Preventive machine learning models incorporating health checkup data and hair mineral analysis for low bone mass identification.

Machine learning (ML) models have been increasingly employed to predict osteoporosis. However, the incorporation of hair minerals into ML models remains unexplored. This study aimed to develop ML models for predicting low bone mass (LBM) using health checkup data and hair mineral analysis. A total of 1206 postmenopausal women and 820 men aged 50 years or older at a health promotion center were included in this study. LBM was defined as a T-score below - 1 at the lumbar, femur neck, or total hip area. The proportion of individuals with LBM was 59.4% (n = 1205). The features used in the models comprised 50 health checkup items and 22 hair minerals. The ML algorithms employed were Extreme Gradient Boosting (XGB), Random Forest (RF), Gradient Boosting (GB), and Adaptive Boosting (AdaBoost). The subjects were divided into training and test datasets with an 80:20 ratio. The area under the receiver operating characteristic curve (AUROC), accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and an F1 score were evaluated to measure the performances of the models. Through 50 repetitions, the mean (standard deviation) AUROC for LBM was 0.744 (± 0.021) for XGB, the highest among the models, followed by 0.737 (± 0.023) for AdaBoost, and 0.733 (± 0.023) for GB, and 0.732 (± 0.021) for RF. The XGB model had an accuracy of 68.7%, sensitivity of 80.7%, specificity of 51.1%, PPV of 70.9%, NPV of 64.3%, and an F1 score of 0.754. However, these performance metrics did not demonstrate notable differences among the models. The XGB model identified sulfur, sodium, mercury, copper, magnesium, arsenic, and phosphate as crucial hair mineral features. The study findings emphasize the significance of employing ML algorithms for predicting LBM. Integrating health checkup data and hair mineral analysis into these models may provide valuable insights into identifying individuals at risk of LBM.

OsMYB14, an R2R3-MYB transcription factor, regulates plant height through the control of hormone metabolism in rice.

Plant growth must be regulated throughout the plant life cycle. The myeloblastosis (MYB) transcription factor (TF) family is one of the largest TF families and is involved in metabolism, lignin biosynthesis, and developmental processes. Here, we showed that OsMYB14, a rice R2R3-MYB TF, was expressed in leaves and roots, especially in rice culm and panicles, and that it localized to the nucleus. Overexpression of OsMYB14 (OsMYB14-ox) in rice resulted in a 30% reduction in plant height compared to that of the wild type (WT), while the height of the osmyb14-knockout (osmyb14-ko) mutant generated using the CRISPR/Cas9 system was not significantly different. Microscopic observations of the first internode revealed that the cell size did not differ significantly among the lines. RNA sequencing analysis revealed that genes associated with plant development, regulation, lipid metabolism, carbohydrate metabolism, and gibberellin (GA) and auxin metabolic processes were downregulated in the OsMYB14-ox line. Hormone quantitation revealed that inactive GA19 accumulated in OsMYB14-ox but not in the WT or knockout plants, suggesting that GA20 generation was repressed. Indole-3-acetic acid (IAA) and IAA-aspartate accumulated in OsMYB14-ox and osmyb14-ko, respectively. Indeed, real-time PCR analysis revealed that the expression of OsGA20ox1, encoding GA20 oxidase 1, and OsGH3-2, encoding IAA-amido synthetase, was downregulated in OsMYB14-ox and upregulated in osmyb14-ko. A protein-binding microarray revealed the presence of a consensus DNA-binding sequence, the ACCTACC-like motif, in the promoters of the OsGA20ox1 and GA20ox2 genes. These results suggest that OsMYB14 may act as a negative regulator of biological processes affecting plant height in rice by regulating GA biosynthesis and auxin metabolism.

P7C3 ameliorates barium chloride-induced skeletal muscle injury activating transcriptomic and epigenetic modulation of myogenic regulatory factors.

Skeletal muscle injury affects the quality of life in many pathologies, including volumetric muscle loss, contusion injury, and aging. We hypothesized that the nicotinamide phosphoribosyltransferase (Nampt) activator P7C3 improves muscle repair following injury. In the present study, we tested the effect of P7C3 (1-anilino-3-(3,6-dibromocarbazol-9-yl) propan-2-ol) on chemically induced muscle injury. Muscle injury was induced by injecting 50 µL 1.2% barium chloride (BaCl2) into the tibialis anterior (TA) muscle in C57Bl/6J wild-type male mice. Mice were then treated with either 10 mg/kg body weight of P7C3 or Vehicle intraperitoneally for 7 days and assessed for histological, biochemical, and molecular changes. In the present study, we show that the acute BaCl2-induced TA muscle injury was robust and the P7C3-treated mice displayed a significant increase in the total number of myonuclei and blood vessels, and decreased serum CK activity compared with vehicle-treated mice. The specificity of P7C3 was evaluated using Nampt+/- mice, which did not display any significant difference in muscle repair capacity among treated groups. RNA-sequencing analysis of the injured TA muscles displayed 368 and 212 genes to be exclusively expressed in P7C3 and Veh-treated mice, respectively. There was an increase in the expression of genes involved in cellular processes, inflammatory response, angiogenesis, and muscle development in P7C3 versus Veh-treated mice. Conversely, there is a decrease in muscle structure and function, myeloid cell differentiation, glutathione, and oxidation-reduction, drug metabolism, and circadian rhythm signaling pathways. Chromatin immunoprecipitation-quantitative polymerase chain reaction (qPCR) and reverse transcription-qPCR analyses identified increased Pax7, Myf5, MyoD, and Myogenin expression in P7C3-treated mice. Increased histone lysine (H3K) methylation and acetylation were observed in P7C3-treated mice, with significant upregulation in inflammatory markers. Moreover, P7C3 treatment significantly increased the myotube fusion index in the BaCl2-injured human skeletal muscle in vitro. P7C3 also inhibited the lipopolysaccharide-induced inflammatory response and mitochondrial membrane potential of RAW 264.7 macrophage cells. Overall, we demonstrate that P7C3 activates muscle stem cells and enhances muscle injury repair with increased angiogenesis.

Activation of CGRP neurons in the parabrachial nucleus suppresses addictive behavior.

Punishment such as electric shock or physical discipline employs a mixture of physical pain and emotional distress to induce behavior modification. However, a neural circuit that produces behavior modification by selectively focusing the emotional component, while bypassing the pain typically induced by peripheral nociceptor activation, is not well studied. Here, we show that genetically silencing the activity of neurons expressing calcitonin gene-related peptide (CGRP) in the parabrachial nucleus blocks the suppression of addictive-like behavior induced by footshock. Furthermore, activating CGRP neurons suppresses not only addictive behavior induced by self-stimulating dopamine neurons but also behavior resulting from self-administering cocaine, without eliciting nocifensive reactions. Moreover, among multiple downstream targets of CGRP neurons, terminal activation of CGRP in the central amygdala is effective, mimicking the results of cell body stimulation. Our results indicate that unlike conventional electric footshock, stimulation of CGRP neurons does not activate peripheral nociceptors but effectively curb addictive behavior.

AFM Imaging Reveals MicroRNA-132 to be a Positive Regulator of Synaptic Functions.

The modification of synaptic and neural connections in adults, including the formation and removal of synapses, depends on activity-dependent synaptic and structural plasticity. MicroRNAs (miRNAs) play crucial roles in regulating these changes by targeting specific genes and regulating their expression. The fact that somatic and dendritic activity in neurons often occurs asynchronously highlights the need for spatial and dynamic regulation of protein synthesis in specific milieu and cellular loci. MicroRNAs, which can show distinct patterns of enrichment, help to establish the localized distribution of plasticity-related proteins. The recent study using atomic force microscopy (AFM)-based nanoscale imaging reveals that the abundance of miRNA(miR)-134 is inversely correlated with the functional activity of dendritic spine structures. However, the miRNAs that are selectively upregulated in potentiated synapses, and which can thereby support prospective changes in synaptic efficacy, remain largely unknown. Using AFM force imaging, significant increases in miR-132 in the dendritic regions abutting functionally-active spines is discovered. This study provides evidence for miR-132 as a novel positive miRNA regulator residing in dendritic shafts, and also suggests that activity-dependent miRNAs localized in distinct sub-compartments of neurons play bi-directional roles in controlling synaptic transmission and synaptic plasticity.

Advantages of Using 3D Spheroid Culture Systems in Toxicological and Pharmacological Assessment for Osteogenesis Research.

Bone differentiation is crucial for skeletal development and maintenance. Its dysfunction can cause various pathological conditions such as rickets, osteoporosis, osteogenesis imperfecta, or Paget's disease. Although traditional two-dimensional cell culture systems have contributed significantly to our understanding of bone biology, they fail to replicate the intricate biotic environment of bone tissue. Three-dimensional (3D) spheroid cell cultures have gained widespread popularity for addressing bone defects. This review highlights the advantages of employing 3D culture systems to investigate bone differentiation. It highlights their capacity to mimic the complex in vivo environment and crucial cellular interactions pivotal to bone homeostasis. The exploration of 3D culture models in bone research offers enhanced physiological relevance, improved predictive capabilities, and reduced reliance on animal models, which have contributed to the advancement of safer and more effective strategies for drug development. Studies have highlighted the transformative potential of 3D culture systems for expanding our understanding of bone biology and developing targeted therapeutic interventions for bone-related disorders. This review explores how 3D culture systems have demonstrated promise in unraveling the intricate mechanisms governing bone homeostasis and responses to pharmacological agents.

Dutasteride in the treatment of frontal fibrosing alopecia: Systematic review and meta-analysis.

Frontal fibrosing alopecia (FFA) is a scarring alopecia with fronto-temporo-parietal hairline recession. Although no proven treatment for FFA exists, dutasteride has been suggested as a potential treatment option. We aimed to evaluate the therapeutic response of oral dutasteride in FFA patients. The identification and selection of studies were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis 2020 criteria. To assess the risk of bias for each study, we used the Cochrane's risk of bias in non-randomized studies of interventions (ROBINS-I) assessment tool. A random effects model meta-analysis was performed. Estimated proportion of stabilization for eligible studies was calculated to evaluate the effectiveness of dutasteride for treating FFA. Among patients who achieved stabilization, subgroup analysis was conducted on those showing improvement. Seven studies including 366 patients who received oral dutasteride were identified. The estimated proportion of patients who experienced stabilization of FFA with oral dutasteride was 0.628 (95% CI: 0.398-0.859). In subgroup analyses of patients who experienced improvement, the estimated proportion of improvement was 0.356 (95% CI: 0.163-0.549). In this systematic review and meta-analysis, oral dutasteride revealed to be a good treatment option for disease stabilization or improvement in patients with FFA.

Incidence and survival rates of primary cutaneous malignancies in Korea, 1999-2019: A nationwide population-based study.

Primary cutaneous malignancies are among the most commonly diagnosed types of cancer worldwide. We aimed to examine the incidence and 5-year survival rates of all types of primary cutaneous malignancies in the Korean population. Data from the Korean Nationwide Cancer Registry from 1999 to 2019 were analyzed. The crude incidence rates, age-standardized incidence rates, and 5-year relative survival rates of each type of skin cancer were calculated. A total of 89 965 patients were diagnosed with primary cutaneous malignancies, which was a 7-fold increase from 1999 to 2019. The age-standardized incidence rates increased 3.4-fold in basal cell carcinoma (3.7/100 000 person-years), 2.0-fold in squamous cell carcinoma (1.6/100 000 person-years), 12.0-fold in Bowen disease (1.2/100 000 person-years), and 1.8-fold in malignant melanoma (0.7/10 000 person-years) in 2019. Average annual percentage changes in age-standardized incidence rates were statistically significant in basal cell carcinoma (15.8%), Bowen disease (5.8%), squamous cell carcinoma (5.1%), malignant melanoma (1.2%), melanoma in situ (1.1%), dermatofibrosarcoma protuberans (1.2%), mycosis fungoides (0.5%), primary cutaneous CD30+ T-cell proliferations (0.5%), adnexal and skin appendage carcinoma (0.4%), extramammary Paget's disease (0.2%), and Merkel cell carcinoma (0.2%). The 5-year relative survival rates were the highest in basal cell carcinoma (103.3%), followed by dermatofibrosarcoma protuberans (99.7%) and mycosis fungoides (96.6%), and lowest in angiosarcoma (24.7%). The 5-year relative survival rates steadily increased in extramammary Paget's disease (23.6%), cutaneous B-cell lymphoma (21.3%), mycosis fungoides (20.2%), extranodal NK/T-cell lymphoma, nasal type (18.1%), and malignant melanoma (16.1%) from 1996-2000 to 2015-2019. Most primary cutaneous malignancies have increased in incidence and survival rates in the Korean population, but to varying extents depending on the type of skin cancer.

Retrospective Study of Preoperative Laser Peripheral Iridotomy Versus Intraoperative Surgical Peripheral Iridectomy in Descemet Membrane Endothelial Keratoplasty.

PURPOSE: The aim of this study was to examine the outcomes of laser peripheral iridotomy (LPI) and surgical peripheral iridectomy (SPI) for Descemet membrane endothelial keratoplasty (DMEK) and DMEK with cataract extraction (triple DMEK). METHODS: This retrospective interventional study included 135 eyes of 135 patients who underwent DMEK alone or triple DMEK. Primary outcomes were graft detachments necessitating rebubbling, repeat grafts, and pupillary block. The secondary outcomes included rejection, cystoid macular edema, uveitis, intraoperative hyphema, visual disturbances, and surgical time. RESULTS: Thirty-one eyes in the LPI group and 104 eyes in the SPI group were included. Fifty-six eyes had DMEK alone, and 79 had triple DMEK. Visually significant graft detachments occurred in 7 of 31 eyes in the LPI group versus 19 of 104 eyes in the SPI group ( P = 0.61). No statistical significance in DMEK alone versus triple DMEK groups ( P = 0.61 vs. P > 0.99). Two patients in the LPI group and 5 in the SPI group required regraft ( P = 0.66). One (3.2%) experienced pupillary block compared with 5 (4.8%) ( P = 0.99) in the LPI and SPI groups, respectively. Secondary outcomes were similar in both groups ranging from 0% to 3% ( P > 0.99). None had visual disturbances. In DMEK alone, duration of surgery was significantly shorter in the LPI versus SPI group (32.8 vs. 44.1 minutes, P = 0.02). CONCLUSIONS: This study demonstrated similar outcomes between LPI and SPI, although the LPI group had a shorter duration of surgery when DMEK was performed alone. The remainder of the outcomes demonstrated no statistically significant differences.

Association between De Ritis ratio and intraoperative blood transfusion in patients undergoing surgical clipping of unruptured intracranial aneurysms: a single center, retrospective, propensity score-matched study.

BACKGROUND: Although elective surgery for unruptured intracranial aneurysms (UIA) has increased, few studies have evaluated the risk factors for transfusion during UIA surgery. We evaluated the association between the preoperative De Ritis ratio (aspartate transaminase/alanine transaminase) and the incidence of intraoperative transfusion in patients who had undergone surgical UIA clipping. METHODS: Patients who underwent surgical clipping of UIA were stratified into two groups according to the preoperative De Ritis ratio cutoff levels (< 1.54 and ≥ 1.54), and the propensity score (PS)-matching analysis was performed to compare the incidence of intraoperative transfusion. Logistic regression analyses were performed to determine the risk factors for intraoperative transfusion. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) analyses were performed to verify the improvement in the intraoperative transfusion predictive model upon addition of the De Ritis ratio. RESULTS: Intraoperative transfusion incidence was 15.4% (77/502). We observed significant differences in the incidence of intraoperative transfusion (16.2% vs. 39.7%, P = 0.004) between the groups after matching. In the logistic regression analyses, the De Ritis ratio ≥ 1.54 was an independent risk factor for transfusion (odds ratio [OR]: 3.04, 95% CI [1.53, 6.03], P = 0.002). Preoperative hemoglobin (Hb) value was a risk factor for transfusion (OR: 0.33, 95% CI [0.24, 0.47], P < 0.001). NRI and IDI analyses showed that the De Ritis ratio improved the intraoperative blood transfusion predictive models (P = 0.031 and P = 0.049, respectively). CONCLUSIONS: De Ritis ratio maybe a significant risk factor for intraoperative transfusion in UIA surgery.

Serum zinc deficiency is a potential risk factor for the occurrence of levodopa-induced dyskinesia in drug-naïve Parkinson's disease.

Background: Since environmental factors, especially heavy metals, were highlighted in the pathogenesis of Parkinson's disease (PD), there are many epidemiologic studies regarding heavy metals and PD risk. However, longitudinal studies regarding the impacts of heavy metals on motor and nonmotor symptoms of PD are scarce. Methods: In the current study, we compared the serum levels of five heavy metals, such as zinc(Zn), copper(Cu), lead(Pb), mercury(Hg), and manganese(Mn), in 111 previously drug-naïve PD patients (n = 111) retrospectively. Among these 111 patients, 65 were PD patients without levodopa-induced dyskinesia (LID), while the other 46 had LID. We assembled clinical characteristics of PD and performed correlation analysis with heavy metal levels. At baseline, all subjects were examined with 18F-N-(3-fluoropropyl)-2ß-carboxymethoxy-3ß-(4-iodophenyl) nortropane positron emission tomography/computed tomography (FP-CIT PET/CT). We used Cox proportional hazards regression analysis for determining factors relevant to the time to LID development in PD subjects. Results: Zn deficiency was significantly higher in the PD with LID group than in the PD without LID group (79.58 ± 12.28 versus 88.16 ± 15.15 µg/L). Lower serum Zn levels were significantly correlated with age of onset, levodopa equivalent daily dose (LEDD) at 3 months, and Korean version of the Mini-Mental State Examination (K-MMSE) scores (r = 0.16, p < 0.05, r = - 0.20, p < 0.01, r = 0.28, p < 0.01). Additionally, Zn deficiency was associated with a reduced time to LID development in the adjusted model (HR 0.978, 95% CI 0.956-0.999). Conclusion: This study suggests that serum Zn deficiency might be a risk factor for LID in drug-naïve PD patients.

Development and testing of nanoparticles delivery for P7C3 small molecule using injury models.

The use of nanoparticles (NPs) has emerged as a potential tool for safe and effective drug delivery. In the present study, we developed small molecule P7C3-based NPs and tested its efficacy and toxicity along with the tissue specific aptamer-modified P7C3 NPs. The P7C3 NPs were prepared using poly (D, L-lactic-co-glycolic acid) carboxylic acid (PLGA-COOH) polymer, were conjugated with skeletal muscle-specific RNA aptamer (A01B P7C3 NPs) and characterized for its cytotoxicity, cellular uptake, and wound healing in vitro. The A01B P7C3 NPs demonstrated an encapsulation efficiency of 30.2 ± 2.6%, with the particle size 255.9 ± 4.3 nm, polydispersity index of 0.335 ± 0.05 and zeta potential of + 10.4 ± 1.8mV. The FTIR spectrum of P7C3 NPs displayed complete encapsulation of the drug in the NPs. The P7C3 NPs and A01B P7C3 NPs displayed sustained drug release in vitro for up to 6 days and qPCR analysis confirmed A01B aptamer binding to P7C3 NPs. The C2C12 cells viability assay displayed no cytotoxic effects of all 3 formulations at 48 and 72 h. In addition, the cellular uptake of A01B P7C3 NPs in C2C12 myoblasts demonstrated higher uptake. In vitro assay mimicking wound healing showed improved wound closure with P7C3 NPs. In addition, P7C3 NPs significantly decreased TNF-α induced NF-κB activity in the C2C12/NF-κB reporter cells after 24-hour treatment. The P7C3 NPs showed 3-4-fold higher efficacy compared to P7C3 solutions in both wound-closure and inflammation assays in C2C12 cells. Furthermore, the P7C3 NPs showed 3-4-fold higher efficacy in reducing the infarct size and protected mouse hearts from ex vivo ischemia-reperfusion injury. Overall, this study demonstrates the safe and effective delivery of P7C3 NPs.

Total Intravenous Anesthesia Protocol for Decreasing Unacceptable Movements during Cerebral Aneurysm Clipping with Motor-Evoked Potential Monitoring: A Historical Control Study and Meta-Analysis.

Injury can occur during intraoperative transcranial motor-evoked potential (MEP) monitoring caused by patient movement related to insufficient neuromuscular blocking agent use. Here, we evaluated the incidence of unacceptable movements in patients undergoing intraoperative MEP monitoring following our anesthetic protocol. We reviewed the anesthesia records of 419 patients who underwent unruptured cerebral aneurysm clipping with intraoperative MEP monitoring. The anesthetic protocol included target-controlled infusion with a fixed effect-site propofol concentration of 3 µg/mL and an adjustable effect-site remifentanil concentration of 10-12 ng/mL. We compared our findings of the intraoperative parameters and incidence of spontaneous movement and respiration with those of published meta-analysis studies. Spontaneous movement and respiration occurred in one (0.2%) patient each. The meta-analysis included six studies. The pooled proportions of spontaneous movement and respiration were 6.9% (95% confidence interval [CI], 1.3-16.5%) and 4.1% (95% CI, 0.5-14.1%), respectively. The proportion of spontaneous movement in our study was significantly lower than that in previous studies (p = 0.013), with no significant difference in spontaneous respiration (p = 0.097). Following our center's anesthesia protocol during cerebral aneurysm clipping resulted in a low incidence of spontaneous respiration and movement, indicating its safety for patients undergoing intraoperative MEP monitoring.

Chemokine/ITGA4 Interaction Directs iPSC-Derived Myogenic Progenitor Migration to Injury Sites in Aging Muscle for Regeneration.

The failure of muscle to repair after injury during aging may be a major contributor to muscle mass loss. We recently generated muscle progenitor cells (MPCs) from human-induced pluripotent stem-cell (iPSC) cell lines using small molecules, CHIR99021 and Givinostat (Givi-MPCs) sequentially. Here, we test whether the chemokines overexpressed in injured endothelial cells direct MPC migration to the site by binding to their receptor, ITGA4. ITGA4 was heavily expressed in Givi-MPCs. To study the effects on the mobilization of Givi-MPCs, ITGA4 was knocked down by an ITGA4 shRNA lentiviral vector. With and without ITGA4 knocked down, cell migration in vitro and cell mobilization in vivo using aged NOD scid gamma (NSG) mice and mdx/scid mice were analyzed. The migration of shITGA4-Givi-MPCs was significantly impaired, as shown in a wound-healing assay. The knockdown of ITGA4 impaired the migration of Givi-MPCs towards human aortic endothelial cells (HAECs), in which CX3CL1 and VCAM-1 were up-regulated by the treatment of TNF-α compared with scramble ones using a transwell system. MPCs expressing ITGA4 sensed chemokines secreted by endothelial cells at the injury site as a chemoattracting signal to migrate to the injured muscle. The mobilization of Givi-MPCs was mediated by the ligand-receptor interaction, which facilitated their engraftment for repairing the sarcopenic muscle with injury.

Marchf6 E3 ubiquitin ligase critically regulates endoplasmic reticulum stress, ferroptosis, and metabolic homeostasis in POMC neurons.

The metabolic prohormone pro-opiomelanocortin (POMC) is generally translocated into the endoplasmic reticulum (ER) for entry into the secretory pathway. Patients with mutations within the signal peptide (SP) of POMC or its adjoining segment develop metabolic disorders. However, the existence, metabolic fate, and functional outcomes of cytosol-retained POMC remain unclear. Here, we show that SP-uncleaved POMC is produced in the cytosol of POMC neuronal cells, thus inducing ER stress and ferroptotic cell death. Mechanistically, the cytosol-retained POMC sequesters the chaperone Hspa5 and subsequently accelerates degradation of the glutathione peroxidase Gpx4, a core regulator of ferroptosis, via the chaperone-mediated autophagy. We also show that the Marchf6 E3 ubiquitin ligase mediates the degradation of cytosol-retained POMC, thereby preventing ER stress and ferroptosis. Furthermore, POMC-Cre-mediated Marchf6-deficient mice exhibit hyperphagia, reduced energy expenditure, and weight gain. These findings suggest that Marchf6 is a critical regulator of ER stress, ferroptosis, and metabolic homeostasis in POMC neurons.

Npas4-mediated dopaminergic regulation of safety memory consolidation.

Amygdala circuitry encodes associations between conditioned stimuli and aversive unconditioned stimuli and also controls fear expression. However, whether and how non-threatening information for unpaired conditioned stimuli (CS-) is discretely processed remains unknown. The fear expression toward CS- is robust immediately after fear conditioning but then becomes negligible after memory consolidation. The synaptic plasticity of the neural pathway from the lateral to the anterior basal amygdala gates the fear expression of CS-, depending upon neuronal PAS domain protein 4 (Npas4)-mediated dopamine receptor D4 (Drd4) synthesis, which is precluded by stress exposure or corticosterone injection. Herein, we show cellular and molecular mechanisms that regulate the non-threatening (safety) memory consolidation, supporting the fear discrimination.