Biology subjects

O'Toole, N.

Publications and source records attributed to O'Toole, N..

6 recordsLinked to original sources

bioRxiv2026

A glucocorticoid-responsive polygenic signature in the anterior cingulate cortex moderates the association of early-life adversity and vulnerability for depression

Stress exposure is a major risk factor for psychopathology, yet how stress mediators shape long-term psychiatric vulnerability in humans remains unclear. Glucocorticoids, central effectors of the stress response, regulate gene expression through tissue-specific transcriptional programs, suggesting that glucocorticoid-responsive networks may shape sensitivity to adversity. Using RNA-sequencing following chronic glucocorticoid exposure in a non-human primate model, we identified a gene co-expression network specific to the anterior cingulate cortex (ACC) that was highly preserved across human post-mortem brain datasets relevant to depression. We derived an expression-based polygenic score (ePGS) reflecting genetic variation in network activity and tested its interaction with adversity in the UK Biobank. The ACC-specific glucocorticoid-responsive ePGS moderated the association between adversity and depressive symptoms in adult females, with the strongest effects for early-life adversity. Network genes were enriched for neurodevelopmental processes and showed stronger co-expression during childhood, highlighting a developmentally sensitive, region-specific mechanism linking stress exposure to depression risk.

neuroscience↗

bioRxiv2025

Insulin modulates mPFC gene expression and emotional behavior in a sex-specific manner following fetal growth restriction

Exposure to prenatal adversity (e.g., stress, malnutrition) is a major risk factor for lifelong vulnerability to neuropsychiatric and metabolic disorders, and alterations in the function of peripheral hormones in the brain are suggested as a possible and unexplored mechanism. Although insulin is well known for its peripheral metabolic functions, it also influences brain development and emotional regulation, particularly within the medial prefrontal cortex (mPFC). Here, we identify insulin signaling as a key mechanistic link between prenatal stress and long-term alterations in brain function and behavior. Using a validated rat model of prenatal adversity (prenatal food restriction, FR), we found that insulin administration selectively modulates gene expression in FR animals at P0, P21 and P90, affecting pathways involved in neurodevelopment and stress regulation, such as Wnt/{beta}-catenin signaling. Targeted insulin infusion into the mPFC of adult animals reversed behavioral phenotypes induced by FR in a sex- and context-dependent manner, decreasing emotional reactivity to environmental cues. These findings offer novel insight into the neurodevelopmental role of insulin and suggest that insulin signaling may serve as a therapeutic target to mitigate the long-term brain and behavioral consequences of prenatal adversity.

genomics↗

bioRxiv2024

Effects of prenatal maternal immune activation and exposure to circadian disruption during adolescence: exploring the two-hit model of neurodevelopmental disorders

BackgroundAround 80% of individuals with neurodevelopmental disorders (NDDs) such as schizophrenia and autism spectrum disorders experience disruptions in sleep/circadian rhythms. We explored whether prenatal infection, an established risk factor for NDDs, and environmental circadian disruption synergistically induced sex-specific deficits in mice. MethodsA maternal immune activation (MIA) protocol was used by injecting pregnant mice (at E9.5) with a viral mimic poly IC or saline. Then, juvenile/adolescent offspring (3-7 weeks old) were subjected to either standard lighting (12:12LD) or constant light (LL). ResultsWe found interactions of the two factors on behaviors related to cognition, anxiety, and sociability. Also, poly IC exposure led to a more activated profile of hippocampal microglia in males only, while LL diminished these effects. Using RNA sequencing in the dorsal hippocampus, we found that poly IC exposure led to many differentially expressed genes in males (but not females), and fewer differentially expressed genes were observed after LL exposure. Using the WGCNA analysis, we found several significant gene modules positively associated with poly IC (in comparison to saline exposure) and LL (in comparison to LD exposure) in males, and less so in females. Interestingly, many of the identified hub bottleneck genes were homologous to human genes associated with both sleep/circadian rhythms and neurodevelopmental disorders as identified by GWA studies. ConclusionsOur work demonstrates that in a mouse model of prenatal infection, disruptions in circadian rhythms induced by LL play a role in modulating the effects of MIA at behavioral, cellular, and molecular levels.

neuroscience↗

bioRxiv2021

Genomic Modules and Intramodular Network Convergency of Susceptibility and Resilience in Multimodeled Stress in Male Mice

The multifactorial etiology of stress-related disorders is a challenge in developing synchronized medical standards for treatment and diagnosis. It is largely unknown whether there exists molecular convergence in preclinical models of stress generated using disparate construct validity. Using RNA-sequencing (RNA-seq), we investigated the genomic signatures in the ventral hippocampus, which mostly regulates affective behavior, in mouse models that recapitulate the hallmarks of anxiety and depression. Chronic oral corticosterone (CORT), a model that causes a blunted endocrine response to stress, induced anxiety- and depression-like behavior in wildtype mice and mice heterozygous for the gene coding for brain-derived neurotrophic factor (BDNF) Val66Met, a variant associated with genetic susceptibility to stress. In a separate set of mice, chronic social defeat stress led to a susceptible or a resilient population, whose proportion was dependent on housing conditions, standard housing or enriched environment. A rank-rank-hypergeometric (RRHO) analysis of the RNA-seq data set across models demonstrated that in mice treated with CORT and susceptible mice raised in standard housing differentially expressed genes (DEGs) converged toward gene networks involved in similar biological functions. Weighted gene co-expression analysis generated 54 unique modules of interconnected gene hubs, two of which included a combination of all experimental groups and were significantly enriched in DEGs, whose function was consistent with that predicted in the RRHO GO analysis. This multimodel approach showed transcriptional synchrony between models of stress with hormonal, environmental or genetic construct validity shedding light on common genomic drivers that embody the multifaceted nature of stress-related disorders.

neuroscience↗

bioRxiv2019

Epigenetic signatures of chronic social stress in stress-susceptible animals

Exposure of mice to chronic social defeat stress (CSDS) produces depressive- and anxiety-like behaviors and widespread transcriptomic changes in several brain regions in susceptible animals. Here we present the first study of genome-wide cytosine methylation patterns of mice susceptible to CSDS using whole-genome bisulfite sequencing on DNA from the nucleus accumbens, a critical region for CSDS effects on behavior. We found extensive evidence for differential methylation following exposure to CSDS in susceptible animals, with a greater proportion of CG hypermethylation than hypomethylation in CSDS-susceptible mice compared to non-stressed controls; non-CG methylation shows the opposite trend. Several genes previously implicated in the effects of CSDS are among those with the greatest number of differentially methylated sites, including estrogen receptor alpha (Esr1), the deleted in colorectal cancer (Dcc) gene and Cacna1c, which has been associated with a range of psychiatric conditions. Informatic analysis of DM sites revealed a gene network with {beta}-catenin as the hub gene of a network that included the {beta}-catenin-related WNT/frizzled signaling pathway as well as both Esr1 and Dcc. Finally, we found considerable overlap between DM genes associated with CSDS in susceptible animals and those associated with human neuroticism in a genome-wide association study. Analysis of these overlapping genes revealed WNT signaling as the top pathway, which features {beta}-catenin as the primary hub gene. These findings reveal a striking convergence between the molecular pathways identified through either transcriptional or epigenomic analyses of the mouse model of susceptibility to chronic stress and the genomic architecture of increased stress susceptibility reflected in neuroticism in humans.

neuroscience↗

bioRxiv2018

Genetic and behavioural requirements for structural brain plasticity

1Human MRI studies show that experience can lead to changes in the volume of task-specific brain regions; however, the behavioural and molecular processes driving these changes remain poorly understood. Here, we used in-vivo mouse MRI and RNA sequencing to investigate the neuroanatomical and transcriptional changes induced by environmental enrichment, exercise, and social interaction. Additionally, we asked whether the volume changes require CREB, a transcription factor critical for memory formation and neuronal plasticity. Enrichment rapidly increased cortical and hippocampal volume, and these effects were not attributable to exercise or social interaction. Instead, they likely arise from learning and sensorimotor experience. Nevertheless, the volume changes were not attenuated in mice with memory impairments caused by loss of CREB, indicating that these effects are driven by processes distinct from this canonical learning and memory pathway. Finally, within brain regions that underwent volume changes, enrichment increased the expression of genes associated with axonogenesis, dendritic spine development, synapse structural plasticity, and neurogenesis, suggesting these processes underlie the volume changes detected with MRI.

neuroscience↗