The Effects And Mechanism Of Different Lights On Relieving Chronic Unpredictable Mild Stress Induced Depressive-Like Behavior In Female Rats

ObjectiveDepression is a chronic and recurrent mental illness that is typically characterized by decreased affect-impaired cognition and mental disorder and the pathogenesis of depression is still elusive. The solar cycle allows humans to synchronize their circadian rhythms to the correct temporal, changes in shift-work lead to depression. Seasonal affective disorder is a recurrent major depressive disorder, in which episodes of depression occur in winter followed by full remissions in spring and summer, light therapy is one of the most effective treatments for SAD and also has a certain therapeutic effect for depression, but the clinical application of standards for the therapy light source has not been unified.Melatonin is a type of internal clock circuitries that primarily secreted by the pineal gland in a specific circadian pattern in accordance with the light-dark cycle and the seasonal cycle. Research has indicated that the development of depression depends on melatonin, and improved melatonin concentration can effectively ameliorate the symptoms of depression. BDNF has been shown to play an important role in depression, humans have shown decreased plasma levels of BDNF in depressed patients. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates the initiation of protein translation, and is expressed in dendritic development that controls new protein synthesisthe, the activation of mTOR play a role of antidepressant through downstream proteins.This experiment will choose four different light conditions light sources include microwave sulfur lamp(MSL), warm light lamp(WLL),fluorescent lamp(FL) and light emitting diode lamp(LED) for light therapy about 45 days and evaluated for their capacity to phase advance the cognitive function and mood. This study will focuses on the MT, BDNF and mTOR signaling to discuss the mechanism of light therapy.Methods·The first part1.Establish the chronic mild unpredictable stress (CUMS) procedureThe stressed groups were exposed for 45 days to a variety of unpredictable stressors including:food deprivation for 48h; water deprivation for 24h; soiled cage (200ml water in 1 OOg sawdust bedding) for 24h; cage tilting (45°) for 24h; tail pinching with a forceps hamostatic placed 1 cm distal from the beginning of the tail for 1 min; level shaking for 10 min; swimming in 4℃ cold water for 5 min; swimming in 40 ℃ hot water for 5 min; light/dark perversion.2.The group of experiment(1) Control(2) CUMS(3) MSL group:CUMS+MSL(microwave sulfur lamp)(4) WLL group:CUMS+WLL(warm light lamp)(5) FL group:CUMS+FL(fluorescent lamp)(6) LED group:CUMS+LED(light emitting diode lamp)3. General situation:Record body weight of rats during the experiment4. Sucrose preference test (SPT):SPF was a key depressive-like behavior in rats used to operationally determine stressed induced anhedonia state5. Forced swimming test (FST):To detect the behavior desperate state of rats6. Open-field test (OFT):To assess spontaneous locomotors activity of rats7. Morris water maze:To assess the spatial location and spatial memory ability.8. Histopathological observation·The second part1. Enzyme-linked immunosorbent assay:MT and BDNF levels in serum samples were detected by ELISA kits2. Western blot analysis:To reaveal the expression of MT, BDNF, ERK, CREB, mTOR, p70s6k,4EBP1All data were expressed as means±SD and analyzed by SPSS 18.0 software. Comparisons between experimental and control groups were performed by one-way ANOVA test. The value of P< 0.05 was considered to be statistically significant.Results·The first part1. General situationAfter modeling the body weight increasing trend began slowed down, the Control group showed an increasing trend, but there were no significant difference(p> 0.05). After lighting the therapy groups increased significantly compared with Control group(P<0.05).2. Sucrose preference test (SPT)Sucrose preference% of modeling groups decreased significantly compared with Control group (p< 0.05). After lighting the sucrose preference% of therapy groups increased significantly, there were no significant difference compared with Control group (p> 0.05); CUMS group show a significant difference compared with before modeling (p< 0.05).3. Forced swimming test (FST)Immobile time of modeling groups increased significantly, CUMS group, MSL Group, WLL group and LED group show a significant difference compared with before modeling (p< 0.05). After lighting the immobile time of therapy groups decreased, there were no significant difference compared with Control group (p> 0.05); immobile time of CUMS group continued to increase, show a significant difference compared with before modeling and after modeling (p<0.05).4. Open-field test (OFT)Open-field test scores decreased significantly compared with before modeling (p< 0.05). After lighting the MSL Group, WLL group and FL group show a increasing trend,, but there were no significant difference compared with Control group (p>0.05).5. Morris water mazeThe escape latency and swimming distance increased significantly compared with before modeling (p< 0.001). After lighting the escape latency of therapy groups decreased significantly compared with CUMS group (p< 0.001); MSL Group and LED Group has no significant difference compared with Control group (p> 0.05).After lighting the swimming distance of therapy groups decreased compared with CUMS group, MSL Group show a significant difference compared with Control group P<0.001).6. Histopathological observationSignificant histopathological changes were found in the brain of rats after CUMS, light therapy can reduce the pathological changes, microwave sulfur lamp have the best effect.·The second part1. Enzyme-linked immunosorbent assayCompared with before modeling, the concentration of MT and BDNF in the brain of rats decreased significantly (p<0.01). After lighting the MT concentration of therapy groups higher than CUMS group, MSL Group has no significant difference compared with Control group (p> 0.05). After lighting the BDNF concentration of therapy groups higher than CUMS group, MSL Group show a significant difference compared with CUMS group (p< 0.05) and has no significant difference compared with Control group (p>0.05).2. Western blot analysis:2.1 The MT expression of CUMS group decreased significantly compared with Control group (p< 0.001). After lighting the MT expression of MSL groups increased significantly compared with CUMS group (p<0.001)and has no significant difference compared with Control group (p>0.05)..2.2 The expression of BDNF, phospho-ERK and phospho-CREB of CUMS group decreased significantly compared with Control group(p< 0.001).After lighting the BDNF and phospho-ERK expression of MSL groups increased significantly compared with CUMS group (p<0.01) and has no significant difference compared with Control group (p>0.05). After lighting the phospho-CREB expression of therapy groups increased significantly compared with CUMS group (p<0.01)2.3 The expression of phospho-mTOR and phospho-p70s6k of CUMS group decreased significantly compared with Control group(p< 0.001).After lighting the phospho-mTOR expression of MSL groups increased significantly compared with CUMS group (p< 0.001) and the expression of WLL group, FL group and LED group lower than CUMS group (p<0.05). After lighting the phospho-p70s6k expression of therapy groups increased compared with CUMS group, MSL group and FL group show a significant difference with CUMS group(p< 0.001). The expression of phospho-4EBP1 of CUMS group increased significantly compared with Control group(p< 0.001); after lighting the expression of phospho-4EBP1 of MSL groups decreased compared with CUMS group (p< 0.001) and MSL group and LED group show a significant difference with CUMS group (p<0.05).ConclusionThe experimental results confirmed that light therapy has a certain therapeutic effect for depression. Four light sources show different therapeutic effect, microwave sulfur lamp have the best effect.The mechanism of light therapy may be related to MT, BDNF and phospho-mTOR expression in brain tissue. The low concentration of MT in the brain of depression rats lead BDNF and phospho-mTOR decreased. The expression of MT upregulated after light therapy, than MT regulates the active of BDNF and downstream protein like ERK and CREB, enhancement of neuronal plasticity.At the same time MT and BDNF regulates the active of phospho-mTOR and downstream protein like p70s6k and 4EBP1 to promote neurogenesis,relieve depression symptoms.