The altered sensitivity of acute stress induced anxiety-related behaviors by modulating insular cortex-paraventricular thalamus-bed nucleus of the stria terminalis neural circuit.

The dysregulation of neuronal networks contributes to the etiology of psychiatric diseases, including anxiety. However, the neural circuits underlying anxiety symptoms remain unidentified. We observed acute restraint stress activating excitatory neurons in the paraventricular thalamus (PVT). Activation of PVT neurons caused anxious behaviors, whereas suppression of PVT neuronal activity induced an anxiolytic effect, achieved by using a chemogenetic method. Moreover, we found that the PVT neurons showed plentiful neuronal projections to the bed nucleus of the stria terminalis (BNST). Activation of PVT-BNST neural projections increased the susceptibility of stress-induced anxiety-related behaviors, and inhibition of this neural circuit produced anxiolysis. The insular cortex (IC) is an important upstream region projecting to PVT. Activation of IC-PVT neuronal projections enhanced susceptibility to stress induced anxious behaviors. Inhibiting this neural circuit suppressed anxious behaviors. Moreover, anterograde monosynaptic tracing results showed that the IC exerts strong neuronal projections to PVT, forming synaptic connections with its neurons, and these neurons throw extensive neuronal fibers to form synapse with BNST neurons. Finally, our results showed that ablation of neurons in PVT receiving monosynaptic input from IC attenuated the anxiety-related phenotypes induced by activating IC neurons. Lesions of the neurons in BNST synaptic origination from PVT blocked the anxiety-related phenotypes induced by activating PVT neurons. Our findings indicate that the PVT is a crucial anxiety-regulating nucleus, and the IC-PVT-BNST neural projection is an essential pathway affecting anxiety morbidity and treatment.

Involvement of eIF2α in halofuginone-driven inhibition of TGF-ß1-induced EMT.

Halofuginone (HF) is an extract from the widely used traditional Chinese medicine (TCM) Dichroa febrifuga that facilitates the recovery of wounds and attenuates hepatic fibrosis. However, the role of HF in the epithelial-mesenchymal transition (EMT) of IPEC-J2 cells remains unclear. The current study explored the anti-EMT effect of HF in IPEC-J2 cells and illustrates its molecular mechanism. Transforming growth factor ß1 (TGF-ß1), as a recognized profibrogenic cytokine, decreased the level of the epithelial marker E-cadherin and increased the level of the mesenchymal markers, such as N-cadherin, fibronectin (FN), vimentin (Vim), and α-smooth muscle actin (α-SMA), in IPEC-J2 cells depending on the exposure time and dose. HF markedly prevented the EMT induced by TGF-ß1. Dissection of the mechanism revealed that HF inhibited IPEC-J2 cell EMT via modulating the phosphorylation of SMAD2/3 and the SMAD2/3-SMAD4 complex nuclear translocation. Furthermore, HF could promote the phosphorylation of eukaryotic translation initiation factor-2α (eIF2α), which modulates the SMAD signaling pathway. These results suggested that HF inhibits TGF-ß1-induced EMT in IPEC-J2 cells through the eIF2α/SMAD signaling pathway. Our findings suggest that HF can serve as a potential anti-EMT agent in intestinal fibrosis therapy.