ß2-Adrenoceptors in the Medial Prefrontal Cortex Excitatory Neurons Regulate Anxiety-like Behavior in Mice.

The medial prefrontal cortex (mPFC) and ß-adrenoceptors (ßARs) have been implicated in modulating anxiety-like behavior. However, the specific contributions of the ß2-AR subtype in mPFC in anxiety are still unclear. To address this issue, we used optogenetic and microRNA-based (miRNA) silencing to dissect the role of ß2-AR in mPFC in anxiety-like behavior. On the one hand, we use a chimeric rhodopsin/ß2-AR (Opto-ß2-AR) with in vivo optogenetic techniques to selectively activate ß2-adrenergic signaling in excitatory neurons of the mPFC. We found that opto-activation of ß2-AR is sufficient to induce anxiety-like behavior and reduce social interaction. On the other hand, we utilize the miRNA silencing technique to specifically knock down the ß2-AR in mPFC excitatory neurons. We found that the ß2-AR knock down induces anxiolytic-like behavior and promotes social interaction compared to the control group. These data suggest that ß2-AR signaling in the mPFC has a critical role in anxiety-like states. These findings suggest that inhibiting of ß2-AR signaling in the mPFC may be an effective treatment of anxiety disorders.

Loss of tyrosine catabolic enzyme HPD promotes glutamine anaplerosis through mTOR signaling in liver cancer.

The liver plays central roles in coordinating different metabolic processes, such as the catabolism of amino acids. In this study, we identify a loss of tyrosine catabolism and a concomitant increase in serum tyrosine levels during liver cancer development. Liver cells with disordered tyrosine catabolism, as exemplified by the suppression of a tyrosine catabolic enzyme 4-hydroxyphenylpyruvate dioxygenase (HPD), display augmented tumorigenic and proliferative potentials. Metabolomics profiling and isotope tracing reveal the metabolic reliance of HPD-silenced cells on glutamine, coupled with increased tricarboxylic acid cycle metabolites and their associated amino acid pools. Mechanistically, HPD silencing reduces ketone bodies, which regulate the proliferative and metabolic phenotypes via the AMPK/mTOR/p70S6 kinase pathway and mTOR-dependent glutaminase (GLS) activation. Collectively, our results demonstrate a metabolic link between tyrosine and glutamine metabolism, which could be exploited as a potentially promising anticancer therapy for liver cancer.