Chronic stress is a critical factor in the aetiology of anxiety disorders; however, in the clinic, enduring and preventive measures are not available, and therapeutic drugs are associated with inevitable side effects. Our study established an anxiety rat model using chronic restraint stress (CRS) and assessed these animals using the open‐field test, elevated plus‐maze test, and light‐dark box test. Jie‐Yu‐He‐Huan capsule (JYHH), a Chinese medicine formula, was used as a preventative drug. The HPA axis‐mediated release of corticotropin‐releasing hormone, adrenocorticotropic hormone, and corticosterone from the hypothalamus was tested. In the hippocampus and prefrontal cortex, concentrations of 5‐HT and its metabolite 5‐hydroxyindoleacetic acid, as well as monoamine oxidase A, glucocorticoid receptor, and 5‐HT1A receptor expression levels, were measured. Furthermore, we examined protein and mRNA expression of cAMP‐PKA‐CREB‐BDNF pathway components. The results showed that JYHH had a significant preventative effect on the anxiety‐like behaviour induced by CRS and prevented abnormal changes in the HPA axis and 5‐HT system. Furthermore, CRS inhibited the cAMP‐PKA‐CREB‐BDNF pathway, which returned to normal levels following JYHH treatment. This might be the underlying molecular mechanism of the antianxiety effect of JYHH, which could provide a new clinical target for preventative anxiolytic drugs for chronic stress.

Aims: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a life‐threatening, inherited, nonhypertensive arteriole disease of the brain. Therapeutic strategy for CARASIL is limited because its pathogenesis is not clear. We previously reported the first family with CARASIL in China, which involves a high‐temperature requirement serine protease gene mutation (HtrA1^L364P). Based on this previous study, we constructed a CARASIL mouse model (Mut‐hHtrA1^L364P mouse, hereinafter referred to as Mut). This paper aimed to systematically study the behavior, pathology, and molecular biology of Mut mice and explore the pathogenesis and possible therapeutic strategies of CARASIL.Methods: Food maze and water maze experiments were used in the behavioral studies. Pathological studies were carried out by arteriole labeling staining and electron microscopy. The mRNA and protein expression levels of the key factors of TGF‐β/Smad signaling pathway (TGF‐β, Smad2, Smad3, and Smad4) in the brain of the model mice were detected by immunohistochemistry, real‐time quantitative polymerase chain reaction (RT‐PCR), and Western blot assay.Results: The food maze and water maze experiment data showed significant differences between the Mut and wild‐type (WT) mice in the first time to find food, the time to contact the escape table for the first time, and the number of times to travel in the escape table quadrant (p < 0.001). The results of vascular labeling staining showed that some small arteries in the brain of Mut mice lost normal structure. The results of electron microscopy showed that the cell morphologies in the cortex and hippocampus of Mut mice were abnormal; the number of synapses was reduced; the walls of capillaries, venules, and arterioles thickened; lumen stenosis and other abnormal phenomenon occurred; and lipofuscin deposition and autophagosomes were found in the hippocampus. Immunohistochemistry, RT‐PCR, and Western Blot results showed that the mRNA and protein expression levels of TGF‐β, Smad2, and Smad3 in the brain of Mut mice increased to different degrees.Conclusions: The most significant innovation of this study is the first study on the pathogenesis of CARASIL disease using model animals. The Mut mice can well simulate the pathogenesis of CARASIL in behavioral and pathological aspects. The TGF‐β/Smad signaling pathway, which is involved in the pathogenesis of CARASIL, is abnormally upregulated in the brain of Mut mice.