Dysregulated prefrontal control over amygdala is engaged in the pathogenesis of psychiatric diseases including depression and anxiety disorders. Here we show that, in a rodent anxiety model induced by chronic restraint stress (CRS), the dysregulation occurs in basolateral amygdala projection neurons receiving mono-directional inputs from dorsomedial prefrontal cortex (dmPFC→BLA PNs) rather than those reciprocally connected with dmPFC (dmPFC↔BLA PNs). Specifically, CRS shifts the dmPFC-driven excitatory-inhibitory balance towards excitation in the former, but not latter population. Such specificity is preferential to connections made by dmPFC, caused by enhanced presynaptic glutamate release, and highly correlated with the increased anxiety-like behavior in stressed mice. Importantly, low-frequency optogenetic stimulation of dmPFC afferents in BLA normalizes the enhanced prefrontal glutamate release onto dmPFC→BLA PNs and lastingly attenuates CRS-induced increase of anxiety-like behavior. Our findings thus reveal a target cell-based dysregulation of mPFC-to-amygdala transmission for stress-induced anxiety.
This study aims to construct the stromal immunotype, which could improve the prediction of postsurgical survival and adjuvant platinum-based chemotherapy in muscle-invasive bladder cancer (MIBC). A total of 118 patients with MIBC from Shanghai Cancer Center, 140 patients with MIBC from Zhongshan Hospital, and 287 patients with MIBC from TCGA cohort were included in the study. Immune cell infiltration was evaluated by IHC staining or CIBERSORT method. Five immune features were selected out of 22 immune features to construct immunotypes based on the LASSO Cox regression model. Using the LASSO model, we classified patients with MIBC into stromal immunotype A subgroup (CTLNKTregMacrophageMC) and stromal immunotype B subgroup (CTLNKTregMacrophageMC). Significant differences were found between immunotype A and immunotype B in the combined cohort with 5-year overall survival (OS, 76.0% vs. 44.0%; < 0.001) and 5-year disease-free survival (DFS, 62.8% vs. 48.3%; < 0.001). Stromal immunotype was revealed to be an independent prognostic indicator in multivariate analysis in all cohorts separately. Either OS or DFS was not improved by adjuvant chemotherapy (ACT) in pT2 stage patients or pT3+pT4 patients, but further analysis revealed that OS and disease-free was significantly improved by ACT in pT3+pT4 patients ( = 0.016 and = 0.006, respectively). Finally, stromal immunotype A showed higher immune checkpoint molecules (PD-L1, PD-1, and CTLA-4) expression. The stromal immunotypes could effectively predict survival and recurrence of MIBC. Furthermore, the immunotypes might be a practical predictive tool to identify pT3+pT4 patients who would benefit from ACT. .
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