Effects Of Raphe-specific Deletion Of5-hydroxytryptamine On Depression-like Behaviors And HPA Axis Activity In Mice

Two popular hypotheses, monoamine theory and stress hypothesis, have been proposed for the underlying mechanism of depression The former one emphasizes lack of monoamine transmitters including5-HT lead to depression The latter one insists hyperactivity of hypothalamus-pituitary-adrenal (HPA) axis as the chief reasoa The dynamic interplay between5-HT and HPA axis has not been extensively investigated.5-HT innervation of limbic forebrain CRF neurons origins from the midbrain raphe. Meanwhile, CRF also could affect the activity of5-HT neurons through CRF-R1or CRF-R2. In this study, we investigated the relationship between absence of5-HT and depression-like behaviors under normal condition and chronic restraint stress condition by5-HT deficient mice (raphe nuclei-specific conditional knock out, CKO).1)5-HT, HPA axis and animal behaviors under normal conditionIn contrast with WT mice, an enhanced depression-like behavior was found in sucrose preference test and reduced anxiety-like behavior was found in novelty-suppressed feeding test in CKO mice. However, other tasks show no significant difference between two groups of mice. We examined mRNA expression of CRF in various brain regions and level of corticosteron in serum, and there was no significant change indicating that5-HT deficient didn’t influence the activity of HPA axis. In5-HT deficient mice, mRNA levels of5HT2B,5HT1A,5HT6receptor subtypes in hypothalamus were makedly increased.2) The behavioral and HPA axis activity change in5-HT deficient mice response to chronic stressAfter chronic restraint stress, less anxiety behavior was developed in CKO mice than WT mice, but depression behavior discovered no significant difference. Increased CRF mRNA level was only found in the cortex but not significantly changed in other brain regions. The level of corticortisteron in serum was also not significantly changed. To our surprise, mRNA levels of CRF-R1and5-HT2A receptor markedly decreased in the hypothalamus, however, significantly increased in the prefrontal cortex in CKO mice. We speculate the effect of5-HT on CRF neurons might be opposite in the hypothalamus and the prefrontal cortex, which leads to no change in HPA axis activity and behaviors. In conclusion, our results suggested5-HT deficiency in the rap he nuclei would not affect HPA axis activity and depression-like behaviors after chronic restraint stress. We assumed that5-HT might have inhibitory effect on CRF neurons in the prefrontal cortex, but excitatory effect on CRF neurons in the hypothalamus. Absence of5-HT might disrupt both effects and rebalance HPA axis physiological activity, therefore no change was found in depression-like behaviors. Future experiments would provide more evidences for our hypothesis and a new angle of view for the research on the pathogenesis of depression.