Retinoic acid modulation of granule cell activity and spatial discrimination in the adult hippocampus.

Retinoic acid (RA), derived from vitamin A (retinol), plays a crucial role in modulating neuroplasticity within the adult brain. Perturbations in RA signaling have been associated with memory impairments, underscoring the necessity to elucidate RA's influence on neuronal activity, particularly within the hippocampus. In this study, we investigated the cell type and sub-regional distribution of RA-responsive granule cells (GCs) in the mouse hippocampus and delineated their properties. We discovered that RA-responsive GCs tend to exhibit a muted response to environmental novelty, typically remaining inactive. Interestingly, chronic dietary depletion of RA leads to an abnormal increase in GC activation evoked by a novel environment, an effect that is replicated by the localized application of an RA receptor beta (RARß) antagonist. Furthermore, our study shows that prolonged RA deficiency impairs spatial discrimination-a cognitive function reliant on the hippocampus-with such impairments being reversible with RA replenishment. In summary, our findings significantly contribute to a better understanding of RA's role in regulating adult hippocampal neuroplasticity and cognitive functions.

Maladaptation of dentate gyrus mossy cells mediates contextual discrimination deficit after traumatic stress.

Fear overgeneralization is a maladaptive response to traumatic stress that is associated with the inability to discriminate between threat and safety contexts, a hallmark feature of post-traumatic stress disorder (PTSD). However, the neural mechanisms underlying this deficit remain unclear. Here, we show that traumatic stress exposure impairs contextual discrimination between threat and safety contexts in the learned helplessness (LH) model. Mossy cells (MCs) in the dorsal hippocampus are suppressed in response to traumatic stress. Bidirectional manipulation of MC activity in the LH model reveals that MC inhibition is causally linked to impaired contextual discrimination. Mechanistically, MC inhibition increases the number of active granule cells in a given context, significantly overlapping context-specific ensembles. Our study demonstrates that maladaptive inhibition of MCs after traumatic stress is a substantial mechanism underlying fear overgeneralization with contextual discrimination deficit, suggesting a potential therapeutic target for cognitive symptoms of PTSD.

Hippocampal mossy cell involvement in behavioral and neurogenic responses to chronic antidepressant treatment.

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.

Effects of smartphone-based memory training for older adults with subjective memory complaints: a randomized controlled trial.

OBJECTIVES: 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). METHOD: 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. RESULTS: 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). CONCLUSION: 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.

A Study of Core Humanistic Competency for Developing Humanism Education for Medical Students.

The authors conducted a survey on essential humanistic competency that medical students should have, and on teaching methods that will effectively develop such attributes. The participants consisted of 154 medical school professors, 589 medical students at Seoul National University College of Medicine, 228 parents, and 161 medical school and university hospital staff. They answered nine questions that the authors created. According to the results, all groups chose "morality and a sense of ethics," a "sense of accountability," "communication skills," and "empathic ability" were selected as essential qualities. According to the evaluation on the extent to which students possess each quality, participants believed students had a high "sense of accountability" and "morality," whereas they thought students had low "empathic ability," "communicate," or "collaborate with others". In terms of effective teaching methods, all sub-groups preferred extracurricular activities including small group activities, debates, and volunteer services. With regard to the speculated effect of humanism education and the awareness of the need for colleges to offer it, all sub-groups had a positive response. However the professors and students expressed a relatively passive stance on introducing humanism education as a credited course. Most participants responded that they preferred a grading method based on their rate of participation, not a relative evaluation. In order to reap more comprehensive and lasting effects of humanism education courses in medical school, it is necessary to conduct faculty training, and continuously strive to develop new teaching methods.

Effects of Smart-Tablet-Based Neurofeedback Training on Cognitive Function in Children with Attention Problems.

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.

The Relation between Nonverbal IQ and Postoperative CI Outcomes in Cochlear Implant Users: Preliminary Result.

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 induces expression of Lrp2 in the murine uterus.

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.

Extracellular signal-regulated kinase 1/2 signaling pathway is required for endometrial decidualization in mice and human.

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 ß (C/EBPß), 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/EBPß as a downstream target of ERK1/2.

ß-Catenin activation contributes to the pathogenesis of adenomyosis through epithelial-mesenchymal transition.

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/ß-catenin signalling molecules are important and should be tightly regulated for uterine function. To investigate the role of ß-catenin signalling in adenomyosis, the expression of ß-catenin was examined. Nuclear and cytoplasmic ß-catenin expression was significantly higher in epithelial cells of human adenomyosis compared to control endometrium. To determine whether constitutive activation of ß-catenin in the murine uterus leads to development of adenomyosis, mice that expressed a dominant stabilized ß-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 ß-catenin contributes to adenomyosis development through the induction of EMT.

Signal transducer and activator of transcription-3 (Stat3) plays a critical role in implantation via progesterone receptor in uterus.

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 (PR(cre/+) Stat3(f/f); Stat3(d/d)). Our studies revealed that ovarian function and uterine development of Stat3(d/d) mice were normal. However, Stat3(d/d) female mice were infertile due to defective embryo implantation. Unlike Stat3(f/f) mice, Stat3(d/d) mice exhibited an unclosed uterine lumen. Furthermore, uteri of Stat3(d/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 Stat3(d/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.

Light intensity and wavelength during embryo manipulation are important factors for maintaining viability of preimplantation embryos in vitro.

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.

Adenosine triphosphate synthesis, mitochondrial number and activity, and pyruvate uptake in oocytes after gonadotropin injections.

OBJECTIVE: To determine the effects of gonadotropin injection on the energy generation of mature oocytes. DESIGN: Randomized prospective study. SETTING: Gamete and stem cell biotechnology laboratory at Seoul National University in Korea. ANIMAL(S): Twelve- to 15-week-old golden hamsters (Mesocricetus auratus). INTERVENTION(S): 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. MAIN OUTCOME MEASURE(S): Adenosine triphosphate (ATP) synthesis, mitochondrial population number and activity, and pyruvate uptake were measured. RESULT(S): 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. CONCLUSION(S): 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.

Influence of ovarian hyperstimulation and ovulation induction on the cytoskeletal dynamics and developmental competence of oocytes.

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.