Locus coeruleus noradrenergic neurons phase-lock to prefrontal and hippocampal infra-slow rhythms that synchronize to behavioral events.

The locus coeruleus (LC) is the primary source of noradrenergic projections to the forebrain, and, in prefrontal cortex, is implicated in decision-making and executive function. LC neurons phase-lock to cortical infra-slow wave oscillations during sleep. Such infra-slow rhythms are rarely reported in awake states, despite their interest, since they correspond to the time scale of behavior. Thus, we investigated LC neuronal synchrony with infra-slow rhythms in awake rats performing an attentional set-shifting task. Local field potential (LFP) oscillation cycles in prefrontal cortex and hippocampus on the order of 0.4 Hz phase-locked to task events at crucial maze locations. Indeed, successive cycles of the infra-slow rhythms showed different wavelengths, as if they are periodic oscillations that can reset phase relative to salient events. Simultaneously recorded infra-slow rhythms in prefrontal cortex and hippocampus could show different cycle durations as well, suggesting independent control. Most LC neurons (including optogenetically identified noradrenergic neurons) recorded here were phase-locked to these infra-slow rhythms, as were hippocampal and prefrontal units recorded on the LFP probes. The infra-slow oscillations also phase-modulated gamma amplitude, linking these rhythms at the time scale of behavior to those coordinating neuronal synchrony. This would provide a potential mechanism where noradrenaline, released by LC neurons in concert with the infra-slow rhythm, would facilitate synchronization or reset of these brain networks, underlying behavioral adaptation.

The prognostic value of tumor mutational burden and immune cell infiltration in esophageal cancer patients with or without radiotherapy.

Growing evidence highlighted the tumor mutational burden (TMB) as an important feature of carcinogenesis and therapeutic efficacy in esophageal cancer (EC). Our study aimed to explore the genomic landscape and the correlation between TMB and immune cell infiltration in EC patients with or without radiotherapy. The EC patients were categorized into high TMB (TMB-H) and low TMB (TMB-L) groups by the ESTIMATE algorithm, and subgroup analysis was performed based on receiving radiotherapy or not. Univariate regression analysis indicated TMB and TNM stages as high-risk prognostic factors (Hazard ratio > 1 and P < 0.05). Multivariate regression analysis suggested TMB as an independent prognostic factor (Hazard ratio = 1.051, P = 0.003). Kaplan-Meier analysis showed no significant difference of the overall survival (OS) between TMB-H and TMB-L groups (P = 0.082). However, EC patients without radiotherapy in the TMB-H group had significantly decreased OS (P = 0.038) and increased Tregs cell infiltration (P = 0.033). These results suggested TMB as a prognostic marker for EC patients. Especially for patients who did not receive radiotherapy, the prognosis of TMB-H patients was significantly poorer than that of TMB-L patients, which might result from the different regulatory T cell infiltration.

MiR-195 restrains lung adenocarcinoma by regulating CD4+ T cell activation via the CCDC88C/Wnt signaling pathway: a study based on the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and bioinformatic analysis.

BACKGROUND: To systematically identity microRNA signatures, as well as miRNA-gene axes, for lung adenocarcinoma (LUAD) and to explore the potential biomarkers and mechanisms associated with the LUAD immune responses. METHODS: LUAD-related data were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), and these data were then used to identify the differentially expressed miRNAs that were downregulated in tumor tissues. Summary receiver operating characteristic curve analysis, survival analysis and meta-analysis were applied to evaluate the clinical significance and diagnostic value of the identified miRNAs. The presumed targets of the integrated-signature miRNAs were identified via 3 different target prediction algorithms: TargetScan, miRDB and DIANA-TarBase. Immunologic signature gene sets were enriched by gene set enrichment analysis (GSEA). Tumor-infiltrating lymphocytes were profiled by the Tumor IMmune Estimation Resource (TIMER). After pathway enrichment analysis using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases, pathway-gene networks were constructed using Cytoscape software. RESULTS: After integrated analysis of 4 GEO data sets (GSE48414, GSE51853, GSE63805 and GSE74190) and TCGA databases, miR-195 was identified as a potential clinical diagnostic marker. A total of 287 miR-195 target genes were screened, and 3 functional gene sets (GSE13485, GSE21379 and GSE29164) were enriched. GSE21379 was associated with the upregulation of CD4+ T cells in tumors, and the core genes were validated via the TIMER database. The CCDC88C expression level was significantly correlated with CD4+ T cell activation (partial.cor =0.437, P<0.001). Enrichment analysis revealed that CCDC88C was significantly enriched in the Wnt signaling pathway. CONCLUSIONS: MiR-195, as a suppressor of lung adenocarcinoma, regulates CD4+ T cell activation via CCDC88C.

Behavioral correlates of activity of optogenetically identified locus coeruleus noradrenergic neurons in rats performing T-maze tasks.

The nucleusLocus Coeruleus (LC) is the major source of forebrain norepinephrine. LC is implicated in arousal, response to novelty, and cognitive functions, including decision-making and behavioral flexibility. One hypothesis is that LC activation promotes rapid shifts in cortical attentional networks following changes in environmental contingencies. Recent recordings further suggest LC is critical for mobilizing resources to deal with challenging situations. In the present study optogenetically identified LC neuronal activity was recorded in rats in a self-paced T-maze. Rats were trained on visual discrimination; then place-reward contingencies were instated. In the session where the animal shifted tasks the first time, the LC firing rate after visual cue onset increased significantly, even as the animal adhered to the previous rule. Firing rate also increased prior to crossing photodetectors that controlled stimulus onset and offset, and this was positively correlated with accelerations, consistent with a role in mobilizing effort. The results contribute to the growing evidence that the noradrenergic LC is essential for behavioral adaptation by promoting cognitive flexibility and mobilizing effort in face of changing environmental contingencies.