Brain-derived Neurotrophic Factor In Brain Regulates The Impact Of Anxiety To Visceral Hypersensitivity

BackgroundIrritable bowel syndrome(IBS) is characterized by recurrent abdominal pain or abdominal discomfort associated with concurrently abnormal bowel habits. Growing clinical and preclinical evidence suggests that the pathophysiology of the increased pain sensitivity in IBS may involve dysfunction of brain-gut axis. A high percentage of patients of IBS display comorbid affective disturbances including symptoms of depression and anxiety, and numerous studies have found that enhanced perception of visceral signal in IBS is modulated by anxiety and depression at the level of brain. There is also evidence to suggest that affective disturbances-especially anxiety has an important role on visceral hypersensitivity in IBS. However, the mechanism that anxiety induces visceral hypersensitivity in IBS remains unclear.Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is highly expressed in the central nervous system. Previous studies with mice indicate that BDNF in some areas of brain has an unexpected facilitatory effect on generation of anxiety. Many animals’ studies have revealed that mice overexpressing BDNF in the hippocampus show greater anxiety in the elevated plus maze and open-field test. In humans, an FMRI study has showed that IBS patients who increased anxiety levels had more activation in the hippocampus, In addition, BDNF in colonial epithelial of IBS patients also may play a critical role in hypersensitivity. These studies raise the possibility that endogenous BDNF in hippocampus may regulate the impact of anxiety to visceral hypersensitivity in IBS. It has been proved that the level of BDNF in serum can reflect the level of BDNF in brain, so we analyze the expression of BDNF in serum, then analyze whether it is consistent with the expression of BDNF in hippocampus.ObjectiveMaternal separation is an excellent animal model of brain-gut axis dysfunction, and it could mimics the characteristic of co-morbid anxiety and visceral hypersensitivity in IBS. Thus, we used this model to explode the expression of BDNF in hippocampus, then to analysis the relationship between expression of BDNF in hippocampus and anxiety or hypersensitivity, respectively, to study whether BDNF in hippocampus regulated the impact of anxiety to visceral hypersensitivity.MethodThe male pups which is randomly selected are subjected to maternal separation group, and the others belong to non-handled group. According to the well established protocol, pups of MS group were separated with their mother.1On PND70, male rats of both groups underwent the open field test(OFT) to assess the anxious-like behavior.2After OFT, then the visceromotor responses to colorectal balloon distension (CRD) were assessed by abdominal withdrawal reflex (AWR).3The protein expression of BDNF in hippocampus3.1Some rats were rapidly decapitated on the following day after CRD, and the expression of BDNF in hippocampus was determined by enzyme-linked immunosorbent assay (ELISA).3.2Immunohistochemistry was used to determine the expression of BDNF in each area of hippocampus.4The mRNA level of BDNF in hippocampus was determined by RT-PCR.5When the rats were rapidly decapitated, the blood of each rat was collected, and the expression of BDNF in serum were was determined by ELISA. Then analyze the correlation between the expression of BDNF in serum and its expression in hippocampus.6The correlation between anxiety and visceral hypersensitivity was analyzed in MS rats, then the correlations between the expression of BDNF in hippocampus and anxiety or the expression of BDNF in hippocampus and visceral hypersensitivity were analyzed.7All data given were expressed as mean values±SD. For open field text, the Elisa data, the RE-PCR data and positive cellular numbers of BDNF, independent Student t test was used. For AWR scores, repeated ANOVA was used. Correlations between two parameters were assessed by Pearson correlation. Differences were considered significant at p<0.05.Results1Compared with control rats, MS rats developed more anxious (P<0.05).2Compared with control rats, MS rats had more visceral pain (P<0.05) in response to each CRD pressure gradient(20,40,60,80mmHg).3Compared with control rats, the protein expression of BDNF was increased in hippocampus of MS rats (P<0.05), especially in the CA1and CA3areas of hippocampus (P<0.05).4Compared with control rats, the mRNA level of BDNF was increased in hippocampus of MS rats (P<0.05).5The expression of BDNF in serum of MS rats was not different with its expression in control rats, and the expression of BDNF in serum was not correlated with its expression in hippocampus.6The level of anxiety was positively correlated with the hypersensitivity in MS rats, and the expression of BDNF in the hippocampus was positively correlated not only with the level of anxiety but also with hypersensitivity.Conclusions1MS rats had a high level of anxiety and hypersensitivity, and it has proved that anxiety can induce hypersensitivity in MS rats. 2Upregulation of BDNF expression in hippocampus plays an essential role in anxiety-induced visceral hypersensitivity in IBS.3The expression of BDNF in serum can not reflect its expression in hippocampus in IBS.