ABSTRACT
Chronic stress leads to many psychiatric disorders, including social and anxiety disorders that are associated with over-activation of neurons in the basolateral amygdala (BLA). However, not all individuals develop psychiatric diseases, many showing considerable resilience against stress exposure. Whether BLA neuronal activity is involved in regulating an individual's vulnerability to stress remains elusive. In this study, using a mouse model of chronic social defeat stress (CSDS), we divided the mice into susceptible and resilient subgroups based on their social interaction behavior. Using in vivo fiber photometry and in vitro patch-clamp recording, we showed that CSDS persistently (after 20 days of recovery from stress) increased BLA neuronal activity in all the mice regardless of their susceptible or resilient nature, although impaired social interaction behavior was only observed in susceptible mice. Increased anxiety-like behavior, on the other hand, was evident in both groups. Notably, the CSDS-induced increase of BLA neuronal activity correlated well with the heightened anxiety-like but not the social avoidance behavior in mice. These findings provide new insight to our understanding of the role of neuronal activity in the amygdala in mediating stress-related psychiatric disorders.
Subject(s)
Avoidance Learning , Stress, Psychological , Amygdala , Animals , Anxiety/etiology , Anxiety Disorders , Mice , Mice, Inbred C57BL , Social Behavior , Stress, Psychological/complicationsABSTRACT
AIMS: Glioblastoma is one of the most invasive tumors of the central nervous system, and has a high degree of malignancy and poor prognosis. Harmine, an active ingredient extracted from perennial herbs, has been reported to have obvious antitumor effects on various tumors. However, the effects of harmine on glioblastoma growth remain unknown. We here explored the effects of harmine on glioblastoma and its underlying molecular mechanisms related to tumorigenesis. MATERIALS AND METHODS: CCK-8 and immunofluorescent assay were performed to measure anti-proliferative effect of harmine on U251-MG and U373-MG cells. Wound healing assay was performed to measure the effects of harmine on cell migration. qRT-PCR and western blot were performed to detect the protein/gene expression. BALB/c nude mice bearing U251-MG xenografts was used to measure the effects of harmine on the growth of glioblastoma in vivo. KEY FINDINGS: Harmine treatment significantly suppressed the proliferation of U251-MG and U373-MG cells in a dose and time-dependent way. Mechanistically, harmine reduced the basal and EGF-enhanced the phosphorylation level of FAK and AKT. Moreover, harmine inhibited the cell viability of U251-MG and U373-MG cells by downregulating the phosphorylation of the FAK/AKT pathway. Besides, harmine significantly suppressed the migration of U251-MG cells by suppressing the expression of MMP2, MMP9 and VEGF. Subsequently, orthotopic xenograft models revealed that harmine treatment dramatically inhibited the growth of glioblastoma in vivo. SIGNIFICANCE: In conclusion, these results suggest that harmine suppresses the proliferation and migration of U251-MG and U373-MG cells by inhibiting the FAK/AKT signaling pathway. Our findings elucidate harmine could be a promising drug for glioblastoma therapy.
Subject(s)
Glioblastoma/metabolism , Harmine/pharmacology , Animals , Brain Neoplasms/pathology , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , China , Focal Adhesion Kinase 1/metabolism , Glioblastoma/drug therapy , Harmine/metabolism , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , Xenograft Model Antitumor Assays/methodsABSTRACT
Two-factor designs are quite commonly used in scientific research. If the two factors have interactions, research designs like the factorial design and the orthogonal design can be adopted; however, these designs usually require many experiments. If the two factors have no interaction or the interaction is not statistically significant on result in theory and in specialty, and the measuring error of the experimental data under a certain condition (usually it is one of the experimental conditions which is formed by the complete combination of the levels of two factors) is allowed in specialty, researchers can use random block design without repeated experiments, balanced non-complete random block design without repeated experiments, single factor design with a repeatedly measured factor, two-factor design without repeated experiments and two-factor nested design. This article introduced the first three design types with examples.
