Post-traumatic stress disorder (PTSD) is a psychiatric disorder that afflicts many individuals. However, its molecular and cellular mechanisms remain largely unexplored. Here, we found PTSD susceptible mice exhibited significant up-regulation of alpha-Ca 2+ /calmodulin-dependent kinase II (αCaMKII) in the lateral amygdala (LA). Consistently, increasing αCaMKII in the LA not only caused PTSD-like behaviors such as impaired fear extinction and anxiety-like behaviors, but also attenuated N-methyl-D-aspartate receptor (NMDAR)-dependent long-term depression (LTD) at thalamo-lateral amygdala (T-LA) synapses, and reduced GluA1-Ser845/Ser831 dephosphorylation and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization. Suppressing the elevated αCaMKII to normal levels completely rescued both PTSD-like behaviors and the impairments in LTD, GluA1-Ser845/Ser831 dephosphorylation, and AMPAR internalization. Intriguingly, deficits in GluA1-Ser845/Ser831 dephosphorylation and AMPAR internalization were detected not only after impaired fear extinction, but also after attenuated LTD. Our results suggest that αCaMKII in the LA may be a potential molecular determinant of PTSD. We further demonstrate for the first time that GluA1-Ser845/Ser831 dephosphorylation and AMPAR internalization are molecular links between fear extinction and LTD.

Background: Acute lung injury (ALI) is a severe respiratory disease with high rates of morbidity and mortality. Many mediators regarding endogenous or exogenous are involved in the pathophysiology of ALI. Here, we have uncovered the involvement of integrins and matrix metalloproteinases, as critical determinants of excessive inflammation and endothelial permeability, in the regulation of ALI. Methods: Inflammatory cytokines were measured by quantitative real-time PCR for mRNA levels and ELISA for secretion levels. Endothelial permeability assay was detected by the passage of rhodamine B isothiocyanate-dextran. Mice lung permeability was assayed by Evans blue albumin (EBA). Western blot was used for protein level measurements. The intracellular reactive oxygen species (ROS) were evaluated using a cell-permeable probe, DCFH-DA. Intratracheal injection of lipopolysaccharide (LPS) into mice was conducted to establish the lung injury model. Results: Exogenous MMP-9 significantly aggravated the inflammatory response and permeability in mouse pulmonary microvascular endothelial cells (PMVECs) treated by LPS, whereas knockdown of MMP-9 exhibited the opposite phenotypes. Knockdown of integrin β3 or β5 in LPS-treated PMVECs significantly downregulated MMP-9 expression and decreased inflammatory response and permeability in the presence or absence of exogenous MMP-9. Additionally, the interaction of MMP-9 and integrin β5 was impaired by a ROS scavenger, which further decreased the pro-inflammatory cytokines production and endothelial leakage in PMVECs subjected to co-treatment (LPS with exogenous MMP-9). In vivo studies, exogenous MMP-9 treatment or knockdown β3 integrin significantly decreased survival in ALI mice. Notably, knockdown of β5 integrin alone had no remarkable effect on survival, but which combined with anti-MMP-9 treatment significantly improved the survival by ameliorating excessive lung inflammation and permeability in ALI mice. Conclusion: These findings support the β3/5 integrin-MMP-9 axis as an endogenous signal that could play a pivotal role in regulating inflammatory response and alveolar-capillary permeability in ALI.

Background: Whole body vibration (WBV) has been used to treat various musculoskeletal diseases in recent years. However, there is limited knowledge about its effects on the lumbar segments in upright posture mice. This study was performed to investigate the effects of axial Whole body vibration on the intervertebral disc (IVD) and facet joint (FJ) in a novel bipedal mouse model.Methods: Six-week-old male mice were divided into control, bipedal, and bipedal + vibration groups. Taking advantage of the hydrophobia of mice, mice in the bipedal and bipedal + vibration groups were placed in a limited water container and were thus built standing posture for a long time. The standing posture was conducted twice a day for a total of 6 hours per day, 7 days per week. Whole body vibration was conducted during the first stage of bipedal building for 30 min per day (45 Hz with peak acceleration at 0.3 g). The mice of the control group were placed in a water-free container. At the 10th-week after experimentation, intervertebral disc and facet joint were examined by micro-computed tomography (micro-CT), histologic staining, and immunohistochemistry (IHC), and gene expression was quantified using real-time polymerase chain reaction. Further, a finite element (FE) model was built based on the micro-CT, and dynamic Whole body vibration was loaded on the spine model at 10, 20, and 45 Hz.Results: Following 10 weeks of model building, intervertebral disc showed histological markers of degeneration, such as disorders of annulus fibrosus and increased cell death. Catabolism genes’ expression, such as Mmp13, and Adamts 4/5, were enhanced in the bipedal groups, and Whole body vibration promoted these catabolism genes’ expression. Examination of the facet joint after 10 weeks of bipedal with/without Whole body vibration loading revealed rough surface and hypertrophic changes at the facet joint cartilage resembling osteoarthritis. Moreover, immunohistochemistry results demonstrated that the protein level of hypertrophic markers (Mmp13 and Collagen X) were increased by long-durationstanding posture, and Whole body vibration also accelerated the degenerative changes of facet joint induced by bipedal postures. No changes in the anabolism of intervertebral disc and facet joint were observed in the present study. Furthermore, finite element analysis revealed that a larger frequency of Whole body vibration loading conditions induced higher Von Mises stresses on intervertebral disc, contact force, and displacement on facet joint.Conclusion: The present study revealed significant damage effects of Whole body vibration on intervertebral disc and facet joint in a bipedal mouse model. These findings suggested the need for further studies of the effects of Whole body vibration on lumbar segments of humans.