| Schizophrenia is one of the most complex,etiologically elusive,and chronically debilitating mental illnesses,affecting approximately 1% of the world’s population.Due to its diverse array of symptoms and poorly understood pathogenesis,treating schizophrenia poses significant challenges.The second-generation antipsychotic drug representative,risperidone,is a dopamine 2 receptor and serotonin 2A receptor antagonist.Due to its effectiveness,safety,and relatively low side effects,it has been widely used in clinical practice and has become the mainstream medication for treating schizophrenia today.However,the specific targets and therapeutic mechanisms of risperidone are not yet clear.The lateral habenula(LHb)is an important intersection of many crucial neural pathways in the brain and has direct fiber projections and functional connections with nuclei closely related to the pathogenesis of schizophrenia,such as the midbrain striatum and prefrontal cortex.Additionally,the LHb can regulate various monoaminergic neurotransmitters such as dopamine,serotonin,and norepinephrine,which play important roles in the pathogenesis of schizophrenia.Significantly,schizophrenia patients often exhibit obvious calcification in the habenula.Prolonged administration of amphetamine(a drug inducing schizophrenia)injections in rats can cause significant degenerative changes in the efferent pathways of the habenula.These results suggest that reduced LHb activity may be closely related to the pathogenesis of schizophrenia,but its role in schizophrenia remains to be elucidated.Therefore,the purpose of this study is to clarify the role of the lateral habenula in the pathogenesis of schizophrenia,further elucidate whether the lateral habenula can become a new target for the treatment of schizophrenia,mediate the anti-schizophrenic effect of risperidone,and explore its mechanism of action to propose new strategies for the clinical treatment of schizophrenia.Methods:(1)Establishment of a rat model of schizophrenia and confirmation of the therapeutic effect of risperidone: Continuous intraperitoneal injection of MK801 was used to prepare the schizophrenia model,and behavioral experiments(open field test,social interaction test,sucrose preference test,and Morris water maze test)were conducted to identify whether the model was successful.In the risperidone treatment group,risperidone was intraperitoneally injected simultaneously with MK801,and changes in behavior were observed.Behavioral changes were observed to confirm the establishment of the rat model of schizophrenia and the therapeutic effect of risperidone.(2)Changes in the activity of lateral habenula neurons in normal rats,schizophrenia model rats,and rats after risperidone treatment;changes in the expression of the activity marker c-Fos in lateral habenula neurons were observed using immunohistochemical methods,and the electrical activity of lateral habenula neurons was recorded using patch clamp techniques.Transmission electron microscopy was used to observe the state of lateral habenula neurons.(3)Whether changes in lateral habenula neuron activity are related to schizophrenia-like behaviors in rats: Chemical genetic methods were used to activate lateral habenula neuron activity,and whether this could improve schizophrenia-like behaviors in model rats was observed.Chemical genetic methods were used to inhibit lateral habenula neuron activity,and whether this could reverse the therapeutic effect of risperidone on schizophrenia-like behaviors in rats was observed.(4)The effect of risperidone on the activity of lateral habenula neurons: Patch clamp techniques were used to detect whether risperidone could cause changes in the electrical activity of lateral habenula neurons;the specific mechanism was studied through molecular docking experiments,immunoblotting,and immunohistochemical staining.(5)Whether changes in lateral habenula BDNF are involved in schizophrenia-like behaviors in rats: Adeno-associated virus was locally microinjected into the lateral habenula to overexpress BDNF,and whether this improved schizophrenia-like behaviors in rats was observed;local knockdown of BDNF was performed,and whether this could reverse the therapeutic effect of risperidone on schizophrenia-like behaviors in rats was observed.In addition,the effects of BDNF overexpression and knockdown on the activity of lateral habenula neurons were observed through immunofluorescence staining and Nissl staining.Results:(1)The open field test revealed that the schizophrenia model group covered a greater distance in the open field compared to both the normal group and the risperidone treatment group.Social interaction experiments showed that the schizophrenia model group engaged in less social interaction time than the normal group and the risperidone treatment group.In the sucrose preference test,the schizophrenia model group exhibited a lower ratio of sucrose consumption compared to the normal group and the risperidone-treated group.In the Morris water maze experiment,after five days of learning training,the schizophrenia model group took longer to find the platform and had fewer crossings over it compared to both the normal group and the risperidone-treated group.These behavioral results collectively indicate that the rat model of schizophrenia has been successfully established,and risperidone treatment exhibits a favorable effect on ameliorating schizophrenia-like behaviors.(2)Compared with normal rats and risperidone-treated rats,the expression of the activity marker c-Fos in lateral habenula neurons was low in schizophrenia model rats,and the firing frequency of lateral habenula neurons was low with a higher membrane potential.Transmission electron microscopy showed neuronal damage.The results indicate that reduced activity of lateral habenula neurons may be related to the onset of schizophrenia.(3)Chemogenetic activation of lateral habenula neuron activity can improve schizophrenia-like behavior in rats,as evidenced by increased social interaction time,higher sucrose preference ratios,and stronger learning ability to locate the platform in the chemogenetically activated group compared to the chemogenetic control group.Conversely,chemogenetic inhibition of lateral habenula neuron activity can reverse the therapeutic effects of risperidone on schizophrenia-like behavior in rats,as demonstrated by longer distances traveled in the open field,shorter social interaction times,lower sucrose preference ratios,and weaker learning ability to locate the platform in the chemogenetically inhibited group compared to the chemogenetic control group.These findings collectively suggest that decreased activity of lateral habenula neurons plays a critical role in the development of schizophrenia.(4)Risperidone can increase the firing of lateral habenula neurons and decrease membrane potential.NMDA receptor antagonists can block the effect of risperidone on the lateral habenula;systemic and local administration of risperidone can cause corresponding changes in the expression of NMDAR2 B,p CREB,and BDNF proteins in the lateral habenula.Furthermore,molecular docking experiments demonstrate that risperidone can bind to Tryptophan 391 and Serine 255 residues within the NMDA2 B receptor.It is indicating that risperidone promotes p CREB and BDNF protein expression by binding to the NMDAR2 B receptor,thus activating the NMDAR2B-p CREB-BDNF signaling pathway to improve the activity of lateral habenula neurons and achieve its anti-schizophrenic effect.(5)Overexpression of BDNF locally in the lateral habenula can improve the neuronal state damaged in the lateral habenula;increase c-Fos expression in lateral habenula neurons;and ameliorate schizophrenia-like behavior in model mice,as evidenced by longer social interaction times and enhanced learning ability to locate the platform in the BDNF overexpression group compared to the schizophrenia model group.Conversely,local knockdown of BDNF in the lateral habenula can impair lateral habenula neuron,decrease c-Fos expression in these neurons,and block the therapeutic effects of risperidone on schizophrenia-like behavior in rats,as shown by longer distances traveled in the open field,shorter social interaction times,and weaker learning ability to locate the platform in the BDNF knockdown group compared to the risperidone-treated group.These results collectively indicate that BDNF in the lateral habenula plays a critical role in the pathogenesis of schizophrenia and mediates the antipsychotic actions of risperidone.Moreover,the level of BDNF is regulated by the NMDAR2B-p CREB-BDNF signaling pathway.Conclusion:(1)Lateral habenula neurons in the rat model of schizophrenia show reduced activity;risperidone can increase the activity of lateral habenula neurons.(2)Reduced activity of the lateral habenula plays an important role in the onset of schizophrenia and mediates the anti-schizophrenic effect of risperidone.(3)BDNF in the lateral habenula plays an important role in the onset of schizophrenia,and reduced activity of the lateral habenula is associated with decreased BDNF levels.Risperidone may increase BDNF expression levels by activating the NMDAR2B-p CREB-BDNF pathway,thereby enhancing the activity of lateral habenula neurons and achieving its anti-schizophrenic effect. |
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