Time-course analysis of frontal gene expression profiles in the rat model of posttraumatic stress disorder and a comparison with the conditioned fear model.

Posttraumatic stress disorder (PTSD) is a complex disorder that involves physiological, emotional, and cognitive dysregulation that may occur after exposure to a life-threatening event. In contrast with the condition of learned fear with resilience to extinction, abnormal fear with impaired fear extinction and exaggeration are considered crucial factors for the pathological development of PTSD. The prefrontal cortex (mPFC) is considered a critical region of top-down control in fear regulation, which involves the modulation of fear expression and extinction. The pathological course of PTSD is usually chronic and persistent; a number of studies have indicated temporal progression in gene expression and phenotypes may be involved in PTSD pathology. In the current study, we use a well-established modified single-prolonged stress (SPS&FS) rat model to feature PTSD-like phenotypes and compared it with a footshock fear conditioning model (FS model); we collected the frontal tissue after extreme stress exposure or fear conditioning and extracted RNA for transcriptome-level gene sequencing. We compared the genetic profiling of the mPFC at early (<2 h after solely FS or SPS&FS exposure) and late (7 days after solely FS or SPS&FS exposure) stages in these two models. First, we identified temporal differences in the expressional patterns between these two models and found pathways such as protein synthesis factor eukaryotic initiation factor 2 (EIF2), transcription factor NF-E2-related factor 2 (NRF2)-mediated oxidative stress response, and acute phase responding signaling enriched in the early stage in both models with significant p-values. Furthermore, in the late stage, the sirtuin signaling pathway was enriched in both models; other pathways such as STAT3, cAMP, lipid metabolism, Gα signaling, and increased fear were especially enriched in the late stage of the SPS&FS model. However, pathways such as VDR/RXR, GP6, and PPAR signaling were activated significantly in the FS model's late stage. Last, the network analysis revealed the temporal dynamics of psychological disorder, the endocrine system, and also genes related to increased fear in the two models. This study could help elucidate the genetic temporal alteration and stage-specific pathways in these two models, as well as a better understanding of the transcriptome-level differences between them.

Early- and late-phase changes of brain activity and early-phase neuromodulation in the posttraumatic stress disorder rat model.

Posttraumatic stress disorder (PTSD) is a complex syndrome that may occur after life-threatening events. Fear memory abnormalities may play vital roles in the pathogenesis of PTSD. Previous work has found that fear memories are not rigid; the retrieval of fear memories may change over time. Furthermore, prior studies suggest that theta wave (4 Hz) activity is highly correlated with fear expression in an animal model. However, the relationship between pathological fear memory and potential brain wave features in PTSD remains largely uncharacterized. Here, we hypothesized that after traumatic stress exposure, the longitudinal dynamics of abnormal fears in PTSD animal models could be reflected by the measurement of local field potentials (LFPs). Using a well-established modified single-prolonged stress and footshock (SPS & FS) PTSD rat model, animals were restrained for 2 h and subsequently subjected to 20 min of forced swimming, then exposed to diethyl ether until they lost consciousness and placed in a conditioning chamber for fear conditioning. To characterize the temporal changes, we characterized freezing behavior brain wave features during the conditioning chamber re-exposure in the early (10 and 30 min; 2, 4, and 6 h) and late (day 1, 3, 7, and 14) phases after traumatic stress exposure. Our results indicate that SPS & FS rats showed co-morbid PTSD phenotypes including significantly higher levels of anxiety-, depression-, and anhedonia-like behaviors, and impaired fear extinction. Delta wave (0.5-4 Hz) suppression in the medial prefrontal cortex, amygdala, and ventral hippocampus occurred 10 and 30 min after traumatic stress, followed by continuous delta wave activity from 2 h to day 14, correlating with fear levels. tDCS reduced delta activity and alleviated PTSD-like phenotypes in the SPS & FS group. In this study, profiling abnormal fears with brain wave correlates may improve our understanding of time-dependent pathological fear memory retrieval in PTSD and facilitate the development of effective intervention strategies.

Sleep problems in preschool children at the child development center with different developmental status: A questionnaire survey.

Objective: To investigate the relationship between sleep problems and development in preschool children with suspected developmental delay. Methods: A total of 192 preschool children (mean age 4 years; 131 males, 61 females) were recruited from the Child Development Clinic, including 98 preterm children and 94 age- and sex-matched full-term children. All participants underwent evaluation of gross motor, fine motor and speech performance. All parents of all participants completed the Children's Sleep Habits Questionnaire (CSHQ). Some of the participants also underwent psychological evaluation. Correlation analysis and community network analysis were used to investigate the interactions. Results: The developmental status was: 75.5% developmental delay, 19.3% borderline development, and 5.2% normal development. Eighty-nine percent of the subjects had abnormal CSHQ scores. Age, gestational age, speech development, cognitive development, and socio-emotional development were significantly correlated with the CSHQ. Significant interactions between sleep problems and development were noted mostly in the preterm group. Conclusion: High prevalence of sleep disturbances in children at the Child Development Center was noted and associated with multiple factors. Therefore, during the multidisciplinary evaluation of children with possible developmental delay, inquiring about their sleep quality and habits is strongly recommended. Mitigating sleep problems enhances the efficacy of early intervention programs.

BDNF Protein and BDNF mRNA Expression of the Medial Prefrontal Cortex, Amygdala, and Hippocampus during Situational Reminder in the PTSD Animal Model.

Whether BDNF protein and BDNF mRNA expression of the medial prefrontal cortex (mPFC; cingulated cortex area 1 (Cg1), prelimbic cortex (PrL), and infralimbic cortex (IL)), amygdala, and hippocampus (CA1, CA2, CA3, and dentate gyrus (DG)) was involved in fear of posttraumatic stress disorder (PTSD) during the situational reminder of traumatic memory remains uncertain. Footshock rats experienced an inescapable footshock (3 mA, 10 s), and later we have measured fear behavior for 2 min in the footshock environment on the situational reminder phase. In the final retrieval of situational reminder, BDNF protein and mRNA levels were measured. The results showed that higher BDNF expression occurred in the Cg1, PrL, and amygdala. Lower BDNF expression occurred in the IL, CA1, CA2, CA3, and DG. BDNF mRNA levels were higher in the mPFC and amygdala but lower in the hippocampus. The neural connection analysis showed that BDNF protein and BDNF mRNA exhibited weak connections among the mPFC, amygdala, and hippocampus during situational reminders. The present data did not support the previous viewpoint in neuroimaging research that the mPFC and hippocampus revealed hypoactivity and the amygdala exhibited hyperactivity for PTSD symptoms. These findings should be discussed with the previous evidence and provide clinical implications for PTSD.

Ethanol Extracts of Fresh Davallia formosana (WL1101) Inhibit Osteoclast Differentiation by Suppressing RANKL-Induced Nuclear Factor- κ B Activation.

The rhizome of Davallia formosana is commonly used to treat bone disease including bone fracture, arthritis, and osteoporosis in Chinese herbal medicine. Here, we report the effects of WL1101, the ethanol extracts of fresh rhizomes of Davallia formosana on ovariectomy-induced osteoporosis. In addition, excess activated bone-resorbing osteoclasts play crucial roles in inflammation-induced bone loss diseases, including rheumatoid arthritis and osteoporosis. In this study, we examined the effects of WL1101 on receptor activator of nuclear factor- κ B ligand (RANKL)-induced osteoclastogenesis. Treatment with WL1101 significantly inhibited RANKL-stimulated osteoclastogenesis. Two isolated active compounds, ((-)-epicatechin) or WL14 (4-hydroxy-3-aminobenzoic acid) could also inhibit RANKL-induced osteoclastogenesis. WL1101 suppressed the RANKL-induced nuclear factor- κ B (NF- κ B) activation and nuclear translocation, which is the key process during osteoclastogenesis, by inhibiting the activation of I κ B kinase (IKK) and I κ B α . In animal model, oral administration of WL1101 (50 or 200 mg/kg/day) effectively decreased the excess bone resorption and significantly antagonized the trabecular bone loss in ovariectomized rats. Our results demonstrate that the ethanol extracts of fresh rhizomes of Davallia formosana inhibit osteoclast differentiation via the inhibition of NF- κ B activation and effectively ameliorate ovariectomy-induced osteoporosis. WL1101 may thus have therapeutic potential for the treatment of diseases associated with excessive osteoclastic activity.