Dataset Information

Therapeutic Action of Fluoxetine is Associated with a Reduction in Prefrontal Cortical miR-1971 Expression Levels in a Mouse Model of Posttraumatic Stress Disorder.

ABSTRACT: MicroRNAs (miRNA) are a class of small non-coding RNAs that have recently emerged as epigenetic modulators of gene expression in psychiatric diseases like schizophrenia and major depression. So far, miRNAs have neither been studied in patients suffering from posttraumatic stress disorder (PTSD) nor in PTSD animal models. Here, we present the first study exploring the connection between miRNAs and PTSD. Employing our previously established PTSD mouse model, we assessed miRNA profiles in prefrontal cortices (PFCs) dissected from either fluoxetine or control-treated wildtype C57BL/6N mice 74?days after their subjection to either a single traumatic electric footshock or mock-treatment. Fluoxetine is an antidepressant known to be effective both in PTSD patients and in mice suffering from a PTSD-like syndrome. Screening for differences in the relative expression levels of all potential miRNA target sequences of miRBase 18.0 by pairwise comparison of the PFC miRNA profiles of the four mouse groups mentioned resulted in identification of five miRNA candidate molecules. Validation of these miRNA candidates by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) revealed that the therapeutic action of fluoxetine in shocked mice is associated with a significant reduction in mmu-miR-1971 expression. Furthermore, our findings suggest that traumatic stress and fluoxetine interact to cause distinct alterations in the mouse PFC miRNA signature in the long-term.

SUBMITTER: Schmidt U

PROVIDER: S-EPMC3706988 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Therapeutic Action of Fluoxetine is Associated with a Reduction in Prefrontal Cortical miR-1971 Expression Levels in a Mouse Model of Posttraumatic Stress Disorder.

Schmidt Ulrike U Herrmann Leonie L Hagl Kathrin K Novak Bozidar B Huber Christine C Holsboer Florian F Wotjak Carsten T CT Buell Dominik R DR

Frontiers in psychiatry 20130710

MicroRNAs (miRNA) are a class of small non-coding RNAs that have recently emerged as epigenetic modulators of gene expression in psychiatric diseases like schizophrenia and major depression. So far, miRNAs have neither been studied in patients suffering from posttraumatic stress disorder (PTSD) nor in PTSD animal models. Here, we present the first study exploring the connection between miRNAs and PTSD. Employing our previously established PTSD mouse model, we assessed miRNA profiles in prefronta ...[more]

PMID: 23847554

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Project description:BackgroundPrefrontal subregions, including the ventromedial prefrontal cortex (PFC), dorsomedial PFC, and dorsolateral PFC (DLPFC), are differentially implicated in the pathophysiology of posttraumatic stress disorder (PTSD), though few existing studies have examined subregional differences in resting-state functional connectivity (rsFC). We hypothesized that PTSD would involve weaker positive rsFC between ventromedial PFC, dorsomedial PFC, and other default mode network regions and increased negative rsFC between DLPFC and posterior default mode network regions. Additionally, we hypothesized that prefrontal regions exhibiting group differences in rsFC would be characterized by alterations in cortical thickness.MethodsParticipants included 36 healthy control subjects, 30 trauma-exposed control subjects, and 21 individuals with current DSM-IV PTSD resulting from community-acquired trauma. Participants completed the Clinician Administered PTSD Scale, questionnaires (Childhood Trauma Questionnaire, Adverse Childhood Events, Life Events Checklist, Beck Depression Inventory), structural neuroimaging, and resting-state functional magnetic resonance imaging. rsFC of DLPFC, ventromedial PFC, and dorsomedial PFC seeds was evaluated in SPM12 and CONN. Cortical thickness for regions with significant rsFC findings was assessed using FreeSurfer.ResultsRelative to both healthy control and trauma-exposed control subjects, individuals with PTSD showed increased negative rsFC between the DLPFC and a region of precuneus. This finding was associated with increased overall symptom severity but not with trauma load or childhood trauma exposure. Greater negative DLPFC-precuneus connectivity was associated with greater bilateral precuneus thickness.ConclusionsGiven participation of precuneus subregions in the central executive network, increased anticorrelation between right DLPFC and precuneus in this sample may reflect increased opposition between anterior and posterior central executive network hubs in PTSD.

Project description:The neural substrates of pediatric posttraumatic stress disorder (PTSD) remain incompletely understood, but likely involve abnormal function and development of emotion processing circuitry. Valence-specific and age-related abnormalities during emotion processing have not been elucidated. We examined implicit emotional face processing in pediatric PTSD, predicting abnormalities specific to threat-related emotion. Youth (ages 8-18 years) with PTSD (n=25) and healthy youth (n=28) completed a dynamic emotional face task during fMRI, viewing faces changing from neutral to angry or happy, or changing shape control. Group and cross-sectional age-related differences in activation and functional connectivity were examined in amygdala/hippocampus, medial prefrontal cortex (mPFC), and whole-brain analyses. The post hoc analyses examined the relationship of neural abnormalities with symptom measures of PTSD, anxiety, and depression. Compared with decreased activation with age in healthy youth, PTSD youth showed increased amygdala activation to emotional faces with age. In a group by emotion interaction, PTSD youth showed dorsal (d)ACC hyperactivation to happy faces relative to healthy youth, with no difference for angry faces. Connectivity analyses revealed paradoxical coupling in prefrontal-amygdala circuits, including dACC-dorsomedial (dm)PFC, amygdala-dmPFC, and amygdala-ventrolateral (vl)PFC. In each case, PTSD youth showed reduced connectivity to angry faces, but increased connectivity to happy faces, the reverse of healthy youth. Valence-abnormal recruitment was associated with greater symptom severity, implicating a role in trauma-related psychopathology in youth. Notably, impaired recruitment during angry faces and heightened recruitment to happy faces may reflect increased salience and ambiguity of positive emotional expressions in pediatric PTSD. Finally, age-related findings suggest a developmental sensitization of the amygdala across emotional expressions in youth with PTSD. These findings provide novel insights into the underlying pathophysiology of pediatric PTSD, extending beyond abnormal neural responses to canonical threat.

Project description:Prior studies have demonstrated reduced dendritic spine density in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia. However, it remains unclear how generalizable this finding is in schizophrenia and if it is seen in bipolar disorder, a historically distinct psychiatric condition.To assess whether spine loss is present in the DLPFC of individuals with schizophrenia and individuals with bipolar disorder.This study used postmortem human brain tissue from individuals with schizophrenia (n=14), individuals with bipolar disorder (n=9), and unaffected control participants (n=19). Tissue samples containing the DLPFC (Brodmann area 46) were Golgi-stained, and basilar dendrites of pyramidal cells in the deep half of layer III were reconstructed.The number of spines per dendrite, spine density, and dendrite length were compared across groups. We also assessed for the potential effects of clinical and demographic variables on dendritic parameters.The mean (SD) spine density was significantly reduced (ie, by 10.5%) in individuals with bipolar disorder (0.28 [0.04] spines/?m) compared with control participants (0.31 [0.05] spines/?m) (P=.02). In individuals with schizophrenia, the mean (SD) spine density was also reduced (by 6.5%; 0.29 [0.03] spines/?m) but just missed significance when compared with control participants (P=.06). There was a significant reduction in the mean (SD) number of spines per dendrite in both individuals with schizophrenia (72.8 [24.9] spines per dendrite) and individuals with bipolar disorder (68.9 [12.9] spines per dendrite) compared with controls (92.8 [31.1] spines per dendrite) (individuals with schizophrenia vs controls: 21.6% reduction [P=.003]; individuals with bipolar disorder vs controls: 25.8% reduction [P=.005]). In addition, both individuals with schizophrenia and individuals with bipolar disorder had a reduced mean (SD) dendrite length (246.5 [67.4] and 245.6 [29.8] ?m, respectively) compared with controls (301.8 [75.1] ?m) (individuals with schizophrenia vs controls: 18.3% reduction [P=.005]; individuals with bipolar disorder vs controls: 18.6% reduction [P=.005]).Dendritic spine loss in the DLPFC was seen in both individuals with schizophrenia and individuals with bipolar disorder, suggesting that the 2 disorders may share some common pathophysiological features.

Dataset Information

Therapeutic Action of Fluoxetine is Associated with a Reduction in Prefrontal Cortical miR-1971 Expression Levels in a Mouse Model of Posttraumatic Stress Disorder.

Publications

Therapeutic Action of Fluoxetine is Associated with a Reduction in Prefrontal Cortical miR-1971 Expression Levels in a Mouse Model of Posttraumatic Stress Disorder.

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