Biology subjects

Gaine, M. E.

Publications and source records attributed to Gaine, M. E..

7 recordsLinked to original sources

bioRxiv2026

Sub-Chronic Chlorpyrifos Exposure Leads to Epigenetic and Sex-Specific Behavioral Changes in Adult Mice

Chlorpyrifos is a widely used organophosphate pesticide that exerts its primary toxic effect through inhibition of acetylcholinesterase (AChE). Although the acute neurotoxicity of chlorpyrifos is well characterized, the lasting biochemical, behavioral, and epigenetic consequences of sub-chronic exposure remain poorly understood, particularly when considering sex-specific differences. Therefore, we exposed male and female C57BL/6J mice to either peanut oil (n=19), low chlorpyrifos exposure (1 mg/kg/day; n=19), or high chlorpyrifos exposure (10 mg/kg/day n=10) repeatedly for 21 days via subcutaneous injection. Blood AChE activity, behavior, and hippocampal DNA methylation were measured across groups. During exposure, AChE activity decreased in both males and females but only returned to baseline after behavioral testing in females exposed to low chlorpyrifos levels. Behavioral tests also revealed a sex-specific phenotype, with females in the low exposure group exhibiting reduced forced swim test immobility and a significant time by exposure interaction in open field habituation. No significant behavioral effects were observed in males. Significant DNA methylation changes were observed at 3,538 CpG sites in male and female mice after high exposure. Sex-specific analyses revealed two female-specific differentially methylated CpGs after high exposure. Pathways enriched for differentially methylated genes included several related to synaptic remodeling, cholinergic synapse, and various endocrine systems. These findings demonstrate that repeated high chlorpyrifos exposure leads to persistent cholinergic disruption and DNA methylation changes. However, the female-specific behavioral changes seen are independent of AChE activity and widespread DNA methylation changes, suggesting additional mechanisms, present only in females, may underlie behavioral sensitivity to chlorpyrifos. New and NoteworthySub-chronic chlorpyrifos exposure in adult mice produced dose-dependent blood AChE suppression and widespread hippocampal DNA methylation changes in both sexes, with pathway enrichment including cholinergic synapse and endocrine systems. Behavioral effects were subtle, with females in the low exposure group showing reduced forced swim immobility and altered locomotor habituation. Notably, the female-specific behavioral changes seen are independent of AChE activity and DNA methylation changes, suggesting novel mechanisms may underlie female behavioral sensitivity to chlorpyrifos.

neuroscience↗

bioRxiv2025

Complement contributes to hyperactive behavior in the 16p11.2 hemideletion mouse model

The complement system is a major component of the innate immune system and plays an important role in immune surveillance. Recent research has demonstrated that the complement system also plays pivotal roles in brain development, and dysregulation of complement is involved in neurodegenerative and neuropsychiatric disorders. However, the mechanisms by which the complement system contributes to neurodevelopmental disorders (NDDs) remain poorly understood. In this study, we find that the expression of a central regulator of the complement cascade, complement component 3 (C3), is upregulated in the striatum of mice modeling the 16p11.2 hemideletion (16p11.2 del). 16p11.2 del is among the most common copy number variations associated with NDDs including attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disability (ID). Pharmacological inhibition of the C3a receptor alleviates hyperactivity in 16p11.2 del mice, suggesting that elevated complement contributes to NDD-relevant behavioral changes. Due to the pro-inflammatory actions of the C3a receptor, we assess the cytokine environment in the striatum, a key neural substrate for locomotor behavior, and find that several inflammatory factors are upregulated in 16p11.2 del mice. Collectively, these results indicate that increased expression of the complement system, especially C3, mediates hyperactive behavior and is associated with a pro-inflammatory environment in the striatum of 16p11.2 del mice. Our results suggest that inhibition of an overactive complement system may be an effective strategy to ameliorate NDD symptoms resulting from 16p11.2 hemideletion including those associated with ADHD.

neuroscience↗

bioRxiv2023

16p11.2 Microduplication is Associated with Lobule-Specific Abnormalities in Cerebellar Structure and Function

The 16p11.2 microduplication (16p11.2dp/+) is associated with several neuropsychiatric disorders including schizophrenia, autism spectrum disorder, bipolar disorder, intellectual disability, and attention deficit/hyperactivity disorder (ADHD). Cerebellar abnormalities have been increasingly implicated in these neuropsychiatric disorders, including those conferred by 16p11.2 microduplication. In 16p11.2dp/+ mouse models, the cerebellum is a site of transcriptional dysregulation, and cerebellar microcephaly has been reported in humans with 16p11.2 microduplication. Despite mounting evidence indicating a role for the cerebellum in neuropsychiatric disorders associated with this CNV, cerebellar cellular structure and cerebellar-dependent behavior in mice with 16p11.2 microduplication remain uncharacterized. To address this, we histologically labeled Purkinje cells (PCs) and molecular layer interneurons (MLIs) in a mouse model of 16p11.2 microduplication. We did not find any structural differences in cerebellar lobule IV/V, nor did we observe impairments in gait or motor coordination, behaviors that are associated with lobule IV/V. In contrast, we discovered a significant increase in calbindin/parvalbumin-positive PCs mislocalized to the granule layer of cerebellar lobule VI in 16p11.2dp/+ mice compared to wild-type (WT) littermates. Additionally, we found a significant decrease in parvalbumin-positive MLIs without a decrease in total DAPI-positive cell counts in lobule VI of 16p11.2dp/+ mice compared to WT littermates. Cerebellar lobule VI is associated with delay eyeblink conditioning, and 16p11.2dp/+ mice are impaired in cerebellum-dependent associative learning on this task. Specifically, 16p11.2dp/+ mice showed deficits in both conditioned response (CR) percentage and CR onset latency relative to WT mice. These results suggest that lobule VI-specific alterations to PC localization and MLI parvalbumin expression in 16p11.2dp/+ mice impair both cerebellar learning and adaptive timing of cerebellar-driven, conditioned responses. Thus, we have identified novel structural and functional alterations in the cerebellum that are associated with 16p11.2 microduplication. Importantly, individuals with schizophrenia and ADHD also show CR acquisition deficits in delay eyeblink conditioning. Together, these data suggest that the behavioral impairments in 16p11.2dp/+ mice resemble impairments seen in neuropsychiatric disorders linked to 16p11.2 microduplication in humans. Further investigation of cerebellar cortex neurons in 16p11.2dp/+ mice may provide insights into the pathogenesis of neuropsychiatric disorders linked to this copy number variant.

neuroscience↗

bioRxiv2023

Cerebellar Morphological Differences in Bipolar Disorder Type I

BackgroundThe neural underpinnings of bipolar disorder (BD) remain poorly understood. The cerebellum is ideally positioned to modulate emotional regulation circuitry yet has been understudied in BD. Previous studies have suggested differences in cerebellar activity and metabolism in BD, however findings on cerebellar structural differences remain contradictory. MethodsWe collected 3T anatomical MRI scans from participants with (N = 131) and without (N = 81) BD type I. Differences in cerebellar volumes were assessed along with factors that influence the results. ResultsThe cerebellar cortex was smaller bilaterally in participants with BD. Polygenic propensity score (bipolar N = 103, control N = 64) did not predict any cerebellar volumes, suggesting that non-genetic factors may have greater influence on the cerebellar volume difference we observed in BD. Cerebellar white matter volumes increased with more adverse childhood events, but we did not observe any associations with parental psychiatric illness. We also evaluated time from onset and symptom burden and found no associations with cerebellar volumes, suggesting neurodevelopment may differ prior to onset. Finally, we found taking sedatives was associated with larger cerebellar white matter and non-significantly larger cortical volume. LimitationsThis study was cross-sectional, limiting interpretation of possible mechanisms. Most of our participants were White, which could limit the generalizability. Additionally, we did not account for potential polypharmacy interactions. ConclusionsThese findings suggest that external influences, such as medications, may influence cerebellum structure in BD and may mask underlying differences. Accounting for medication may be critical for consistent findings in future studies.

neuroscience↗

bioRxiv2023

Dissecting 16p11.2 hemi-deletion to study sex-specific striatal phenotypes of neurodevelopmental disorders

Neurodevelopmental disorders (NDDs) are polygenic in nature and copy number variants (CNVs) are ideal candidates to study the nature of this polygenic risk. The disruption of striatal circuits is considered a central mechanism in NDDs. The 16p11.2 hemi-deletion (16p11.2 del) is one of the most common CNVs associated with NDD, and 16p11.2 del/+ mice show sex-specific striatum-related behavioral phenotypes. However, the critical genes among the 27 genes in the 16p11.2 region that underlie these phenotypes remain unknown. Previously, we applied a novel strategy to identify candidate genes associated with the sex-specific phenotypes of 16p11.2 del/+ mice and identified 3 genes of particular importance within the deleted region: thousand and one amino acid protein kinase 2 (Taok2), seizure-related 6 homolog-like 2 (Sez6l2), and major vault protein (Mvp). Using the CRISPR/Cas9 technique, we generated 3 gene hemi-deletion (3g del/+) mice carrying null mutations inTaok2, Sez6l2, and Mvp. We assessed striatum-dependent phenotypes of these 3g del/+ mice in behavioral, molecular, and imaging studies. Hemi-deletion of Taok2, Sez6l2, and Mvp induces sex-specific behavioral alterations in striatum-dependent behavioral tasks, specifically male-specific hyperactivity and impaired motivation for reward seeking, resembling behavioral phenotypes of 16p11.2 del/+ mice. Moreover, RNAseq analysis revealed that 3g del/+ mice exhibit gene expression changes in the striatum similar to 16p11.2 del/+ mice, but only in males. Pathway analysis identified ribosomal dysfunction and translation dysregulation as molecular mechanisms underlying male-specific, striatum-dependent behavioral alterations. Together, the mutation of 3 genes within the 16p11.2 region phenocopies striatal sex-specific phenotypes of 16p11.2 del/+ mice, unlike single gene mutation studies. These results support the importance of a polygenic approach to study NDDs and our novel strategy to identify genes of interest using gene expression patterns in brain regions, such as the striatum, which are impacted in these disorders.

neuroscience↗

bioRxiv2021

Altered hippocampal transcriptome dynamics following sleep deprivation

Widespread sleep deprivation is a continuing public health problem in the United States and worldwide affecting adolescents and adults. Acute sleep deprivation results in decrements in spatial memory and cognitive impairments. The hippocampus is vulnerable to acute sleep deprivation with changes in gene expression, cell signaling, and protein synthesis. Sleep deprivation also has long lasting effects on memory and performance that persist after recovery sleep, as seen in behavioral studies from invertebrates to humans. Although previous research has shown that acute sleep deprivation impacts gene expression, the extent to which sleep deprivation affects gene regulation remains unknown. Using an unbiased deep RNA sequencing approach, we investigated the effects of acute sleep deprivation on gene expression in the hippocampus. We identified 1,146 genes that were significantly dysregulated following sleep deprivation with 507 genes upregulated and 639 genes downregulated, including protein coding genes and long non-coding RNAs not previously identified as impacted by sleep deprivation. Notably, genes significantly upregulated after sleep deprivation were associated with RNA splicing and the nucleus. In contrast, downregulated genes were associated with cell adhesion, dendritic localization, the synapse, and postsynaptic membrane. These results clearly demonstrate that sleep deprivation differentially regulates gene expression on multiple transcriptomic levels to impact hippocampal function. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=180 HEIGHT=200 SRC="FIGDIR/small/445021v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1e611eborg.highwire.dtl.DTLVardef@1a26aa2org.highwire.dtl.DTLVardef@6e8e2org.highwire.dtl.DTLVardef@1a388f0_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

The CBP KIX domain regulates long-term memory and circadian activity

CREB-dependent transcription necessary for long-term memory is driven by interactions with CREB-binding protein (CBP), a multi-domain protein that binds numerous transcription factors. Identifying specific domain functions for multi-action proteins is essential to understand processes necessary for healthy living including cognitive function and a robust circadian clock. We investigated the function of the CBP KIX domain in hippocampal memory and gene expression using CBPKIX/KIX mice with mutations that prevent phospho-CREB (Ser133) binding. We found that CBPKIX/KIX mice were impaired in long-term, but not short-term spatial memory in the Morris water maze. Using an unbiased analysis of gene expression after training for hippocampus-dependent memory, we discovered dysregulation of CREB and CLOCK target genes and downregulation of circadian genes in CBPKIX/KIX mice. With our finding that the CBP KIX domain was important for transcription of circadian genes, we profiled circadian activity in CBPKIX/KIX mice. CBPKIX/KIX mice exhibited delayed activity peaks after light offset and longer free-running periods in constant dark, although phase resetting to light was comparable to wildtype. These studies provide insight into the significance of the CBP KIX domain by defining targets of CBP transcriptional co-activation in memory and the role of the CBP KIX domain in vivo on circadian rhythms.

neuroscience↗