Biology subjects

Maras, P. M.

Publications and source records attributed to Maras, P. M..

6 recordsLinked to original sources

bioRxiv2024

A meta-analysis of the effects of early life stress on the prefrontal cortex transcriptome suggests long-term effects on myelin

BackgroundEarly life stress (ELS) refers to exposure to negative childhood experiences, such as neglect, disaster, and physical, mental, or emotional abuse. ELS can permanently alter the brain, leading to cognitive impairment, increased sensitivity to future stressors, and mental health risks. The prefrontal cortex (PFC) is a key brain region implicated in the effects of ELS. MethodsTo better understand the effects of ELS on the PFC, we ran a meta-analysis of publicly available transcriptional profiling datasets. We identified five datasets (GSE89692, GSE116416, GSE14720, GSE153043, GSE124387) that characterized the long-term effects of multi-day postnatal ELS paradigms (maternal separation, limited nesting/bedding) in male and female laboratory rodents (rats, mice). The outcome variable was gene expression in the PFC later in adulthood as measured by microarray or RNA-Seq. To conduct the meta-analysis, preprocessed gene expression data were extracted from the Gemma database. Following quality control, the final sample size was n=89: n=42 controls & n=47 ELS: GSE116416 n=23 (no outliers); GSE116416 n=44 (2 outliers); GSE14720 n=7 (no outliers); GSE153043 n=9 (1 outlier), and GSE124387 n=6 (no outliers). Differential expression was calculated using the limma pipeline followed by an empirical Bayes correction. For each gene, a random effects meta-analysis model was then fit to the ELS vs. Control effect sizes (Log2 Fold Changes) from each study. ResultsOur meta-analysis yielded stable estimates for 11,885 genes, identifying five genes with differential expression following ELS (false discovery rate< 0.05): transforming growth factor alpha (Tgfa), IQ motif containing GTPase activating protein 3 (Iqgap3), collagen, type XI, alpha 1 (Col11a1), claudin 11 (Cldn11) and myelin associated glycoprotein (Mag), all of which were downregulated. Broadly, gene sets associated with oligodendrocyte differentiation, myelination, and brain development were downregulated following ELS. In contrast, genes previously shown to be upregulated in Major Depressive Disorder patients were upregulated following ELS. ConclusionThese findings suggest that ELS during critical periods of development may produce long-term effects on the efficiency of transmission in the PFC and drive changes in gene expression similar to those underlying depression. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=101 SRC="FIGDIR/small/624315v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1619926org.highwire.dtl.DTLVardef@8da510org.highwire.dtl.DTLVardef@14feffcorg.highwire.dtl.DTLVardef@114aae3_HPS_FORMAT_FIGEXP M_FIG C_FIG Key PointsO_LIEarly life stress (ELS) can have long-term effects on the prefrontal cortex (PFC) and its related cognitive and emotional functions. C_LIO_LITo elucidate these long-term effects, we conducted a meta-analysis of five publicly available PFC transcriptional profiling datasets from adult rodents that had previously experienced ELS. C_LIO_LIThis meta-analysis revealed a consistent downregulation of myelin-related genes in the PFC following ELS, and an upregulation of genes related to Major Depressive Disorder. C_LI Plain Language SummaryEarly life stress refers to exposure to negative childhood experiences, such as neglect, disaster, and physical, mental, or emotional abuse. Early life stress can permanently alter the brain, including the prefrontal cortex, which can lead to cognitive and emotional dysfunction that lasts into adulthood. We performed a meta-analysis using five public datasets to identify consistent long-term effects of early life stress on gene expression (mRNA) in the prefrontal cortex of adult rodents. In these studies, rodents that had experienced early life stress consistently showed a decreased amount of mRNA for genes related to myelin. Myelin is the fatty layer that insulates the axons of neurons, allowing them to transmit electrical signals more efficiently. These gene expression changes may suggest long-term effects of early life stress on the efficiency of prefrontal neurotransmission, disrupting cognitive and emotional processing.

neuroscience↗

bioRxiv2023

Adolescent environmental enrichment induces social resilience and alters neural gene expression in a selectively bred rodent model with anxious phenotype

Stress is a major influence on mental health status; the ways that individuals respond to or copes with stressors determine whether they are negatively affected in the future. Stress responses are established by an interplay between genetics, environment, and life experiences. Psychosocial stress is particularly impactful during adolescence, a critical period for the development of mood disorders. In this study we compared two established, selectively-bred Sprague Dawley rat lines, the "internalizing" bred Low Responder (bLR) line versus the "externalizing" bred High Responder (bHR) line, to investigate how genetic temperament and adolescent environment impact future responses to social interactions and psychosocial stress, and how these determinants of stress response interact. Male bLR and bHR rats were exposed to social and environmental enrichment in adolescence prior to experiencing social defeat and were then assessed for social interaction and anxiety-like behavior. Adolescent enrichment caused rats to display more social interaction, as well as nominally less social avoidance, less submission during defeat, and resilience to the effects of social stress on corticosterone, in a manner that seemed more notable in bLRs. For bHRs, enrichment also caused greater aggression during a neutral social encounter and nominally during defeat, and decreased anxiety-like behavior. To explore the neurobiology underlying the development of social resilience in the anxious phenotype bLRs, RNA-seq was conducted on the hippocampus and nucleus accumbens, two brain regions that mediate stress regulation and social behavior. Gene sets previously associated with stress, social behavior, aggression and exploratory activity were enriched with differential expression in both regions, with a particularly large effect on gene sets that regulate social behaviors. Our findings provide further evidence that adolescent enrichment can serve as an inoculating experience against future stressors. The ability to induce social resilience in a usually anxious line of animals by manipulating their environment has translational implications, as it underscores the feasibility of intervention strategies targeted at genetically vulnerable adolescent populations.

neuroscience↗

bioRxiv2021

Characterizing the Behavioral and Neuroendocrine Features of Susceptibility and Resilience to Social Stress

Evaluating and coping with stressful social events as they unfold is a critical strategy in overcoming them without long-lasting detrimental effects. Individuals display a wide range of responses to stress, which can manifest in a variety of outcomes for the brain as well as subsequent behavior. Chronic Social Defeat Stress (CSDS) in mice has been widely used to model individual variation following a social stressor. Following a course of repeated intermittent psychological and physical stress, mice diverge into separate populations of social reactivity: resilient (socially interactive) and susceptible (socially avoidant) animals. A rich body of work reveals distinct neurobiological and behavioral consequences of this experience that map onto the resilient and susceptible groups. However, the range of factors that emerge over the course of defeat have not been fully described. Therefore, in the current study, we focused on characterizing behavioral, physiological, and neuroendocrine profiles of mice in three separate phases: before, during, and following CSDS. We found that following CSDS, traditional read-outs of anxiety-like and depression-like behaviors do not map on to the resilient and susceptible groups. By contrast, behavioral coping strategies used during the initial social stress encounter better predict which mice will eventually become resilient or susceptible. In particular, mice that will emerge as susceptible display greater escape behavior on Day 1 of social defeat than those that will emerge as resilient, indicating early differences in coping mechanisms used between the two groups. We further show that the social avoidance phenotype in susceptible mice is specific to the aggressor strain and does not generalize to conspecifics or other strains, indicating that there may be features of threat discrimination that are specific to the susceptible mice. Our findings suggest that there are costs and benefits to both the resilient and susceptible outcomes, reflected in their ability to cope and adapt to the social stressor.

neuroscience↗

bioRxiv2021

Differences in microglia morphological profiles reflect divergent emotional temperaments: Insights from a selective breeding model

Microglia are known to play critical roles in healthy brain development and function, as well as the neuropathology underlying a range of brain diseases. Despite the growing evidence for a role for microglia in affective regulation and mood disorders, relatively little is known regarding how variation in microglia status relates to individual differences in emotionality. Using a selective breeding model based on locomotor response to novelty, we have generated rat lines with unique temperamental phenotypes that reflect broad emotional traits: low responder rats (bLRs) are novelty-averse and model a passive coping style, whereas high responder rats (bHRs) are highly exploratory and model an active coping style. To identify a possible functional role of microglia in these phenotypes, we administered minocycline, an antibiotic with potent microglia inhibiting properties. We found changes in emotional and social behaviors in bLRs, with no discernable effects in bHRs. Using detailed anatomical analyses, we went on to explore the nature of baseline differences in hippocampal microglia populations associated with the divergent temperaments. Interestingly, we found that although bHRs and bLRs had comparable total numbers of hippocampal microglia, selective breeding was associated with a shift in the morphological features of these cells. Specifically, microglia from bLRs were characterized by a hyper-ramified morphology, with longer processes and more complicated branching patterns than microglia from bHRs. This morphology is thought to reflect an early stage of microglia activation and suggests that microglia from bLRs may be in a reactive state even when animals are not overtly stressed or challenged. Taken together, our results provide novel evidence linking variation in inborn temperament with differences in the baseline morphological status of microglia cells and highlight the importance of considering the role of microglia not only in acute responses to stress but also in shaping enduring characteristics of emotionality.

neuroscience↗

bioRxiv2019

A Meta-Analysis of Hippocampal Transcriptional Profiling Studies in a Selectively-Bred Rat Model Provides Converging Evidence with Genetic Sequencing to Implicate Specific Candidate Genes and Pathways in the Liability for Internalizing and Externalizing Psychiatric Disorders

BackgroundFor over 16 years, we have selectively bred rats to show either high or low levels of exploratory activity within a novel environment. These "bred High Responder" (bHR) and "bred Low Responder" (bLR) rats serve as a model for temperamental extremes, exhibiting large differences in many internalizing and externalizing behaviors relevant to mood and substance abuse disorders. MethodsOur study elucidated persistent differences in gene expression related to bHR/bLR phenotype across development and adulthood in the hippocampus, a region critical for emotional regulation. We meta-analyzed eight transcriptional profiling datasets (microarray, RNA-Seq) spanning 43 generations of selective breeding (adult: n=46, P7: n=22, P14: n=49, P21: n=21; all male). We cross-referenced these results with exome sequencing performed on our colony to pinpoint candidates likely to mediate the effect of selective breeding on behavioral phenotype. ResultsGenetic and transcriptional profiling results converged to implicate two genes with previous associations with metabolism and mood: Thyrotropin releasing hormone receptor and Uncoupling protein 2. Our results also highlighted bHR/bLR functional differences in the hippocampus, including a network essential for neurodevelopmental programming, proliferation, and differentiation, containing hub genes Bone morphogenetic protein 4 and Marker of proliferation ki-67. Finally, we observed differential expression related to microglial activation, which is important for synaptic pruning, including two genes within implicated chromosomal regions: Complement C1q A chain and Milk fat globule-EGF factor 8. ConclusionThese candidate genes and functional pathways have the capability to direct bHR/bLR rats along divergent developmental trajectories and promote a widely different reactivity to the environment.

neuroscience↗

bioRxiv2019

Short-term block of CRH receptor in adults mitigates age-related memory impairments provoked by early-life adversity

In humans, early-life adversity (ELA) is associated with impairments in learning and memory that may emerge later in life. In rodent models, ELA directly impacts hippocampal neuron structure and connectivity with progressive deficits in long-term potentiation and spatial memory function. Previous work has demonstrated that augmented release and actions of the stress-activated neuropeptide, CRH, contribute to the deleterious effects of ELA on hippocampal structure and memory-function. Early-life adversity increases CRH production and levels, and blocking CRH receptor type 1 (CRHR1) within the hippocampus immediately following adversity prevented the memory and LTP problems caused by ELA. Here we queried if blocking CRHR1 during adulthood ameliorates the adverse impact of ELA on memory in middle age. Blocking CRHR1 for a week in two month old male rats prevented ELA-induced deficits in object recognition memory that emerge during middle age. The intervention failed to mitigate the reduction of spatial memory at 4 and 8 months, but restored hippocampus-dependent location memory in ELA-experiencing rats during middle age (12 months of age).\n\nNotably, neither ELA nor blocking CRHR1 influenced anxiety- or depression-related behaviors These findings suggest a sensitive period during which interventions can fully prevent long-lasting effects of ELA, yet indicate that interventions later in life offer significant benefits.

neuroscience↗