Effects of Intranasal Oxytocin on Pup Deprivation-Evoked Aberrant Maternal Behavior and Hypogalactia in Rat Dams and the Underlying Mechanisms

Oxytocin (OT), a hypothalamic neuropeptide, applied through nasal approach (IAO), could improve maternal health during lactation that is disrupted by mother–baby separation; however, the regulation of IAO effects on maternal behaviors and lactation as well as the underlying mechanisms remain unclear. Using lactating rats, we observed effects of intermittent pup deprivation (PD) with and without IAO on maternal behaviors and lactation as well as the activity of OT neurons in the supraoptic nucleus (SON) and the activity of hypothalamic pituitary-adrenal axis, key factors determining the milk-letdown reflex during lactation and maternal behaviors. The results showed that PD reduced maternal behaviors and lactation efficiency of rat dams as indicated by significantly longer latency to retrieve their pups and low litter’s body weight gains during the observation, respectively. In addition, PD caused early involution of the mammary glands. IAO partially improved these changes in rat dams, which was not as significant as IAO effects on control dams. In the SON, PD decreased c-Fos and increased glial fibrillary acidic protein (GFAP) filaments significantly; IAO made PD-evoked c-Fos reduction insignificant while reduced GFAP filament significantly in PD dams. IAO tended to increase the levels of phosphorylated extracellular signal-regulated kinases (pERK) 1/2 in PD dams. Moreover, PD+IAO significantly increased plasma levels of dam adrenocorticotropic hormone and corticosterone but not OT levels. Lastly, PD+IAO tended to increase the level of corticotropin-releasing hormone in the SON. These results indicate that PD disrupts maternal behaviors and lactation by suppressing the activity of hypothalamic OT-secreting system through expansion of astrocytic processes, which are partially reversed by IAO through removing astrocytic inhibition of OT neuronal activity. However, the improving effect of IAO on the maternal health could be compromised by simultaneous activation of hypothalamic pituitary-adrenocortical axis

A study on the association between prefrontal functional connectivity and non-suicidal self-injury in adolescents with depression

ObjectiveAmong adolescents with depression, the occurrence of non-suicidal self-injury (NSSI) behavior is prevalent, constituting a high-risk factor for suicide. However, there has been limited research on the neuroimaging mechanisms underlying adolescent depression and NSSI behavior, and the potential association between the two remains unclear. Therefore, this study aims to investigate the alterations in functional connectivity (FC) of the regions in the prefrontal cortex with the whole brain, and elucidates the relationship between these alterations and NSSI behavior in adolescents with depression.MethodsA total of 68 participants were included in this study, including 35 adolescents with depression and 33 healthy controls. All participants underwent assessments using the 17-item Hamilton Depression Rating Scale (17-HAMD) and the Ottawa Self-Harm Inventory. In addition, functional magnetic resonance imaging (fMRI) data of the participants’ brains were collected. Subsequently, the FCs of the regions in the prefrontal cortex with the whole brain was calculated. The FCs showing significant differences were then subjected to correlation analyses with 17-HAMD scores and NSSI behavior scores.ResultCompared to the healthy control group, the adolescent depression group exhibited decreased FCs in several regions, including the right frontal eye field, left dorsolateral prefrontal cortex, right orbitofrontal cortex, left insula and right anterior cingulate coetex. The 17-HAMD score was positively correlated with the frequency of NSSI behavior within 1 year (rs = 0.461, p = 0.005). The FC between the right anterior cingulate cortex and the right precuneus showed a negative correlation with the 17-HAMD scores (rs = −0.401, p = 0.023). Additionally, the FC between the right orbitofrontal cortex and the right insula, demonstrated a negative correlation with the frequency of NSSI behavior within 1 year (rs = −0.438, p = 0.012, respectively).ConclusionAdolescents with depression showed decreased FCs of the prefrontal cortex with multiple brain regions, and some of these FCs were associated with the NSSI frequency within 1 year. This study provided neuroimaging evidence for the neurophysiological mechanisms underlying adolescent depression and its comorbidity with NSSI behavior

The universal values of science and China’s Nobel Prize pursuit

China does not seem to believe the existence of universally acknowledged values in science and fails to promote the observation of such values that also should be applied to every member of the scientific community and at all times. Or, there is a separation between the practice of science in China and the values represented by modern science. In this context, science, including the pursuit of the Nobel Prize, is more a pragmatic means to achieve the end of the political leadership – the national pride in this case – than an institution laden with values that govern its practices. However, it is the recognition and respect of the latter that could lead to achievement of the former, rather than the other way around

Targeted observation analysis of a Northwestern Tropical Pacific Ocean mooring array using an ensemble-based method

An important supplement for ocean observing systems, the Northwestern Tropical Pacific Ocean (NWTPO) mooring array including 15 moorings equipped with Acoustic Doppler Current Profilers (ADCP) devices was developed by the Chinese Academy of Sciences and deployed in 2013. This study assessed the performance of this mooring array in monitoring the intra-seasonal and low-frequency (above 91 days) variability of oceanic currents by conducting targeted observation analyses using an ensemble-based method. Key regions for monitoring intra-seasonal variability of the NWTPO circulation are the equator, Indonesian throughflow (ITF), headstream of the North Equatorial Countercurrent (NECC), and Subtropical Countercurrent (STCC). For monitoring intra-seasonal variability, the range of each mooring is confined to a local scale. Therefore, NWTPO moorings cannot adequately resolve intra-seasonal variability in areas of the ITF, the headstream of the NECC, and STCC due to location constraints of the moorings. For monitoring low-frequency variability of NWTPO circulation, the key regions are the Western Boundary Current (WBC), NECC, and the Equatorial Undercurrent (EUC). NWTPO moorings performed relatively well in monitoring the low-frequency variability, as indicated by the strong background correlations between each of the currents. The NWTPO mooring array plays an important role in monitoring the location and intensity of background currents. Because moorings are costly and require a high-density distribution for optimal performance, understanding the multi-timescale dynamical nature of the NWTPO current system is critical for the deploying future moorings in this region

Upregulation of protein phosphatase 2A and NR3A-pleiotropic effect of simvastatin on ischemic stroke rats.

Ca(2+) influxes are regulated by the functional state of N-methyl-D-aspartate receptors (NMDARs). Dephosphorylation of NMDARs subunits decreases Ca(2+) influxes. NR3, a novel subunit of NMDARs, also decreases Ca(2+) influxes by forming new NMDARs with NR1 and NR2. It is meaningful to uncover whether protein phosphatase 2A (PP2A) and NR3A play a role in the protective effect of Simvastatin on ischemic stroke. In the present study, the Sprague-Dawley rats were pretreated with Simvastatin for 7 days before middle cerebral artery occlusion was performed to mimic ischemic stroke. The results showed that Simvastatin decreased brain ischemic infarct area significantly while increasing the expression levels of PP2A and NR3A, thus dephosphorylating the serine sites of NR1 (ser896 and ser897) along with increased enzymatic activities of PP2A. The protein levels of NR3A decreased as the enzymatic activities of PP2A were inhibited by okadaic acid. The results indicated that Simvastatin could protect the cerebrum from ischemic injury through a signaling mechanism involving elevated levels of PP2A and NR3A, and that PP2A might involve in the regulatory mechanism of NR3A expression

DZNep inhibits H3K27me3 deposition and delays retinal degeneration in the rd1 mice

Abstract Retinitis pigmentosa (RP) is a group of inherited retinal degenerative diseases causing progressive loss of photoreceptors. Numerous gene mutations are identified to be related with RP, but epigenetic modifications may also be involved in the pathogenesis. Previous studies suggested that both DNA methylation and histone acetylation regulate photoreceptor cell death in RP mouse models. However, the role of histone methylation in RP has never been investigated. In this study, we found that trimethylation of several lysine sites of histone H3, including lysine 27 (H3K27me3), increased in the retinas of rd1 mice. Histone methylation inhibitor DZNep significantly reduced the calpain activity, delayed the photoreceptor loss, and improved ERG response of rd1 retina. RNA-sequencing indicated that DZNep synergistically acts on several molecular pathways that regulate photoreceptor survival in rd1 retina, including PI3K-Akt and photoreceptor differentiation pathways, revealing the therapeutic potential of DZNep for RP treatment. PI3K-Akt pathway and H3K27me3 form a feedback loop in rd1 retina, thus PI3K inhibitor LY294002 reduces phosphorylation of Ezh2 at serine 21 and enhances H3K27me3 deposition, and inhibiting H3K27me3 by DZNep can activate PI3K-Akt pathway by de-repressing gene expression of PI3K subunits Pik3r1 and Pik3r3. These findings suggest that histone methylation, especially H3K27me3 deposition is a novel mechanism and therapeutic target for retinal degenerative diseases, similar to H3K27me3-mediated ataxia-telangiectasia in Atm −/− mouse

Preclinical Short-term and Long-term Safety of Human Bone Marrow Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) have become a promising therapeutic method. More safety data are needed to support clinical studies in more diseases. The aim of this study was to investigate the short- and long-term safety of human bone marrow–derived MSCs (hBMMSCs) in mice. In the present study, we injected control (saline infusion only), low (1.0 × 10 6 /kg), medium (1.0 × 10 7 /kg), and high (1.0 × 10 8 /kg) concentrations of hBMMSCs into BALB/c mice. The safety of the treatment was evaluated by observing changes in the general condition, hematology, biochemical indices, pathology of vital organs, lymphocyte subsets, and immune factor levels on days 14 and 150. In the short-term toxicity test, no significant abnormalities were observed in the hematological and biochemical parameters between the groups injected with hBMMSCs, and no significant damage was observed in the major organs, such as the liver and lung. In addition, no significant differences were observed in the toxicity-related parameters among the groups in the long-term toxicity test. Our study also demonstrates that mice infused with different doses of hBMMSCs do not show abnormal immune responses in either short-term or long-term experiments. We confirmed that hBMMSCs are safe through a 150-day study, demonstrating that this is a safe and promising therapy and offering preliminary safety evidence to promote future clinical applications of hBMMSCs in different diseases

Melatonin decreases M1 polarization via attenuating mitochondrial oxidative damage depending on UCP2 pathway in prorenin-treated microglia.

Accumulating evidence suggests that neuroinflammation and oxidative stress in cardiovascular center contribute to the pathological processes underlying hypertension. Microglia activation triggers the inflammation and oxidative stress. Melatonin is a documented potent anti-inflammatory regent and antioxidant, the underlying roles of melatonin in regulating microglia activation via mitochondria remain unclear. In present study, we investigated the protective role of melatonin in decreasing M1 phenotype switching via attenuating mitochondrial oxidative damage in dependence on uncoupling protein 2 (UCP2) pathway in microglia. Prorenin (20 nmol/L; 24 hr) was used to induce inflammation in cultured microglia. Mitochondrial morphology was detected by transmission electron microscope. The reactive oxygen species (ROS) production by using DCFH-DA fluorescence imaging and mitochondrial membrane potential (MMP, ΔΨm) was evaluated by JC-1 staining. The indicator of the redox status as the ratio of the amount of total NADP+ to total NADPH, and the expression of 6 subunits of NADPH oxidase is measured. The pro-inflammatory cytokines releasing was measured by qPCR. UCP2 and activated AMPKα (p-AMPKα) expression were examined by immunoblot. Melatonin (100 μM) markedly alleviated the M1 microglia phenotype shifting and abnormal mitochondria morphology. Melatonin attenuated prorenin-induced ΔΨm increasing and ROS overproduction. Melatonin decreased the redox ratio (NADP+/NADPH) and the p47phox and gp91phox subunits of NADPH oxidase expression in prorenin-treated microglia. These effects were reversed in the presence of UCP2 siRNA. Our results suggested that the protective effect of melatonin against prorenin-induced M1 phenotype switching via attenuating mitochondrial oxidative damage depending on UCP2 upregulation in prorenin-treated microglia