELA leads to structural and regulatory alterations contributing to disease vulnerability. This includes the dysregulation of the immune response. However, the molecular link between ELA and the risk for SAD in adulthood remain largely unclear. Evidence is emerging that long-lasting changes of gene expression patterns play an important role in the biological mechanisms linking ELA and SAD. Therefore, we conducted a transcriptome study of SAD and ELA performing RNA sequencing in peripheral blood samples. Analyzing differential gene expression between individuals suffering from SAD with high or low levels of ELA and healthy individuals with high or low levels of ELA, 13 significantly differentially expressed genes (DEGs) were identified with respect to SAD whilst no significant differences in expression were identified with respect to ELA. The most significantly expressed gene was MAPK3 (p=0.003) being upregulated in the SAD group compared to control individuals. In contrary, weighted gene co-expression network analyses (WGCNA) identified only modules significantly associated with ELA (p≤0.05), not with SAD. Furthermore, analyzing interaction networks of the genes from the ELA-associated modules and the SAD-related MAPK3) revealed complex interactions of those genes. Gene functional enrichment analyses indicate a role of signal transduction pathways as well as inflammatory responses supporting an involvement of the immune system in the association of ELA and SAD. In conclusion, we did not identify a direct molecular link between ELA and adult SAD by transcriptional changes. However, our data indicate an indirect association of ELA and SAD mediated by the interaction of genes involved in immune-related signal transduction.

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Single-Cell Transcriptomics of hypothalamic CRH-expressing neurons informs mechanisms by which Early-Life Adversity sculpts stress-responses enduringly

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