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Peptide signaling in the paraventricular thalamus is essential for disrupted adult reward behaviors consequent to early-life adversity [baseline dataset]

ABSTRACT: Early-life adversity (ELA) is strongly linked to emotional disorders including depression, and dysregulated reward behaviors including diminished motivation for and/or enjoyment of rewards (anhedonia). However, how transient ELA is encoded and how it dysregulates reward behaviors enduringly is unknown. One emerging key node of the reward circuit is the paraventricular nucleus of the thalamus (PVT). The PVT is the only area that distinguishes ELA from typical rearing in the mouse brain, and inhibiting specific PVT domains alleviates ELA-induced reward deficits in a sex-specific manner. Therefore, the PVT could be directly impacted by ELA, “remember” the ELA experience and mediate the consequences of ELA on adult reward behavior. Here, we first screen the translatome of PVT cells activated early in life (TRAPed cells) both at rest and in the context of reward, and identify genes that are regulated by reward in a sex-specific way. Combining data- and hypotheses-driven approaches, we identify the corticotropin-releasing hormone receptor type 1 (Crhr1) as a potential mediator of the aberrant reward behaviors consequence ELA. Indeed, CRISPR-Cas9-mediated Crhr1 deletion specifically in TRAPed-PVT cells restores typical reward behaviors in ELA mice. Our results provide insight into the developmental origin of mental illness and identify potentially powerful molecular targets for prevention or mitigation of the consequences of ELA.

ORGANISM(S): Mus musculus

PROVIDER: GSE326563 | GEO | 2026/09/16

REPOSITORIES: GEO

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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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Peptide signaling in the paraventricular thalamus is essential for disrupted adult reward behaviors consequent to early-life adversity [baseline dataset]

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