| Depression is a common neuropsychiatric disease with multi system disorders,whose incidence rate is increasing year by year,have became a serious social and medical problems needed to be solved.The incidence of depression related with a variety of factors and its pathogenesis has not been fully elucidated,The role of circadian rhythm disorder in depression attracted the attention of many scholars.clinical feature of spirits,temperature changes,endocrine disorders,sleep disorders,etc in depression are accompanied with circadian rhythm changes.circadian rhythm changes is listed as one of the important biological marker of depression diagnosis,and promote the development of depression,recurrence,and even lead to one of the important risk factors of suicide.Studies have proved that activity of central neurons in some brain regions associate depression has the characteristics of circadian rhythm,involved in the regulation of the body’s circadian rhythms.However,little is known about the mechanism of these brain regions in the incidence of depression and their circadian rhythms change.As a result,from the perspective of circadian rhythm to know the role of these brain areas on the pathogenesis of depression,will put forward a new explanation to the pathogenesis of depression.The Lateral habenula nucleus(LHb)in thalamus is a hub connecting edge forebrain to brain stem,involving a variety of physiological functions of regulation,especially in recent years,it was reported that LHb play an important role in the onset of depression through affecting the central circadian rhythms regulation,and draw a lot of attention.It is known that the LHb is closely related with depression.Animal studies have shown that LHb metabolism are enhanced in four different depression model,its activity can inhibit the function of Dorsal raphe nucleus,leading to 5-Hydroxytryptamine(5-HT)levels down-regulation.On the other hand,the damaged LHb can increase the level of 5-HT within DRN,thus improving depressive symptoms.And clinical studies have shown that antidepressants are often regulated the treatment of depression through influencing the LHb 5-HT system.Functional magnetic resonance imaging(FMRI)studies have found that habenula nucleus(Habenular nucleus,Hb)metabolism of depression patients is increased.In addition,by inhibiting the activity of the LHb,high-frequency DBS will cure long-term and depressive symptoms in patients with refractory depression.All above indicates that the LHb play a role in depression were confirmed though animal experiments and the treatment of patients with clinical depression,the mechanism was related with the DRN function inhibition,leading to a lower 5-HT concentration.In addition,the LHb in circadian rhythm also plays an important role in the control system.Hypothalamic Suprachiasmatic nucleus(SCN)is major pacemaker of the mammalian circadian,the LHb is one of the few brain kernels which were proved to be similarly with SCN rhythmic oscillation,and still exist close anatomical and functional connections with SCN.At the same time,the LHb can directly accept projection from the retina fiber in vitro,present rhythmic neuron discharge activity which was high in daytime but low at night,and with circadian clock gene expression.Considering the close relationship between the LHband depression,it is reasonable to speculate LHb is likely to play an important role in regulating in the circadian rhythm of depression rats activities alteration.From the perspective of the possible mechanism and role of LHb participation in depression rat circadian rhythm changes,thus for providing theoretical support for the pathogenesis of depression research and clinical practice.This experiment preparated international commonly used the endogenous depression model rats firstly,and applied the Sucrose preference test(SPT),forced swimming test(FST)(record in climbing time and the immobile time)and Open field test(OFT)(determination of the total movement distance and velocity)to verify the validity of the model,and applied the above three trials to determine the behavior performance of depression group and normal group rats in the normal light dark cycle(turn on the light at 7:00,turn off the lights at 19;00)under the condition of six time points(9:00,13:00,17:00,21:00,1:00,5:00),observe the behavior changes of circadian rhythm in depression group rats;And applied real-time quantitative PCR and HPLC(High performance liquid chromatography,HPLC),to measure LHb main circadian Clock genes(Perl fires our Bmall,Clock,Per2,Cry1,Cry2)rhythm expression of the two groups rats separately at above six points and its downstream 5-HT expression of within DRN regions.The Results were as follows:1.Model validation:SPT results show that the depression model rats sugar water preference rate dropped significantly compared with normal group rats.FST results show that compared with normal group rats,the depression model rats showed up time reduced and immobile time extended.OFT results show that the depression model rats total movement distance and the speed is lower than normal group of rats.The above results show that the model is well simulated by the three core symptoms of depression,lack of pleasure,depressed and movement.2.Behavior of rats circadian rhythm results:(1)The SPT results:normal rats and depression rats sugar water preference rate reflects the rhythm changes,high at night and low in daytimetime,but compared with normal group,depression rats the rhythm amplitude of oscillation sugar water preference rate in depression rats was down-regulated,in addition,there was no significant difference between sugar water preference of two groups rats in the daytime of and in the night.Depression rats’ sugar water preference rate is lower than normal rats.(2)The FST results:normal rats and depression rats in time all embody the high rhytlumic oscillation;high at night and low in daytimetime,but circadian oscillation amplitude of climbing time of depression rats is down-regulated compared with normal rats.At the same time,two groups of rats climbing time has no obvious differences in the daytime,but at night depression rats on darting time was shorter than normal rats.In the immobile time,two groups of rats were not reflecting the circadian oscillation.In the daytime and night,the immobile time of depression group rats was both longer than normal group.(3)The OFT results:two groups of rats in total movement distance and velocity showed no circadian oscillation.The above results showed that the aspects of normal and depression rats in pleasure stimuli sensitive and emotional all showed high rhythm between night and daytime,and the depression rats in the two aspects of circadian rhythm amplitude is declined compared with normal rats,and the difference is mainly embodied the night falling sensitivity to the pleasant sensation stimulation and depressed in depression rats.The symptoms of two groups of rats in sports have not difference in the circadian rhythm.3.Circadian rhythm expression of circadian Clock genes within the LHb:(1)Clock,Perl and Cry2 gene circadian rhythm expression:all three genes expression of two groups rats present a day low night high rhythmic oscillation,but compared with normal rats,depression rats did not present significant differences in both the overall rhythm of the oscillation amplitude and gene expression amount.(2)Circadian rhythm expression of the Bmall,Per2 and Cryl:two groups of rats all three genes are present a day low night high rhythmic oscillation.Compared with normal rats,the above three kinds of gene in the depression rats expression circadian oscillation amplitude is reduced.In addition,two groups of rats to the above three kinds of circadian gene expression in the daytime is no obvious difference,but at night,the three circadian gene expression level is lower in depression rats than normal rats.(4)The circadian rhythm expression of 5-HT within DRN:5-HT within DRN of normal rats and depression rats present rhythmic oscillation(low in daytime and high at night),but compared with the normal group,the level of 5-HT circadian rhythm amplitude is declining in depression rats.In addition,during the dayime,the 5-HT content of two groups of rats did not see obvious difference.And while at night,5-HT in depression rats decreased was obviously compared with normal rats.Based on the above research content,we draw the following conclusions:1.In sucrose preference test,depression rats sugar water preference rate is significantly lower in the night compared with normal rats,lead to the high amplitude of the night and day and a lower sugar water preference rate;Similarly,in the forced swimming test,compared with normal rats,the climbing time of depression rats present a significant decrease in the night time,lead to the climbing time on high amplitude of the night and day,low down.Suggests that depression rats sensitivity to the pleasant sensation stimulation declined and depressed associated with circadian rhythm activity change.2.Bmal1,Clock,Perl,Per2,Cry1,Cry2 gene expression within LHb of normal rats and depression rats presented high at night and low in daytime.Compared with normal rats,circadian rhythm amplitudes reduction of Bmall,Cryl Per2 expression within the LHb in depression rats which related with these three genes expression down-regulation at night,lead to circadian rhythm changes of behavior.3.5-HT within DRN in normal and depression rats showed a circadian oscillation(low in the daytime and high at night).Compared with normal rats,The DRN of 5-HT content is lower during the night,lead to circadian rhythm amplitude of the DRN 5-HT content is reduced,this may be related with the change of Bmall and Cryl Per2 gene expression within LHb in depression rats,which behavior circadian rhythm changes,and remains to be further study. |
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