Personality and Augmenting/Reducing (A/R) in auditory event-related potentials (ERPs) during emotional visual stimulation

An auditory augmenting/reducing ERP paradigm recorded for 5 intensity tones with emotional visual stimulation was used, for the first time, to test predictions derived from the revised Reinforcement Sensitivity Theory (rRST) of personality with respect to two major factors: behavioral inhibition system (BIS), fight/flight/freeze system (FFFS). Higher BIS and FFFS scores were negatively correlated with N1/P2 slopes at central sites (C3, Cz, C4). Conditional process analysis revealed that the BIS was a mediator of the association between the N1/P2 slope and the FFFS scores. An analysis of covariance showed that lower BIS scorers exhibited larger N1/P2 amplitudes across all tone intensities while watching negative, positive and neutral pictures. Additionally, lower FFFS scorers compared to higher FFFS scorers disclosed larger N1/P2 amplitudes to the highest tone intensities and these differences were even more pronounced while watching positive emotional pictures. Findings were explained assuming the operation of two different, but related processes: transmarginal inhibition for the BIS; the attention/emotional gating mechanism regulating cortical sensory input for the FFFS trait. These findings appear consistent with predictions derived from the rRST, which traced fear and anxiety to separate but interacting neurobehavioural systems

Temporo-Spatial Dynamics of Event-Related EEG Beta Activity during the Initial Contingent Negative Variation

In the electroencephalogram (EEG), early anticipatory processes are accompanied by a slow negative potential, the initial contingent negative variation (iCNV), occurring between 500 and 1500 ms after cue onset over prefrontal cortical regions in tasks with cue-target intervals of about 3 s or longer. However, the temporal sequence of the distributed cortical activity contributing to iCNV generation remains unclear. During iCNV generation, selectively enhanced low-beta activity has been reported. Here we studied the temporal order of activation foci in cortical regions assumed to underlie iCNV generation using source reconstruction of low-beta (13–18 Hz) activity. During the iCNV, elicited by a cued simple reaction-time task, low-beta power peaked first (750 ms after cue onset) in anterior frontal and limbic regions and last (140 ms later) in posterior areas. This activity occurred 3300 ms before target onset and provides evidence for the temporally ordered involvement of both cognitive-control and motor-preparation processes already at early stages during the preparation for speeded action

Increased Stathmin1 Expression in the Dentate Gyrus of Mice Causes Abnormal Axonal Arborizations

Pituitary adenylate cyclase-activating polypeptide (PACAP) is involved in multiple brain functions. To clarify the cause of abnormal behavior in PACAP deficient-mice, we attempted the identification of genes whose expression was altered in the dentate gyrus of PACAP-deficient mice using the differential display method. Expression of stathmin1 was up-regulated in the dentate gyrus at both the mRNA and protein levels. PACAP stimulation inhibited stathmin1 expression in PC12 cells, while increased stathmin1expression in neurons of the subgranular zone and in primary cultured hippocampal neurons induced abnormal arborization of axons. We also investigated the pathways involved in PACAP deficiency. Ascl1 binds to E10 box of the stathmin1 promoter and increases stathmin1 expression. Inhibitory bHLH proteins (Hes1 and Id3) were rapidly up-regulated by PACAP stimulation, and Hes1 could suppress Ascl1 expression and Id3 could inhibit Ascl1 signaling. We also detected an increase of stathmin1 expression in the brains of schizophrenic patients. These results suggest that up-regulation of stathmin1 in the dentate gyrus, secondary to PACAP deficiency, may create abnormal neuronal circuits that cause abnormal behavior

Repetitive Pertussis Toxin Promotes Development of Regulatory T Cells and Prevents Central Nervous System Autoimmune Disease

Bacterial and viral infections have long been implicated in pathogenesis and progression of multiple sclerosis (MS). Incidence and severity of its animal model experimental autoimmune encephalomyelitis (EAE) can be enhanced by concomitant administration of pertussis toxin (PTx), the major virulence factor of Bordetella pertussis. Its adjuvant effect at the time of immunization with myelin antigen is attributed to an unspecific activation and facilitated migration of immune cells across the blood brain barrier into the central nervous system (CNS). In order to evaluate whether recurring exposure to bacterial antigen may have a differential effect on development of CNS autoimmunity, we repetitively administered PTx prior to immunization. Mice weekly injected with PTx were largely protected from subsequent EAE induction which was reflected by a decreased proliferation and pro-inflammatory differentiation of myelin-reactive T cells. Splenocytes isolated from EAE-resistant mice predominantly produced IL-10 upon re-stimulation with PTx, while non-specific immune responses were unchanged. Longitudinal analyses revealed that repetitive exposure of mice to PTx gradually elevated serum levels for TGF-β and IL-10 which was associated with an expansion of peripheral CD4+CD25+FoxP3+ regulatory T cells (Treg). Increased frequency of Treg persisted upon immunization and thereafter. Collectively, these data suggest a scenario in which repetitive PTx treatment protects mice from development of CNS autoimmune disease through upregulation of regulatory cytokines and expansion of CD4+CD25+FoxP3+ Treg. Besides its therapeutic implication, this finding suggests that encounter of the immune system with microbial products may not only be part of CNS autoimmune disease pathogenesis but also of its regulation

MicroRNA-21 targets tumor suppressor genes ANP32A and SMARCA4

MicroRNA-21 (miR-21) is a key regulator of oncogenic processes. It is significantly elevated in the majority of human tumors and functionally linked to cellular proliferation, survival and migration. In this study, we used two experimental-based strategies to search for novel miR-21 targets. On the one hand, we performed a proteomic approach using two-dimensional differential gel electrophoresis (2D-DIGE) to identify proteins suppressed upon enhanced miR-21 expression in LNCaP human prostate carcinoma cells. The tumor suppressor acidic nuclear phosphoprotein 32 family, member A (ANP32A) (alias pp32 or LANP) emerged as the most strongly downregulated protein. On the other hand, we applied a mathematical approach to select correlated gene sets that are negatively correlated with primary-miR-21 (pri-miR-21) expression in published transcriptome data from 114 B-cell lymphoma cases. Among these candidates, we found tumor suppressor SMARCA4 (alias BRG1) together with the already validated miR-21 target, PDCD4. ANP32A and SMARCA4, which are both involved in chromatin remodeling processes, were confirmed as direct miR-21 targets by immunoblot analysis and reporter gene assays. Furthermore, knock down of ANP32A mimicked the effect of enforced miR-21 expression by enhancing LNCaP cell viability, whereas overexpression of ANP32A in the presence of high miR-21 levels abrogated the miR-21-mediated effect. In A172 glioblastoma cells, enhanced ANP32A expression compensated for the effects of anti-miR-21 treatment on cell viability and apoptosis. In addition, miR-21 expression clearly increased the invasiveness of LNCaP cells, an effect also seen in part upon downregulation of ANP32A. In conclusion, these results suggest that downregulation of ANP32A contributes to the oncogenic function of miR-21