259 research outputs found
An in vitro stress model of primary oligodendrocytes from anxious and non-anxious mouse strains
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Genetic insights into the neurobiology of anxiety
No full textAnxiety and fear are evolutionarily conserved emotions that increase the likeli-hood of an organism surviving threatening situations. Anxiety and vigilance states are regulated by neural networks involving multiple brain regions. In anx-iety disorders, this intricate regulatory system is disturbed, leading to excessive or prolonged anxiety or fear. Anxiety disorders have both genetic and environ-mental risk factors. Genetic research has the potential to identify specific genetic variants causally associated with specific phenotypes. In recent decades, genome-wide association studies (GWASs) have revealed variants predisposing to neuropsychiatric disorders, suggesting novel neurobiological pathways in the etiology of these disorders. Here, we review recent human GWASs of anxiety dis -orders, and genetic studies of anxiety-like behavior in rodent models. These studies are paving the way for a better understanding of the neurobiological mechanisms underlying anxiety disorders.Peer reviewe
Strong conservation of inbred mouse strain microRNA loci but broad variation in brain microRNAs due to RNA editing and isomiR expression
No full textDiversity in the structure and expression of microRNAs, important regulators of gene expression, arises from SNPs, duplications followed by divergence, production of isomiRs, and RNA editing. Inbred mouse strains and crosses using them are important reference populations for genetic mapping, and as models of human disease. We determined the nature and extent of interstrain miRNA variation by (i) identifying miRNA SNPs in whole-genome sequence data from 36 strains, and (ii) examining miRNA editing and expression in hippocampus (Hpc) and frontal cortex (FCx) of six strains, to facilitate the study of miRNAs in neurobehavioral phenotypes. miRNA loci were strongly conserved among the 36 strains, but even the highly conserved seed region contained 16 SNPs. In contrast, we identified RNA editing in 58.9% of miRNAs, including 11 consistent editing events in the seed region. We confirmed the functional significance of three conserved edits in the miR-379/410 cluster, demonstrating that edited miRNAs gained novel target mRNAs not recognized by the unedited miRNAs. We found significant interstrain differences in miRNA and isomiR expression: Of 779 miRNAs expressed in Hpc and 719 in FCx, 262 were differentially expressed (190 in Hpc, 126 in FCx, 54 in both). We also identified 32 novel miRNA candidates using miRNA prediction tools. Our studies provide the first comprehensive analysis of SNP, isomiR, and RNA editing variation in miRNA loci across inbred mouse strains, and a detailed catalog of expressed miRNAs in Hpc and FCx in six commonly used strains. These findings will facilitate the molecular analysis of neurological and behavioral phenotypes in this model organism.Peer reviewe
The effect of REM-sleep disruption on affective processing : A systematic review of human and animal experimental studies
No full textEvidence on the importance of rapid-eye-movement sleep (REMS) in processing emotions is accumulating. The focus of this systematic review is the outcomes of experimental REMS deprivation (REMSD), which is the most common method in animal models and human studies on REMSD. This review revealed that variations in the applied REMSD methods were substantial. Animal models used longer deprivation protocols compared with studies in humans, which mostly reported acute deprivation effects after one night. Studies on animal models showed that REMSD causes aggressive behavior, increased pain sensitivity, reduced sexual behavior, and compromised consolidation of fear memories. Animal models also revealed that REMSD during critical developmental periods elicits lasting consequences on affective-related behavior. The few human studies revealed increases in pain sensitivity and suggest stronger consolidation of emotional memories after REMSD. As pharmacological interventions (such as selective serotonin reuptake inhibitors [SSRIs]) may suppress REMS for long periods, there is a clear gap in knowledge regarding the effects and mechanisms of chronic REMS suppression in humans.Peer reviewe
Gene expression profiling reveals a role of immune system and inflammation in innate and stress-induced anxiety-like behavior
No full textAnxiety is an evolutionarily conserved response that is essential for survival. Pathological anxiety, however, is a maladaptive response to nonthreatening situations and greatly affects quality of life. The recent COVID-19 pandemic has increased the prevalence of anxiety symptoms and highlighted the urge to identify the molecular events that initiate pathological anxiety. To this aim, we investigated the extent of similarity of brain region-specific gene expression patterns associated with innate and stress-induced anxiety-like behavior. We compared the cortico-frontal (FCx) and hippocampal (Hpc) gene expression patterns of five inbred mouse strains with high or low levels of innate anxiety-like behavior with gene expression patterns of mice subjected to chronic social defeat stress. We found significantly large overlap of the Hpc but small overlap of the FCx gene expression patterns in innate and stress-induced anxiety, that however, converged onto common inflammation and immune system canonical pathways. Comparing the gene expression data with drug-gene interaction datasets revealed drug candidates, including medrysone, simvastatin, captopril, and sulpiride, that produced gene expression changes opposite to those observed in innate or stress-induced anxiety-like behavior. Together, our data provide a comprehensive overview of FCx and Hpc gene expression differences between innate and stress-induced anxiety and support the role of inflammation and immune system in anxiety-like behavior
Genetic background modulates the effect of glucocorticoids on proliferation, differentiation and myelin formation of oligodendrocyte lineage cells
No full textAnxiety disorders are prevalent mental disorders. Their predisposition involves a combination of genetic and environmental risk factors, such as psychosocial stress. Myelin plasticity was recently associated with chronic stress in several mouse models. Furthermore, we found that changes in both myelin thickness and node of Ranvier morphology after chronic social defeat stress are influenced by the genetic background of the mouse strain. To understand cellular and molecular effects of stress-associated myelin plasticity, we established an oligodendrocyte (OL) model consisting of OL primary cell cultures isolated from the C57BL/6NCrl (B6; innately non-anxious and mostly stress-resilient strain) and DBA/2NCrl (D2; innately anxious and mostly stress-susceptible strain) mice. Characterization of naive cells revealed that D2 cultures contained more pre-myelinating and mature OLs compared with B6 cultures. However, B6 cultures contained more proliferating oligodendrocyte progenitor cells (OPCs) than D2 cultures. Acute exposure to corticosterone, the major stress hormone in mice, reduced OPC proliferation and increased OL maturation and myelin production in D2 cultures compared with vehicle treatment, whereas only OL maturation was reduced in B6 cultures. In contrast, prolonged exposure to the synthetic glucocorticoid dexamethasone reduced OPC proliferation in both D2 and B6 cultures, but only D2 cultures displayed a reduction in OPC differentiation and myelin production. Taken together, our results reveal that genetic factors influence OL sensitivity to glucocorticoids, and this effect is dependent on the cellular maturation stage. Our model provides a novel framework for the identification of cellular and molecular mechanisms underlying stress-associated myelin plasticity.We obtained OPC enriched cultures from anxious and non-anxious inbred mouse strains. Genetic background impacts OPC proliferation, differentiation and myelin formation. It also affects sensitivity of OPCs to acute and prolonged glucocorticoid exposure. imagePeer reviewe
Assessing the contributions of childhood maltreatment subtypes and depression case-control status on telomere length reveals a specific role of physical neglect
No full textBackground:Studies have provided evidence that both childhood maltreatment and depressive disorders areassociated with shortened telomere lengths. However, as childhood maltreatment is a risk factor for depression,it remains unclear whether this may be driving shortened telomere lengths observed amongst depressedpatients. Furthermore, it's unclear if the effects of maltreatment on telomere length shortening are morepervasive amongst depressed patients relative to controls, and consequently whether biological ageing maycontribute to depression's pathophysiology. The current study assesses the effects of childhood maltreatment,depression case/control status, and the interactive effect of both childhood maltreatment and depression case/control status on relative telomere length (RTL).Method:DNA samples from 80 depressed subjects and 100 control subjects were utilized from a U.K. sample(ages 20–84), with childhood trauma questionnaire data available for all participants. RTL was quantified usingquantitative polymerase chain reactions. Univariate linear regression analyses were used to assess the effects ofdepression status, childhood maltreatment and depression by childhood maltreatment interactions on RTL. Thefalse discovery rate (q 50 years old). Therewere no significant depression case/control status by childhood maltreatment interactions.Limitations:A relatively small sample limited our power to detect interaction effects, and we were unable toconsider depression chronicity or recurrence.Conclusion:Shortened RTL was specifically associated with childhood physical neglect, but not the othersubtypes of maltreatment or depression case/control status. Our results suggest that the telomere-erodingeffects of physical neglect may represent a biological mechanism important in increasing risk for ageing-relateddisorders. As physical neglect is more frequent amongst depressed cases generally, it may also represent aconfounding factor driving previous associations between shorter RTL and depression case status
A Putative Role for miR-9 in the Remodeling of Hippocampal Pyramidal Neurons Dendritic Arbor Induced by Chronic Stress and Ketamine
No full textBrain activation induced by chronic psychosocial stress in mice
No full textChronic psychosocial stress is a well-established risk factor for neuropsychiatric diseases. Abnormalities in brain activity have been demonstrated in patients with stress-related disorders. Global brain activation patterns during chronic stress exposure are less well understood but may have strong modifying effects on specific brain circuits and thereby influence development of stress-related pathologies. We determined neural activation induced by chronic social defeat stress, a mouse model of psychosocial stress. To assess chronic activation with an unbiased brain-wide focus we used manganese-enhanced magnetic resonance imaging (MEMRI) and immunohistochemical staining of Delta FOSB, a transcription factor induced by repeated neural activity. One week after 10-day social defeat we observed significantly more activation in several brain regions known to regulate depressive and anxiety-like behaviour, including the prefrontal cortex, bed nucleus of stria terminalis, ventral hippocampus and periaqueductal grey in stressed compared to control mice. We further established that the correlation of Delta FOSB positive cells between specific brain regions was altered following chronic social defeat. Chronic activation of these neural circuits may relate to persistent brain activity changes occurring during chronic psychosocial stress exposure, with potential relevance for the development of anxiety and depression in humans.Peer reviewe
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