22 research outputs found
Post-training ethanol disrupts trace conditioned fear in rats: Effects of timing of ethanol, dose and trace interval duration
Ethanol has complex effects on memory performance, although hippocampus-dependent memory may be especially vulnerable to disruption by acute ethanol intoxication occurring during or shortly after a training episode. In the present experiments, the effects of post-training ethanol on delay and trace fear conditioning were examined in adolescent rats. In Experiment 1, 30-day-old Sprague-Dawley rats were given delay or trace conditioning trials in which a 10 s flashing light CS was paired with a 0.5 mA shock US. For trace groups, the trace interval was 10 s. On days 31-33, animals were administered ethanol once daily (0.0 or 2.5 g/kg via intragastric intubation), and on day 34 animals were tested for CS-elicited freezing. Results showed that post-training ethanol affected the expression of trace, but had no effect on delay conditioned fear. Experiment 2 revealed that this effect was dose-dependent; doses lower than 2.5 g/kg were without effect. Experiment 3 evaluated whether proximity of ethanol to the time of training or testing was critical. Results show that ethanol administration beginning 24 h after training was more detrimental to trace conditioned freezing than administration that was delayed by 48 h. Finally, in Experiment 4 animals were trained with one of three different trace intervals: 1, 3 or 10 s. Results indicate that post-training administration of 2.5 g/kg ethanol disrupted trace conditioned fear in subjects trained with a 10 s, but not with a I or 3 s, trace interval. Collectively the results suggest that ethanol administration impairs post-acquisition memory processing of hippocampus-dependent trace fear conditioning. (C) 2008 Elsevier Inc. All rights reserved
Wilms' tumour and a de novo (1;7) translocation in a child with bilateral radial aplasia
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YAP and MRTF-A, transcriptional co-activators of RhoA-mediated gene expression, are critical for glioblastoma tumorigenicity.
The role of YAP (Yes-associated protein 1) and MRTF-A (myocardin-related transcription factor A), two transcriptional co-activators regulated downstream of GPCRs (G protein-coupled receptors) and RhoA, in the growth of glioblastoma cells and in vivo glioblastoma multiforme (GBM) tumor development was explored using human glioblastoma cell lines and tumor-initiating cells derived from patient-derived xenografts (PDX). Knockdown of these co-activators in GSC-23 PDX cells using short hairpin RNA significantly attenuated in vitro self-renewal capability assessed by limiting dilution, oncogene expression, and neurosphere formation. Orthotopic xenografts of the MRTF-A and YAP knockdown PDX cells formed significantly smaller tumors and were of lower morbidity than wild-type cells. In vitro studies used PDX and 1321N1 glioblastoma cells to examine functional responses to sphingosine 1-phosphate (S1P), a GPCR agonist that activates RhoA signaling, demonstrated that YAP signaling was required for cell migration and invasion, whereas MRTF-A was required for cell adhesion; both YAP and MRTF-A were required for proliferation. Gene expression analysis by RNA-sequencing of S1P-treated MRTF-A or YAP knockout cells identified 44 genes that were induced through RhoA and highly dependent on YAP, MRTF-A, or both. Knockdown of F3 (tissue factor (TF)), a target gene regulated selectively through YAP, blocked cell invasion and migration, whereas knockdown of HBEGF (heparin-binding epidermal growth factor-like growth factor), a gene selectively induced through MRTF-A, prevented cell adhesion in response to S1P. Proliferation was sensitive to knockdown of target genes regulated through either or both YAP and MRTF-A. Expression of TF and HBEGF was also selectively decreased in tumors from PDX cells lacking YAP or MRTF-A, indicating that these transcriptional pathways are regulated in preclinical GBM models and suggesting that their activation through GPCRs and RhoA contributes to growth and maintenance of human GBM