| Objectives:Depression is a common mental disorder, which main clinical Characteristics are depressed mood, mental retardation, will hypoactivity, and even suicidal thoughts.Depression seriously affect the patient’s quality of life and social function, and have a heavy burden to the families and society. The disease has become a global public health problem, and its shortage of treatment also caused widespread concern by scholars. Animal models are important tools to study the etiology of depression, and the prerequisite for develop the new and effective antidepressant drugs. The model of Chronic unpredictable mild stress(CUMS) in a rat mimic the behavior of depressed human,and the pathophysiological changes of brain in rats had the similar phenomena associated with the brain anatomy observed in depressed patients, long lasting antidepressants were given can reverse the depression-like behavior.Currently, the pathogenesis of depression is still in the hypothesis stage, the specific mechanisms and virulence genes remains unclear. Multiple lines of evidence suggest a link between depression and changes in hypothalamic-pituitary-adrenal (HPA)-axis hormone dynamics, including altered regulation of the corticotrophin-releasing hormone (CRH) and its main receptor, corticotrophin-releasing hormone receptor1(CRHR1). Increased activity of the HPA axis is the most consistent findings on the pathogenesis of depression. Some scholars believed that the hypothalamic corticotrophin-releasing hormone (corticotrophin-releasing hormone, CRH) secretion in patients with depression may be the main reason for HPA axis hyperactivityt. CRHR1receptors are widely distributed in the brain regions associated with stress, and plays an important role in the pathological process of depression. Our team found that the CRHR1gene rs242939polymorphism loci was associated with depression. For a more in-depth discussion of how CRHR1is involved in the pathogenesis of depression, we studied the epigenetic processes of hypothalamic CRHR1mediated deoression.Epigenetic mechanisms is considered one of the determinants of gene expression in recent years, and may play an important role in the pathogenesis of depression. Epigenetic changes the gene function but does not change the sequence of DNA. Epidemiological evidence suggests that the incidence of depression associated with the environment stimulating factor, especially exposure to negative life events. Recent studies have confirmed the commonly used classical antidepressants monoamine oxidase inhibitors is a histone demethylase (Histone demethylase LSD1) and mood stabilizers valproate is a histone deacetylase (Histone deacetylases, HDACs) inhibitors,which gives us a powerful driving force to study the epigenetic mechanisms of depression. Many studies have shown that epigenetic mechanisms regulating gene expression may cause permanent changes in brain function and may based on the pathophysiologyof mental disorders.This conclusion was confirmed in epilepsy, as well as antipsychotic medication and depression. Nevertheless, we need do more to dicuss the epigenetics on different brain regions, different genes and multiple sites of gene more in-depth discussion.Methods:Male SPF SD rats were randomly divided into normal control group and cums group.The cums group was given one stimuli from seven designed stimuli within twenty-one days everyday.Then to test whether the model was successfully constructed through relative behavioral indicators,the indexes including sugar preferences,open field test.The amount of CRH、CORT、ACTH was measured by enzyme-linked immunosorbent assay.The hypothalami of both group were quickly got on the ice and were reserved in the refrigerator in negative eighy degrees.Measure the expression of mRNA of CRHR1by real-time quantitative PCR.Evaluated the expression of CRHR1by Western blotting. Analyze the Histone methlytion status of CRHR1promoter by Chromatin Immunoprecipitation.Results:1. Compared with the control, weight of rats decreased in the stress group.The sugar consumption were significantly less than normal.The total distance,speed and rearing significantly reduced in the cums group through the open field test.2.The amount of CRH、CORT、ACTH in the cums group was significantly increased than that in the normal control group.3.The mRNA and protein expression of CRHR1in the cums group was significantly higher than that in the control group.4. The levels of H3K9trimethylation at the CRHR1gene promoter in the CUMS group were significantly lower than those in the control group, whereas H3K4trimethylation levels were the same for both groups. Conclusions:Our findings suggest that the increase in CRHR1expression in the hypothalamus of stressed rats correlates with a decrease in the repressive chromatin state caused by reduced H3K9trimethylation levels. These data are the first in vivo evidence of a role for chromatin modifications in the regulation of CRHR1gene expression in the hypothalamus, and may provide novel insight into therapeutic approaches to treat depression. |
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