Project description:Using a miR-138 loss-of-function mouse model, a role for the brain enriched microRNA miR-138 in the regulation of inhibitory synaptic transmission and short-term memory formation was shown.
Project description:Working memory is a form of short-term memory that involves maintaining and updating task relevant information toward goal-directed pursuits. Classical models posit persistent activity in prefrontal cortex (PFC) as a primary neural correlate, but emerging views suggest additional mechanisms may exist. We screened ~200 genetically diverse mice on a working memory task and identified a genetic locus on Chromosome 5 that contributes to a substantial proportion (17%) of the phenotypic variance. Within the locus, we identified a gene encoding an orphan G-protein coupled receptor, Gpr12, which is sufficient to drive substantial and bi-directional changes in working memory. Molecular, cellular, and imaging studies revealed that Gpr12 enables high thalamus-PFC synchrony to support memory maintenance and choice accuracy. These findings identify a novel orphan receptor as a potent modifier of short-term memory, and supplement classical PFC-based models with an emerging thalamus-centric framework for the mechanistic understanding of working memory.
Project description:The environment outside the Earth’s protective magnetosphere is a much more threatening and complex space environment. The dominant causes for radiation exposure, solar particle events and galactic cosmic rays, contain high-energy protons. In space, astronauts need healthy and highly functioning cognitive abilities, of which the hippocampus plays a key role. Therefore, understanding the effects of 1H exposure on hippocampal-dependent cognition is vital for de-veloping mitigative strategies and protective countermeasures for future missions. To investi-gate these effects, we subjected 6-month-old female CD1 mice to 0.75 Gy fractionated 1H (250 MeV) whole-body irradiation at the NASA Space Radiation Laboratory. The cognitive perfor-mance of the mice was tested 3 months after irradiation using Y-maze and morris water maze tests. Both sham-irradiated and 1H-irradiated mice significantly preferred exploration of the novel arm compared to the familiar and start arms, indicating intact spatial and short-term memory. Both groups statistically spent more time in the target quadrant, indicating spatial memory retention. There were no significant differences in neurogenic and gliogenic cell counts after irradiation. In addition, proteomic analysis revealed no significant upregulation or down-regulation of proteins related to behavior, neurological disease, or neural morphology. Our data suggests 1H exposure does not impair hippocampal-dependent spatial or short-term memory in female mice.
Project description:Our data showed that EIF4EBP1, NINJ1, CLIC3, STMN3, SPINK4, CD44, GSN, PRSS23 et al. were strongly downregulated by miR-138-mimics in gastric cancer (GC) cell lines. Besides, miR-138-5p has a profound effect on EMT signaling and proliferation signaling. In the EMT signaling, miR-138-5p negatively regulates the expression of SOX4, VIM, TGFB1, BMP1, ECM1 and CXCL8; In the cell proliferation signaling, miR-138-5p could negatively regulates the expression of PCNA, RHOC and CCND3.
Project description:The goal of this study was to investigate the effects of miR-138 or miR-181ab1 on regulating osteogenesis. Gene expression profiles were analyzed in human de-differentiated chondrocytes (DDCs) over-expressing either miR-138 or miR-181ab1 following day 2 or day 7 of osteogenic induction. DDCs were isolated from human osteoarthritic articular cartilage and over-expression of miR-138 or miR-181ab1 was induced following lentiviral transduction of DDCs over-expressing the precursor form of miR-138 or miR-181ab1. Control DDCs were transduced with lentivirus expressing a non-silencing (NS) control RNA. Total RNA was harvested at day 2 or day 7 following osteogenic induction and subjected to RNA-Seq analysis.
Project description:Considerable evidence suggests loss of function mutations in the chromatin remodeler, CHD2, contribute to a broad spectrum of human neurodevelopmental disorders. However, it is unknown how CHD2 mutations lead to impaired brain function. Here we report mice with heterozygous mutations in Chd2 exhibit deficits in neuron proliferation and a shift in neuronal excitability that included divergent changes in excitatory and inhibitory synaptic function. Further in vivo experiments show Chd2+/- mice displayed aberrant cortical rhythmogenesis and severe deficits in long-term memory, consistent with phenotypes observed in humans. We identified broad, age-dependent transcriptional changes in Chd2+/- mice, including alterations in neurogenesis, synaptic transmission and disease-related genes. Deficits in interneuron density and memory caused by Chd2+/- were reproduced by Chd2 mutation restricted to a subset of inhibitory neurons and corrected by interneuron transplantation. Our results provide initial insight into how Chd2 haploinsufficiency leads to aberrant cortical network function and impaired memory.
Project description:We previously showed that miR-138 can repress herpes simplex virus 1 (HSV-1) ICP0 expression by binding to ICP0 mRNA. However, in this study we found that miR-138 can also repress viral gene expression independent of ICP0. We did not find other confirmed viral targets of miR-138. Therefore we conducted these RNAseq experiments (in combination with PAR-CLIP experiments whose results are uploaded separately) to identify host targets of miR-138 in two cell lines to explain the ICP0-independent effects on HSV-1 gene expression.