The Effect Of Exercise Training On Depression-like Behavior Induced By Chronic Stress Or By Estrogen Deficiency

Depression is a kind of global mental health problem, which is characteristic withhigh incidence, high mortality and high morbidity. It has been implicated that stressand sex hormone might be associated with depression. Ovarian hormones, particularlyestrogens, have profound effect on incidence and/or symptomology of depression.Menopausal declines in circulating estrogen levels are associated with increasedsusceptibility to develop major depressive disorder (MDD). Ovariectomy (OVX),which removes the primary source of estrogens, elicits depression-like behavior inrats. It has also been shown that chronic unpredictable mild stress (CUMS) can inducedepress-like behavior in rodents. However, the main reason of lacking efficient andsafe prevention measures to depression is that the etiology and pathogenesis of thisdisease has not been fully elucidated. Increasing body of evidence has demonstratedthat exercise can not only improve the functions of various organs such as heart andlung, but also can impact emotion. Clinical studies have shown that physical exercisecan significantly ameliorate depressive symptoms.Changed expression of neurotrophic factors, such as brain-derived neurotrophicfactor (BDNF), is associated with depression in both humans and animal models.Studies in rodents have indicated that decreased BDNF level in many brain regions isassociated with the development of depression-like behavior in OVX rats. In addition,it has been implicated that indoleamine2,3dioxygenase (IDO) and inflammation playa pivotal role in mediating the depression-like induced by CUMS. Whether excisetraining can influence the expression of BDNF and the inflammatory state in brainand then leads to improvement of depression-like behavior remains largely unknown.In this study, we investigate（:1）The effects of excise on depression-like behaviorinduced by OVX and the expression level of BDNF and its receptor in hippocampus;（2）The effects of excise training on the depression-like behavior induced by CUMSand the levels of inflammatory cytokines and IDO in brain.The main experimental protocol and results are as followings:Part one: The mechanism involved in exercise training amelioratesdepression-like behavior induced by estrogen deficiency.1. Experimental protocol:A total of56adult female Sprague-Dawley rats (Shanghai SLAC LaboratoryAnimal Co), weighing200±20g, were housed with regular light-dark cycles under controlled temperature (22±2℃) and humidity (50±10%), and were given standarddiet and water ad libitum.We firstly used24rats which were randomly assigned to Sham, OVX andOVX-E2groups (n=8for each group) to examine the depression-like behavior andthe levels of BDNF and TrkB.To determine the effects of exercise on depression-like behavior, we set upanother independent experiment using32rats which were randomly assigned toSham-sedentary (Sham), Sham-exercise (Sham-Ex) groups, OVX-sedentary (OVX)and OVX-exercise (OVX-Ex) groups (n=8for each group). One week after operation,rats were adapted to the treadmill for1week (15min/day at15m/min on a0%slope)and then gradual increase in running time and speed to60min/day at18m/min on a0%slope,5days/week for the next7weeks. Open field test (OFT) and tailsuspension test (TST) were performed. The levels of BDNF were determined byELISA. The expression of TrkB was determined by Western blotting.2. Experimental results:OVX rats showed increased depression-like behavior including decreased totaldistance and number of crossing squares in OFT, and increased number of immobileepisodes in OFT and immobile time in TST (P <0.01vs Sham group). E2replacementsignificantly reduces depression-like behavior in OVX rats (P <0.01). BDNF level inhippocampus was significantly decreased in OVX rats compared to Sham rats(P<0.01), which was reversed by E2treatment (P<0.01vs OVX group). BDNF levelin prefrontal cortex was not significantly differed among Sham, OVX and OVX-E2groups. There was no significant difference in TrkB protein expression inhippocampus and prefrontal cortex among Sham, OVX and OVX-E2groups.Exercise ameliorated depression-like behavior in OVX rats, including increasingtotal distance (P <0.01) and number of crossing squares (P <0.01) and decreasingnumber of immobile episodes (P <0.01) and immobile time in TST (P <0.05).Exercise did not affect the above behaviors in Sham rats. Exercise could also increaseE2level in serum of OVX rats (P <0.05). Exercise significantly increased BDNFlevel in hippocampus but not in prefrontal cortex in both Sham (P <0.05) and OVXrats (P <0.01)Part two: The effect of exercise training on depression-like behavior inducedby chronic stress1. Experimental protocol: Adult male Sprague-Dawley rats, weighing220±20g, were housed with regularlight-dark cycles under controlled temperature (22±2°C) and humidity (50±10%),and were given standard diet and water ad libitum. Rats were randomly divided intocontrol group (Con group), CUMS group, control+swimming exercise group (Con+Swimming group), CUMS+swimming exercise group (CUMS+Swimming group)。The CUMS procedure was performed. Rats in CUMS group were subjected todifferent stressors: cage tilting for24h (45°), wet bedding for24h (200mL of waterper individual cage, which is enough to make the sawdust bedding wet), coldswimming for5min (at4°C), swimming in hot water for5min (at45°C), fastingfor48h, water deprivation for24h, level shaking for10min, tail nip for1min (1cmfrom the end of the tail), and inversion of the light/dark cycle for24h. These ninestressors were applied for21days, during which each stressor was applied2-3times.Rats received one of these stressors at different time every day and the same stressorwas not applied consecutively over two days so that animals could not predict theoccurrence of stimulation. Control group was undisturbed except for necessaryprocedures such as routine cage cleaning.Rats were trained in a moderate swimming program with no weight loading infree style. Daily swimming exercise was performed in a large glass water tank(100cm(L)×60cm(W)×80cm(H)) at32±1°C. The depth of water was60cm.Exercise was performed at the same time every day (between9:00to11:00a.m.).Sucrose consumption test, forced swim test and OFT were used to determine thedepressive-like behavior. The levels of inflammatory cytokines,5-HT and IDO inbrain were determined by ELISA.2. Experimental results:Sucrose consumption test show that: Compared with the Con group, CUMS ratssignificantly reduced the percentage of sucrose consumption in24h(P <0.01), Con+Swimming rats significantly increased the percentage of sucrose consumption in24h;compared with CUMS group, CUMS+Swimming rats significantly increased thepercentage of sucrose consumed(P <0.01). Open field test results show that:Compared with Con group, CUMS group rats show significantly decrease thenumber of poking, the number rearing and central activity(P <0.01); compared withCUMS group, CUMS+Swimming rats show significantly increase the number ofpoking, the number rearing and central activity(P <0.05); Forced swimming testresults showed that: Compared with the Con group, CUMS rats show significantly increased immobility time; compared with CUMS group, CUMS+Swimming ratsshow significantly reduce the immobility time (P <0.01).Furthermore, we use ELISA kit to examine some pro-inflammatory cytokinessuch as IFN-γ, TNF-α and IL-1β, IDO and5-HT expression in prefrontal cortex. Theresults showed that: CUMS exposure significantly increased the levels of IFN-(P<0.01),TNF-α (P <0.05) and IL-1β(P <0.01) in prefrontal cortex compared to thecontrol. CUMS caused a dramatic elevation in the level of IDO in prefrontal cortex(P<0.01vs control). The level of5-HT in prefrontal cortex was significantlydown-regulated in CUMS rats compared to the control (P <0.01).Conclusions:（1）Estrogen deficiency can lead to depression-like behavior on rats, exogenousestrogen therapy and exercise training can ameliorates depression-like behavior onOVX rats;（2）Estrogen deficiency decreased hippocampal BDNF expression,administration of exogenous estrogen therapy and exercise training can increasehippocampal BDNF expressions in OVX rat. BDNF, TrkB expression in prefrontalcortex and TrkB expression in hippocampus did not change significantly.（3）CUMS can lead to increased depressive-like behavior, and exercise trainingcan significantly alleviate the depression-like behavior. CUMS led to increasedinflammatory cytokines such as IFN-γ, TNF-α and IL-1β in prefrontal cortex,increases IDO expression and then reducing5-HT expression.