Search

Most antidepressants, including selective serotonin reuptake inhibitors (SSRIs), initiate their drug actions by rapid elevation of serotonin, but they take several weeks to achieve therapeutic onset. This therapeutic delay suggests slow adaptive changes in multiple neuronal subtypes and their neural circuits over prolonged periods of drug treatment. Mossy cells are excitatory neurons in the dentate hilus that regulate dentate gyrus activity and function. Here we show that neuronal activity of hippocampal mossy cells is enhanced by chronic, but not acute, SSRI administration. Behavioral and neurogenic effects of chronic treatment with the SSRI, fluoxetine, are abolished by mossy cell-specific knockout of p11 or Smarca3 or by an inhibition of the p11/AnxA2/SMARCA3 heterohexamer, an SSRI-inducible protein complex. Furthermore, simple chemogenetic activation of mossy cells using Gq-DREADD is sufficient to elevate the proliferation and survival of the neural stem cells. Conversely, acute chemogenetic inhibition of mossy cells using Gi-DREADD impairs behavioral and neurogenic responses to chronic administration of SSRI. The present data establish that mossy cells play a crucial role in mediating the effects of chronic antidepressant medication. Our results indicate that compounds that target mossy cell activity would be attractive candidates for the development of new antidepressant medications.

Glutamatergic mossy cells (MCs) are responsible for the associational and commissural connectivity of the dentate gyrus. MCs are widely distributed along the dorsoventral axis, but potential heterogeneity within MCs is scarcely explored. Here, we showed that MCs consist of two subpopulations which differ in their neuronal properties and functions. We discovered that MCs, depending on their dorsoventral location, extend distinct axonal projections in the molecular layers. Comparative transcriptional profiling of dorsal and ventral MCs revealed different neurobiological characteristics in axon guidance and synapse assembly. Despite common activation by external stimuli, dorsal MCs, but not ventral MCs, provide net inhibitory control on granule cells across the longitudinal axis. Furthermore, dorsal MC inhibition, unlikely that of ventral MCs, increases behavioral anxiety and disables rapid contextual discrimination. Collectively, dorsoventral heterogeneity of MCs may provide a novel mechanism for functional differentiation as well as distinct association along the longitudinal extent of the hippocampus.

Lysophosphatidic acid (LPA) has been implicated in the pathology of human ovarian cancer. This phospholipid elicits a wide range of cancer cell responses, such as proliferation, trans-differentiation, migration, and invasion, via various G-protein-coupled LPA receptors (LPARs). Here, we explored the cellular signaling pathway via which LPA induces migration of ovarian cancer cells. LPA induced robust phosphorylation of ezrin/radixin/moesin (ERM) proteins, which are membrane-cytoskeleton linkers, in the ovarian cancer cell line OVCAR-3. Among the LPAR subtypes expressed in these cells, LPA1 and LPA2, but not LPA3, induced phosphorylation of ERM proteins at their C-termini. This phosphorylation was dependent on the Gα12/13/RhoA pathway, but not on the Gαq/Ca2+/PKC or Gαs/adenylate cyclase/PKA pathway. The activated ERM proteins mediated cytoskeletal reorganization and formation of membrane protrusions in OVCAR-3 cells. Importantly, LPA-induced migration of OVCAR-3 cells was completely abolished not only by gene silencing of LPA1 or LPA2, but also by overexpression of a dominant negative ezrin mutant (ezrin-T567A). Taken together, this study demonstrates that the LPA1/LPA2/ERM pathway mediates LPA-induced migration of ovarian cancer cells. These findings may provide a potential therapeutic target to prevent metastatic progression of ovarian cancer.

We explored whether newly developed application (Smartphone-based brain Anti-aging and memory Reinforcement Training, SMART) improved memory performance in older adults with subjective memory complaints (SMC).A total of 53 adults (range: 50-68 years; 52.8% female) were randomized into either one of two intervention groups [SMART (n = 18) vs. Fit Brains® (n = 19)] or a wait-list group (n = 16). Participants in the intervention groups underwent 15-20 minutes of training per day, five days per week for 8 weeks. We used objective cognitive measures to evaluate changes with respect to four domains: attention, memory, working memory (WM), and response inhibition. In addition, we included self-report questionnaires to assess levels of SMC, depression, and anxiety.Total WM quotient [t(17) = 6.27, p.001] as well as auditory-verbal WM score [t(17) = 4.45, p.001] increased significantly in the SMART group but not in the control groups. Self-reports of memory contentment, however, increased in the Fit Brains® group only [t(18) = 2.12, p.05).Use of an 8-week smartphone-based memory training program may improve WM function in older adults. However, objective improvement in performance does not necessarily lead to decreased SMC.

Adenomyosis is defined by the presence of endometrial glands and stroma within the myometrium. Despite its frequent occurrence, the precise aetiology and physiopathology of adenomyosis is still unknown. WNT/β-catenin signalling molecules are important and should be tightly regulated for uterine function. To investigate the role of β-catenin signalling in adenomyosis, the expression of β-catenin was examined. Nuclear and cytoplasmic β-catenin expression was significantly higher in epithelial cells of human adenomyosis compared to control endometrium. To determine whether constitutive activation of β-catenin in the murine uterus leads to development of adenomyosis, mice that expressed a dominant stabilized β-catenin in the uterus were used by crossing PR-Cre mice with Ctnnb1(f(ex3)/+) mice. Uteri of PR(cre) (/+) Ctnnb1(f(ex3)/+) mice displayed an abnormal irregular structure and highly active proliferation in the myometrium, and subsequently developed adenomyosis. Interestingly, the expression of E-cadherin was repressed in epithelial cells of PR(cre) (/+) Ctnnb1(f(ex3)/+) mice compared to control mice. Repression of E-cadherin is one of the hallmarks of epithelial-mesenchymal transition (EMT). The expression of SNAIL and ZEB1 was observed in some epithelial cells of the uterus in PR(cre) (/+) Ctnnb1(f(ex3)/+) mice but not in control mice. Vimentin and COUP-TFII, mesenchymal cell markers, were expressed in some epithelial cells of PR(cre) (/+) Ctnnb1(f(ex3)/+) mice. In human adenomyosis, the expression of E-cadherin was decreased in epithelial cells compared to control endometrium, while CD10, an endometrial stromal marker, was expressed in some epithelial cells of human adenomyosis. These results suggest that abnormal activation of β-catenin contributes to adenomyosis development through the induction of EMT.

Objective To optimize embryo culture system by evaluating lighting effect during in vitro manipulation. Design Randomized prospective study using an animal model. Setting Gamete and Stem Cell Biotechnology Laboratory at Seoul National University in Korea. Animal(s) Twelve- to 15-week-old hamsters ( Mesocricetus auratus ). Intervention(s) Two-cell embryos were manipulated in vitro under lighting of different intensities and wavelengths. Main Outcome Measure(s) Preimplantation development, Hsp70 expression, reactive oxygen species (ROS) generation, and blastomere apoptosis. Result(s) A significant increase in morula and blastocyst formation was detected at 200 lux compared with 900 lux visible ray lighting, but not compared with 500 lux. At 200-lux lighting, red (620–750 nm) ray yielded the best development, whereas blue (445–500 nm) decreased blastocyst formation. Compared with the visible ray, Hsp70 expression and ROS generation in morula were increased in the blue ray but decreased in the red ray lighting. The blue ray also reduced blastocyst quality with increasing blastomere apoptosis. Conclusion(s) Specific wavelength of visible ray increases Hsp70 expression, ROS generation, and blastomere apoptosis. Therefore, removing this stress factor improves embryo development.

We sought to determine whether smart-tablet-based neurofeedback could improve executive function—including attention, working memory, and self-regulation—in children with attention problems. Forty children (10-12 years old) with attention problems, as determined by ratings on the Conners Parent Rating Scale, were assigned to either a neurofeedback group that received 16 sessions or a control group. A comprehensive test battery that assessed general intelligence, visual and auditory attention, attentional shifting, response inhibition and behavior rating scales were administered to both groups before neurofeedback training. Several neuropsychological tests were conducted at posttraining and follow-up assessment. Scores on several neuropsychological tests and parent behavior rating scales showed significant improvement in the training group but not in the controls. The improvements remained through the follow-up assessment. This study suggests that the smart-tablet-based neurofeedback training program might improve cognitive function in children with attention problems.

This study was undertaken to determine the effects of gonadotrophin on cytoskeletal dynamics and embryo development and its role in improving the retrieval of developmentally competent oocytes. Female golden hamsters were injected with human chorionic gonadotrophin (hCG; 5-, 7.5- or 15-IU) on the day 4 of estrus, pregnant mare serum gonadotrophin (PMSG; 5-, 7.5- or 15-IU) on the day 1 of estrus, or 15-IU hCG at 56 hr post-15-IU PMSG injection in any cycle except estrus. Increasing the hCG dose decreased not only retrieval rate of 2-cell embryo but development to blastocyst after subsequent in vitro culture. Whereas, although increasing the PMSG dose induced increasing the number of 2-cell embryo and blastocyst, 15-IU PMSG injection caused retardation of development to blastocyst. No 2-cell embryos were retrieved by injecting both PMSG and hCG. The injections of 15-IU hCG and 7.5- or 15-IU PMSG inhibited the proliferation of trophectodermal and inner cell mass cells, respectively. Gonadotrophin injection didn't influence microtubular spindle formation, but 5- or 15-IU hCG, 15-IU PMSG, or PMSG and hCG injections induced aberrant cortical granule (CG) and microfilament distribution. After 15-IU hCG or PMSG and hCG injections, fewer oocytes had enriched cortical actin domains, and the expression of alpha-, beta- and gamma-actin genes was greatly increased. In conclusion, a high dose of gonadotrophins alters the microfilament and CG distribution, which in turn reduces the developmental competence of oocytes. Injecting a reduced dose of PMSG to initiate ovarian hyperstimulation without triggering ovulation contributes to the efficient retrieval of developmentally competent oocytes.

Objectives. This study assessed the correlation between performance intelligence and the postoperative cochlear implant (CI) outcome in Korean-speaking children. In addition, the relationship between the performance intelligence subscales and the post-CI speech outcome was evaluated. Materials and Methods. Thirteen pediatric CI users (five males, eight females; median age at implantation 6.2 (range 1.3–14.2) years; median age at intelligence test 9.3 (range 5–16) years) who were tested using the Korean Educational Development Institute-Wechsler Intelligence Scale for children were studied. The correlations between the intelligence scores and 1-2 years postoperative Categories of Auditory Performance (CAP) scores and between subscales of performance and 1-2 years postoperative CAP scores were analyzed. Results. There was no correlation between the categories of verbal intelligence quotient (IQ) and performance IQ for “mentally retarded” and “average,” respectively (Spearman’s rho = 0.42, P=0.15). There was a strong correlation between performance IQ and the postoperative CAP scale (Spearman’s rho = 0.8977, P=0.0008). “Picture arrangement” and “picture completion,” reflecting social cognition, were strongly correlated with the postoperative CAP scales. Conclusion. Performance intelligence, especially social cognition, was strongly related to the postoperative CI outcome of cochlear implant users. Therefore, auditory rehabilitation, including social rehabilitation, should maximize the postoperative CI outcomes.

Progesterone (P4) and progesterone receptor (PR) have important functions in uterine environment. In previous studies, using high density DNA microarray analysis, we identified low density lipoprotein receptor-related protein 2 (Lrp2) is one of the genes upregulated by P4 and PR. In present studies, we examined the expression of Lrp2 through real-time PCR, in situ hybridization and immunohistochemistry by P4-PR response. Lrp2 mRNA transcript was significantly increased after P4 treatment in the luminal and glandular epithelium of the wild-type mice. However, Lrp2 expression was not observed in the progesterone receptor knock out (PRKO) mice treated with P4. The expression of Lrp2 expression is not regulated by estrogen. During early pregnancy, the expression of Lrp2 was detected at 2.5 dpc and then significantly increased at 3.5 dpc in luminal and glandular epithelium. These results suggest that Lrp2 is a novel target gene by P4 and PR.

Recent studies have shown that activation of the signal transducer and activator of transcription-3 (Stat3) is required for decidualization, interacting with progesterone receptor (PR) in uterus. Based on previous reports, we hypothesized that crosstalk between STAT3 and PR signaling is required for successful implantation. To identify the interaction between STAT3 and PR isoforms, we performed immunoprecipitation following transient cotransfection and found that STAT3 physically interacted with PR-A, which is known to be important for uterine development and function, but not with PR-B. To further investigate the role of Stat3 in uterine function, Stat3 was conditionally ablated only in the PR-positive cells (PRcre/+ Stat3f/f; Stat3d/d). Our studies revealed that ovarian function and uterine development of Stat3d/d mice were normal. However, Stat3d/d female mice were infertile due to defective embryo implantation. Unlike Stat3f/f mice, Stat3d/d mice exhibited an unclosed uterine lumen. Furthermore, uteri of Stat3d/d mice were unable to undergo a well-characterized hormonally induced decidual reaction. The expression of stromal PR was decreased during decidualization and preimplantation period in Stat3d/d mice, and PR target genes were significantly down-regulated after progesterone induction. Our results suggest that STAT3 and PR crosstalk is required for successful implantation in the mouse uterus.—Lee, J. H., Kim, T. H., Oh, S. J., Yoo, J.-Y., Akira, S., Ku, B. J., Lydon, J. P., Jeong, J.-W. Signal transducer and activator of transcription-3 (Stat3) plays a critical role in implantation via progesterone receptor in uterus.

Adenomyosis is defined by the presence of endometrial glands and stroma within the myometrium. Despite its frequent occurrence, the precise aetiology and physiopathology of adenomyosis is still unknown. WNT/β-catenin signalling molecules are important and should be tightly regulated for uterine function. To investigate the role of β-catenin signalling in adenomyosis, the expression of β-catenin was examined. Nuclear and cytoplasmic β-catenin expression was significantly higher in epithelial cells of human adenomyosis compared to control endometrium. To determine whether constitutive activation of β-catenin in the murine uterus leads to development of adenomyosis, mice that expressed a dominant stabilized β-catenin in the uterus were used by crossing PR-Cre mice with Ctnnb1(f(ex3)/+) mice. Uteri of PR(cre) (/+) Ctnnb1(f(ex3)/+) mice displayed an abnormal irregular structure and highly active proliferation in the myometrium, and subsequently developed adenomyosis. Interestingly, the expression of E-cadherin was repressed in epithelial cells of PR(cre) (/+) Ctnnb1(f(ex3)/+) mice compared to control mice. Repression of E-cadherin is one of the hallmarks of epithelial-mesenchymal transition (EMT). The expression of SNAIL and ZEB1 was observed in some epithelial cells of the uterus in PR(cre) (/+) Ctnnb1(f(ex3)/+) mice but not in control mice. Vimentin and COUP-TFII, mesenchymal cell markers, were expressed in some epithelial cells of PR(cre) (/+) Ctnnb1(f(ex3)/+) mice. In human adenomyosis, the expression of E-cadherin was decreased in epithelial cells compared to control endometrium, while CD10, an endometrial stromal marker, was expressed in some epithelial cells of human adenomyosis. These results suggest that abnormal activation of β-catenin contributes to adenomyosis development through the induction of EMT.

To determine the effects of gonadotropin injection on the energy generation of mature oocytes.Randomized prospective study.Gamete and stem cell biotechnology laboratory at Seoul National University in Korea.Twelve- to 15-week-old golden hamsters (Mesocricetus auratus).Injections of pregnant mare serum gonadotropin (PMSG; 5 or 15 IU), of hCG (5 or 15 IU), or of PMSG and hCG (15 IU of each; PMSG + hCG group) were administered to female hamsters.Adenosine triphosphate (ATP) synthesis, mitochondrial population number and activity, and pyruvate uptake were measured.Significant (P.05) differences were found in the ATP levels; compared with the control (no injection), a dramatic increase was detected after injections of 15 IU of hCG or of 15 IU of PMSG and 15 IU of hCG. In the same treatments, the mitochondrial population (mitochondrial DNA copy number) significantly increased, whereas mitochondrial activity measured by the ratio of activated to less-activated mitochondria did not change. A significant increase in pyruvate uptake was detected after the injections of 15 IU of PMSG and 15 IU of hCG.The change in ATP synthesis activity was a major cause for the adverse effect of gonadotropins on oocyte development in the hamster. The injections of 15 IU of hCG, or of 15 IU of PMSG and 15 IU of hCG, dramatically increased the ATP level, the mitochondrial population number, and pyruvate uptake.

Decidualization is a crucial change required for successful embryo implantation and the maintenance of pregnancy. During this process, endometrial stromal cells differentiate into decidual cells in response to the ovarian steroid hormones of early pregnancy. Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) are known to regulate cell proliferation and apoptosis in multiple cell types, including uterine endometrial cells. Aberrant activation of ERK1/2 has recently been implicated in the pathological processes of endometriosis and endometrial cancer. However, the function of ERK1/2 signaling during implantation and decidualization is still unknown. To determine the role and regulation of ERK1/2 signaling during implantation and decidualization, we examine ERK1/2 signaling in the mouse uterus during early pregnancy using immunostaining and qPCR. Interestingly, levels of phospho-ERK1/2 were highest within decidual cells located at the implantation sites. Expression levels of ERK1/2 target genes were also significantly higher at implantation sites, when compared to either inter-implantation sites. To determine if ERK1/2 signaling is also important during human endometrial decidualization, we examined levels of phospho-ERK1/2 in cultured human endometrial stromal cells during in vitro decidualization. Following treatment with a well-established decidualization-inducing steroidogenic cocktail, levels of phospho-ERK1/2 were markedly increased. Treatment with the ERK1/2 inhibitor, U0126, significantly decreased the expression of the known decidualization marker genes, IGFBP1 and PRL as well as inhibited the induction of known ERK1/2 target genes; FOS, MSK1, STAT1, and STAT3. Interestingly, the phosphorylation level of CCAAT/ enhancer binding protein β (C/EBPβ), a protein previously shown to be critical for decidualization, was significantly reduced in this model. These results suggest that ERK1/2 signaling is required for successful decidualization in mice as well as human endometrial stromal cells and implicates C/EBPβ as a downstream target of ERK1/2.

Adenomyosis is a common gynecological disorder defined by the presence of endometrial glands and stroma within the myometrium. Despite its frequent occurrence, the precise etiology of adenomyosis is still unknown, although it has often been associated with endometrioid adenocarcinoma. β-catenin abnormalities are common in endometrioid type endometrial carcinomas. The expression of the dominant stabilized β-catenin in the murine uterus (PRcre/+ Ctnnb1f(ex3)/+) resulted in endometrial glandular hyperplasia. In addition to the glandular hyperplasia phenotype, uteri of PRcre/+ Ctnnb1f(ex3)/+ mice exhibited an abnormal myometrial structure and proceed to develop adenomyosis. Ablation of Mig-6 in the murine uterus (PRcre/+ Mig-6f/f) leads to the development of endometrial hyperplasia and estrogen-induced endometrial cancer. Concomitant stabilization of β -catenin and ablation of Mig-6 dramatically accelerated the development of adenomyosis and glandular hyperplasia compared to stablizing β-catenin alone. The adenomyosis phenotype of ovariectomized Pffre/+ Ctnnb1f Citation Information: Clin Cancer Res 2010;16(14 Suppl):B23.

Two consecutive experiments were conducted for understanding immunity, stemness, and tumorigenesis of the embryonic stem cells (ESCs) in their allograft. In the first series of experiment, we evaluated whether co-injection of the stem cells with somatic cells could evade the immune response. Donor B6CBAF1 mouse ESCs were subcutaneously co-injected either alone or with ovarian stromal cells, fetal fibroblasts, or adult fibroblasts isolated from the recipient B6D2F1 mouse strain. ESCs by themselves induced teratomas (14%). However, when somatic cells were injected together, ESC-mediated teratoma formation significantly increased (33-75%). Especially, the highest rate of the teratoma formation was observed in ESCs and fetal fibroblasts co-injected recipient B6D2F1 mice (75%). Next, we derived ESC-like, cancer stem cells from the teratomas with enzymatic digestion and their differentiation potential was subsequently evaluated. Except for one cell line, other all cell lines showed a similar morphology to that of original ESCs and retained alkaline phosphatase activity, ESC-specific gene expression (Oct-4, Nanog, Cripto, and Rex-1), and Oct-4 protein expression regardless of their increased abnormality in chromosome number. Relative quantification of lineage-specific gene (Nestin, SMA, Desmin, and Krt8) expression of teratoma-derived cell lines showed the significant changes between the ESCs and the teratoma-derived, ESC-like cells derived from the cell co-injection. Variations in the type of co-injected cells led to lineage-specific changes, changes in gene expression in isolated colony-forming cells, and alterations in stem-cell-like cells derived from allografted tissues. In conclusion, our results suggest that cell-to-cell interaction regulates cellular immunity for implanted cells, which further affects tumorigenesis and stemness [Supported by a grant (SC-5160) from Stem Cell Research Center of the 21st Century Frontier Research Program awarded by Jeong-Mook Lim]. Jong-Heum Park and Seo-Jin Oh contributed equally to this work. Citation Information: Clin Cancer Res 2010;16(14 Suppl):B25.