动物造模,精神分裂症动物模型 z-bo 2021-11-03 377

　　Schizophrenia is a common severe mental illness in psychiatric departments, with a very high disability rate and one of the mental disorders with the heaviest disease burden. Its lifetime prevalence accounts for about 1% of the entire population. The cause has not yet been clarified. Most current studies believe that schizophrenia is the result of brain damage caused by biological, psychological and social environments and their interaction. To advance the understanding of the etiology and biological mechanism of schizophrenia, to explore the mechanism of action of antipsychotic drugs, and to identify and evaluate new treatments is inseparable from the establishment of animal models of schizophrenia. Due to the unique human nature of schizophrenia, animal models cannot simulate the mental and psychological factors of patients with schizophrenia. The subject of developing and perfecting animal models is facing an arduous challenge. Therefore, this article will summarize the research progress in this aspect.

　　1 Current status of animal model establishment

　　The animal models of schizophrenia can be roughly divided into three categories: pharmacologically induced animal models, developmental animal models and transgenic animal models according to their different induction strategies [Cil. Pharmacologically induced animal models use drugs to induce schizophrenia-like symptoms. The dopamine hypothesis is the earliest hypothesis of the etiology of schizophrenia, which believes that the symptoms of schizophrenia are caused by excess dopamine in the brain. Inducing abnormal behaviors in animals through stimulant drugs such as amphetamine is a representative of this model. Since the hypothesis of dopamine transmitter imbalance cannot fully explain the pathogenesis of schizophrenia, the hypothesis of glutamate imbalance has attracted widespread attention in recent years. Studies have found that the injection of NMDA receptor antagonist drugs in humans can cause behaviors similar to the symptoms of schizophrenia, including hallucinations, delusions and bizarre behaviors. Similarly, injection of such drugs in rodents can also cause mental illness-like behavior changes, such as sensorimotor gating disorder, hyperactivity, social withdrawal, and learning and memory dysfunction. It is reported that these abnormal behaviors can be restored to normal by injecting some clinical antipsychotic drugs. Therefore, it has become a powerful tool to clarify the pathological mechanism of schizophrenia and test the effectiveness of new antipsychotic drugs. It is also the most commonly used model building method in domestic and foreign research. Its representative drugs are ketamine, PCP and MIA -801. Among them, MIA-801 can simultaneously simulate the negative and positive symptoms of schizophrenia, so it has been widely used in the research of model establishment in recent years. This article will introduce it in detail. In addition, studies have found that neurotensin is related to the pathological mechanism of schizophrenia and participates in the mechanism of action of antipsychotic drugs. This model is still immature and is rarely used in research. The neurodevelopment model is realized by destroying the brains of newborn animals (especially destroying the development of the hippocampus), fetal virus infection or destroying the normal development of animal neurons. Animals will develop some behavioral and neurological aspects of schizophrenia after adulthood. Biological characteristics, these are consistent with the neurodevelopmental hypothesis of schizophrenia: adverse events in prenatal, perinatal and postpartum periods may affect brain development to some extent, as the brain matures in 20 to 30 years Symptoms appeared later. Such models can be used to screen new drugs.

　　翻译结果Be injured. Studies on mice have also reported significant deficits in spatial working memory. Although spatial memory is not significantly different in the learning phase, significant defects will appear when the platform is transferred to the other quadrant of the maze

　　Similarly, the defect of light maze learning can also be observed in rats, and the effect is dose-dependent. Compared with the control group, the rats treated with 0.2 mg/kg took almost twice as long to reach the learning standard, while the rats treated with 0.4 mg/k could not reach the standard at all within the specified time period. . In addition, in another food-rewarded maze test, it was also reported that compared with the control group, the treatment group had a delay in spatial learning ability. Although gradual progress was observed during continuous training, the MIA-801 treatment group had a better performance in the training phase. The control group still performs poorly Van der Stagy FJ et al. believed that whether it is subcutaneously or intramuscularly, rodent administration of MIA-801 as long as it does not exceed 0.1 mg/kg can meet the standards of the cognitive impairment model without causing sensory gating damage. Or toxic effects.

　　4 Long-term effects of MIA-801 on brain morphology and neurochemistry

　　4.1 Brain morphology The decrease in brain weight of rats treated with MIA-801 after birth has been reported. Facchinett F et al. recorded that the brain weight was measured immediately after MK-801 treatment (1-12 d after birth) and found that the brain weight was significantly reduced, and this effect can continue until adulthood. More detailed studies have shown that the effects on different brain regions are not consistent. The areas with the most significant weight loss are the cerebellum and striatum, with the least impact on the hippocampus. Kawahe K et al. [[52] also reported that there was a reduction in brain weight when rats were sacrificed as adults, but they did not try to further understand the characteristics of MIA-801's effects on different brain regions.

　　In addition, the weight loss of the brain may also be the result of a decrease in brain volume and the number of neurons. In the study of the hippocampus, Hari et al. found that the hippocampus has a tendency to decrease in volume when animals are executed at the age of two months, especially in the lower horns of the brain, accompanied by a decrease in the number of neurons in the CA1 region. Similarly, studies have also found that the prefrontal cortex V pyramidal neurons in the adult rat brain tissue have decreased.

　　4.2 Neurochemical Nerve structure and functional imaging studies have found that the prefrontal cortex is one of the main cortex causes of schizophrenia. When Blot K et al. studied the relationship between cognitive impairment and cortical function in rats, they found that a single injection of 0.1 mg/kg of MIA-801 can cause the hippocampus-prefrontal cortex to gradually produce a long-term response, which is consistent with the long-term enhancement. The mechanism is the same. After administration of MIA-801, rats developed cortical-independent cognitive flexibility impairment and hippocampal frontal lobe-related spatial memory impairment. These effects were gradually weakened within 24 hours. Jia Jiao et al. found that blocking NMDA receptors in the neonatal period will cause a compensatory increase in hippocampus NR1 and NR2A in adult rats, and cause a decrease in NGF in the frontal lobe of adolescence. Therefore, blocking NMDA receptors in the neonatal period will cause NGF regulation Changes, long-term compensation of the glutamate system. Research by Tang Yamei and others found that the mPFC area and hippocampal SHIT transmitter system of rats with schizophrenia developmental model induced by repeated treatment of perinatal MIA-801 decreased, and the hippocampal NE transmitter system decreased. Nerve growth factor is an important neurotrophic factor, and research [[54] suggests that changes in its level may be involved in the pathogenesis of schizophrenia. A study in my country confirmed that brain-derived neurotrophic factors have different expression patterns in the prefrontal lobe and hippocampus. The increase observed in the former postpartum period cannot last until adulthood or adolescence, while the latter has a high level of expression in adulthood and adolescence, but not before.

　　Some studies claim that the adult changes in rats treated with MIA-801 in the early life are mainly due to the impact on the main neurotransmitter system. Harris L et al. Czal detailed that the NR1 subtype of NMDA receptors is under-expressed in the dorsal thalamus and hippocampus, but over-expressed in the ventral and ventral CA3 regions. In addition, increased expression of NR1 was also found in the cortex. A study on monoamine metabolism reported that dopamine metabolism increased in the frontal lobe and striatum, while 5-hydroxytryptamine and norepinephrine only increased in the frontal cortex and striatum, respectively, had an effect on neurotransmitters. The qualitative influence also involves the acyanobutyric acid system. Studies have found that compared with control rats, the treatment group lost almost half of the prefrontal cortex microalbumin interneurons.

　　In addition, studies have also shown that MIA-801 has a protective effect on the brain. A 2014 study by Yuan Fenggang and others found that MIA-801 can inhibit the S-nitrosylation of ASIA caused by global cerebral ischemia/reperfusion in SD rats, thereby affecting the ASIA apoptotic signaling pathway and protecting neurons from damage. Zhou Hongxia and others have similar findings. Therefore, the mechanism of MK-801 needs to be further studied.

　　5 Effectiveness evaluation

　　Schizophrenia is a complex group of diseases. It is difficult to replicate all its symptoms in animal models. It is almost impossible to achieve under current science and technology. Therefore, it is necessary to establish a criterion for evaluating these models. For this reason, we explored whether it is reasonable to establish an animal model of schizophrenia by administration of MIA-801. First of all, it is a model of pathogenesis, mainly based on the NMDA receptor hypothesis, based on the dysregulation of dopaminergic neurotransmitter transmission in schizophrenia. Secondly, the change in adulthood stems from the interference of adverse factors in the early life. This model is consistent with the neurodevelopmental model of schizophrenia. In addition, enhanced apoptosis is also implicated in the pathogenesis of schizophrenia, because it can explain the subtle neuropathological changes observed in postmortem tissues, such as decreased nerve fibers and cell structure defects without glial appearance despite the evidence It is shown that the behavioral performance of animals treated with MIA-801 in the early life can mimic some of the symptoms of schizophrenia, but there is still evidence that there are differences between them, especially regarding prepulse inhibition and spontaneous activity, so the surface of this model The validity seems insufficient. Moreover, the reported changes are mainly limited to positive symptoms and cognitive impairment, and the current findings related to negative symptoms are not sufficient, so no clear conclusion can be drawn. Negative symptoms such as social dysfunction and social withdrawal are one of the early manifestations before the onset of the first mental illness and one of the symptoms of poor response to treatment. Therefore, treatment must be adhered to after the remission of psychotic symptoms. Therefore, we believe that the establishment of animal models has played an important role in the discovery of therapeutic drugs, and models that can trigger negative symptoms-related behaviors will have greater value.

　　6 Summary

　　MIA-801 treatment of neonatal rats leads to dysfunction of NMDA receptors, which accelerates the induction of diffuse apoptosis in the immature brain, and then reorganizes cell structure and synapses. These abnormalities may end in psychotic symptoms later in life. MIA-801 can establish a stable animal model of schizophrenia with positive symptoms and cognitive impairment, with reasonable structural validity. Due to the poor reproducibility of some observations, especially in the most extensive prepulse suppression and spontaneous activities in the behavioral study of schizophrenia models, the consistency of its long-term effects on behavior is controversial. Moreover, the behavioral findings related to negative symptoms are insufficient, and further research is needed in this regard. In addition, due to differences in administration methods, dosages, and animal species, research results often vary greatly. Therefore, the establishment of animal models of schizophrenia by administration of MIA-801 is still one of the hot topics of discussion. In order to ensure the consistency of the research results, the method of model establishment needs to be further unified, which can improve the model establishment of negative symptoms of schizophrenia. Further research is needed.

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　　Since it has been confirmed that schizophrenia is a highly hereditary disease, a genetically modified animal model has been created. The use of genetically modified technology can selectively or comprehensively inhibit neurotransmitters related to schizophrenia so as to establish models for related research. This model is under study and will lay the foundation for possible gene therapy in the future.

　　2 MIA-801 administration method, selected dose and animal species

　　Existing research has not unified the choice of experimental animals. Domestic studies mostly use high-dose (> 0. Smg/kg) single injection [[A] or low-dose (0.5 mg/kg) in perinatal or adult Sprague}awley rats for repeated administration C9, io7 To establish a model, there are also single or multiple administrations of different strains of mice [D'Yichuan for related research. Foreign studies mostly use SD rats or Wistar rats. Some authors choose to establish a model and conduct related studies during adulthood, or choose to administer soon after birth (3-7 days), and some studies choose high doses (0. 5-1 mg/kg) single or single-day administration, or choose a low dose ((0. OS0.40 mg/kg) for repeated administration for 2 weeks or longer. There are also some studies using mice to establish models It is also divided into two ways of single and repeated administration. At present, there is no uniform standard for animal species, dosage and time of administration. Therefore, the conclusions of the study are different, and this aspect remains to be clarified.

　　3 Social Behavior Evaluation Model

　　Pre-pulse inhibition (PPI) sensorimotor gating is an important area of information processing, including proper filtering of incoming sensory information, and distributing attention to prominent stimuli by blocking irrelevant or unimportant information. The prepulse suppression of the auditory startle reflex is a measure of the operability of sensorimotor gating. It refers to the reflex response caused by a sudden strong external sensory stimulation, which can be observed and measured in humans or rodents. The phenomenon of prepulse suppression includes the suppression of the automatic startle reflex induced by ambiguous prestimulus. It means that when a pre-pulse that cannot cause startle occurs 30/50 ms before a pulse that can cause startle, regardless of whether they belong to the same sensory form, the intensity of startle reflex is reduced. The weakening of prepulse inhibition indicates impairment of sensorimotor gating, which is particularly pronounced in patients with active psychotic symptoms. Studies have found that the use of antipsychotic drugs can normalize these defects, and the effects of atypical antipsychotics are more pronounced.

　　So far, animals have been treated with MIA-801 soon after birth, and there has been controversy over whether PPI has a long-term effect. Earlier studies indicated that a single injection of MIA-801 on the 3rd day after birth had no effect on the basic prepulse inhibition of rats. However, for older rats, the effect circle of prepulse intensity can be reduced. Newborn rats treated with MIA-801 without prepulse inhibition changes have also been reported in Coleman Jr LG and other studies. Consistent with this, Harris L et al. Czal did not find any change in prepulse inhibition after administration in adult male rats on the 7th day after birth. However, it is interesting that in the same study, adult female rats treated with MIA-801 had prepulse inhibition damage. Zhao YY et al. reported similar findings in 2013. In contrast, another study used female rats who were injected with MIA-801 0.25 mg/kg twice a day from 5 to 14 days after birth, but no prepulse suppression damage was found at 2 to 9 weeks of age}z}} . Therefore, it is difficult to determine whether gender has a decisive influence on the experiment. A few other studies reported positive findings. Uehara T et al. treated rats with MIA-801 from 7 to 10 days after birth and found the dose and age-dependent effects of prepulse inhibition. LiM et al. studied the duration of PPI injury in rats after six consecutive days of administration of NMDA receptor antagonists. One group was administered at a constant dose, and the other group was administered in a gradual manner. The study found that both methods of administration can be used. It causes stable and lasting damage to PPI, but the latter method works better.

　　Considering the problem of making reliable prepulse inhibition changes, the latest study combines the treatment of new born animals with MIA-801 and isolated rearing to simulate the double-click hypothesis of schizophrenia. Through three prepulse inhibition tests, it was found that only MIA-801 treatment of neonatal rats could not produce any prepulse inhibition defects, while only isolation and rearing only produced slight and inconsistent prepulse inhibition defects. However, the combination of the two models caused dramatic changes in prepulse inhibition, consistent with the results of these three tests, so it seems that the combination of the two methods has a more reliable prepulse inhibition change.

　　In recent years, many scholars have done related research on the mechanism of sensory gating disorder caused by MIA-801. Bxaszczyk JW et al. believe that after different doses of MIA-801 treatment, mice have different levels of PPI in the auditory startle reflex, which can be used to explain the glutamate mechanism of the startle reflex. A recent study by Valsamis B et al. also further supports this view, that the excessive activation of glutamate in the central prefrontal cortex is the main mechanism of sensory gating disorder caused by systemic injection of MIA-801. Research by Julia Zangrand et al. pointed out that the expression of PPI in rodents is mediated by glutamate in the lower colliculus. FijaxK et al. [X330 found that in the mechanism of antipsychotics to improve PPI, 5-HT receptors are also part of the role.

　　3.2 Spontaneous activity The most extensive feature of long-term behavioral changes caused by MIA-801 treatment of newborn rats is spontaneous activity. Increased activity in schizophrenia is considered to be related to positive symptoms, and may represent increased activity of the midbrain limbic dopamine system. Most studies have shown that MIA-801 can cause an increase in spontaneous behavior in rats. Park SJ et al. found that after acute administration of MIA-801, spontaneous behaviors increased in mice.

　　Missault S et al. have similar findings in the study of Wilt rats. My team's research found that after MIA-801 was administered at 0.3 mg/kg, the spontaneous activity of rats was lower than that of the control group, suggesting that the effect of MIA-801 on spontaneous activity may be related to the dose. Xiu Y et al. found that after chronic treatment with MIA-801, mice showed increased spontaneous behavior in the open field experiment, decreased exploration of new environments in the orifice experiment, and increased anxiety in the elevated maze test. Latysheva NV et al. found that rats had spontaneous activity reduction during the treatment phase (23 h after injection), but this change was not obvious on the 6th day after the treatment or at the age of 4 months, so it was concluded that the treatment effect could not exist for a long time. Also in mice

　　found that spontaneous movements cannot maintain long-term changes, despite their increased contact behavior. In the gender study, Guo C et al. [09} found that female mice can have an increase in spontaneous behavior after administration, but only female subjects were used in this study, so no conclusions about the other sex could be drawn. Schiffelholz T et al. [Cool injected 0.25 mg/kg MIA-801 on the 6th day after the rat was born]. The rats showed low spontaneous activity in adulthood ((60 d), but increased activity on the 30th day. It is inferred that high activity in childhood may indicate abnormalities before the onset, such as impulsivity. On the contrary, decreased activity in adulthood may reflect psychomotor block and show the state after the onset of the disease. Using the same treatment method, Baier PC et al. reported A very similar finding is that MIA-801 deals with the spontaneous activities of rats. By measuring the moving distance and suspension time in the elevated plus maze, it is found to be significantly reduced on the 60th and 90th days after birth. This result requires attention. , The spontaneous activities measured in the wilderness and elevated plus maze may be very different due to the design connotation and the purpose of the device. Therefore, the results may not accurately reflect the spontaneous activities observed in the standard device (activity room or wilderness), it is very likely Confounded by rat anxiety index. Low spontaneous activity in MIA-801 rats may reflect higher levels of anxiety and increased immobility

　　3.3 Cognitive function

　　3.3.1 New object recognition New object recognition tests are routinely used to assess the recognition memory of rodents. Based on relatively familiar things, animals are more likely to explore the inherent tendency of strange things. In other words, animals spend more time studying new things compared to things they have seen before. Many studies have found that acute administration of MIA-801 can cause new object recognition disorders in animals, and antipsychotic drugs can improve this damage. After Park SJ et al. gave adult mice 0.2 mg/kg of MIA-801 acutely, the mice showed a new object recognition disorder in the test, and this disorder can be significantly improved by acute injection of clozapine. The long-term effects of MIA-801 administered to animals early in life seem to be less certain. MIA-801 was administered at 0.1 mg/kg from 7 to 10 days after birth. Caal such as Stefani MR did not find any damage in the recognition of new objects during the adult test. Similarly, regardless of the choice of high-dose MK-801 or prolonging the injection time by 4 times, Baier PC et al. [Ca i7] also did not find any impairment of recognition memory in mice at any stage of their life. LimAL et al. [29] also did not find any new object recognition defects caused by MIA-801 when evaluating adult rats. Despite insufficient research, the available findings so far show that the NMDA receptor antagonism induced by repeated use of MIA-801 in the early stages of life, after 1.5 h, 2 h, or Sh between the acquisition and retention phases, there is no long-term memory for new things recognition Negatively affect prisoners, but the results outside the interval are still uncertain.

　　3.3.2 Spatial memory Spatial memory is the most influential in the cognitive study of rats treated with MIA-801 early in life. The water maze paradigm is routinely used in the study of rat/mouse spatial memory. Generally speaking, this test involves placing the animal in a circular pool of opaque water, and then allowing it to find and climb on a hidden platform with the help of clues outside the maze to get rid of the trouble of being in the water. Through repeated testing, spatial learning promotes the reduction of escape latency. Even if the platform is removed from the pool Moving out of

　　, the preservation of spatial memory can also encourage animals to still have a longer cruising time in the platform area. Early life MIA-801 treatment leads to a decrease in water maze performance, which is mainly manifested after maturity. McLamb RL et al. did not find any changes in water maze behavior in immature female rats, while Su YA et al. found that female rats had slight functional impairment. My team’s research found that the 6-day-old pups were intraperitoneally injected with 0.3 mg/kg of MIA-801 twice a day for two consecutive weeks. The mouse water maze test was performed one week after the end of administration, and MIA- The learning ability of rats in group 801 decreased, the learning speed slowed down, and the long-term memory was also damaged, but they still had the ability to learn. Li Jitao and others found that intraperitoneal injection of a small dose of MIA-801 destroyed reference memory, spatial working memory and retroactive learning in rats, suggesting that it can simulate cognitive deficits in patients with schizophrenia in multiple cognitive dimensions. After continuous injection of MIA-801 by Wang Yingli and others, rats showed abnormal behaviors and learning similar to human schizophrenia

　　Memory dysfunction, but the impairment of learning and memory is not irreversible. Therefore, it is believed that the correlation between the two needs to be further studied. Domestic and foreign research news reports reported that rats treated with MIA-801 caused acute psychotic attacks, but also caused severe damage to synaptic plasticity and permanent damage to the formation of spatial memory. Su YA and other studies found that

　　Rats treated with MIA-801 in the early stage of birth have moderate working memory impairment in adolescence, but this impairment is abnormally significant in adulthood. However, spontaneous movement and PPI have failed in these two stages.

　　Shòudào sǔnshāng. Duì xiǎo shǔ de yánjiū yěyǒu bàodào cúnzài xiǎnzhù de kōngjiān gōngzuò jìyì quēxiàn. Jǐnguǎn kōngjiān jìyì zài xuéxí jiēduàn méiyǒu xiǎnzhù bùtóng, dànshì dāng bǎ píngtái zhuǎnyí dào mígōng lìng yī xiàngxiàn hòu, huì chūxiàn xiǎnzhù quēxiàn tóngyàng, guāngxiàn mígōng xuéxí de quēxiàn yě zài dà shǔ zhōng kěyǐ guānchá dào, xiàoyìng chéng jìliàng yīlài xìng. Yǔ duìzhào zǔ xiāng bǐ,0. 2 Mg/kg chǔlǐ de dà shǔ jīhū yào huā liǎng bèi cháng shíjiān lái dádào xuéxí biāozhǔn, ér 0. 4Mg/k; chǔlǐ de dà shǔ zài guīdìng de shíjiān duàn nèi gēnběn wúfǎ dádào biāozhǔn wǎng. Cǐwài, zài lìng yīgè shíwù wèi jiǎngshǎng de mígōng cèshì zhōng yě bàodào xiāngduìyú duìzhào zǔ, chǔlǐ zǔ yǒu kòng jiān xuéxí nénglì yánchí, jǐnguǎn liánxù xùnliàn de shíjiān lǐ néng guānchá dào zhúbù de jìnbù, dàn MIA-801 chǔlǐ zǔ zài xùnliàn jiēduàn bǐ duìzhào zǔ yīrán biǎoxiàn yào chà van der Stagy FJ děng rènwéi wúlùn shì píxià zhùshè, háishì jī zhù, nièchǐ lèi dòngwù gěi yào MIA-801 zhǐyào bù chāoguò 0. 1Mg/ kg, jí kě mǎnzú rèn zhī sǔnshāng móxíng de biāozhǔn, qiě bù huì zàochéng gǎnjué mén kòng sǔnshāng huò dúxìng zuòyòng. 4 MIA-801 duì dànǎo xíngtài xué hé shénjīng huàxué de cháng qī yǐngxiǎng 4. 1 Dànǎo xíngtài xué chūshēng hòu MIA-801 chǔlǐ de dà shǔ dànǎo zhòngliàng xiàjiàng jǐ yǒu suǒ bàodào.Facchinett F děng jìlùle MK-801 chǔlǐ (shēng hòu 1 yī 12 d) jiéshù hòu lìjí cèliáng dànǎo zhòngliàng fāxiàn qí xiǎnzhù jiǎnqīng, zhè zhǒng yǐngxiǎng kěyǐ chíxù zhízhì chéngnián. Gèng duō xiángxì de yánjiū xiǎnshì chū duì bùtóng nǎo qū de yǐngxiǎng bìng bùyīzhì, zhòngliàng jiǎnshǎo zuì xiǎnzhù de qūyù shì xiǎonǎo hé wén zhuàng tǐ qū, duì hǎimǎ yǐngxiǎng zuìxiǎo.Kawahe K děng [[52] yě bào gào liǎo dàng dà shǔ chéngnián bèi chǔsǐ shí cúnzài dànǎo zhòngliàng jiǎnshǎo, dàn tāmen méiyǒu chángshì jìnyībù liǎojiě MIA-801 duì bùtóng nǎo qū yǐngxiǎng de tèzhēng. Lìngwài, dànǎo zhòngliàng jiǎnqīng yě kěnéng shì nǎo róngliàng hé shénjīng yuán shùmù jiǎnshǎo de jiéguǒ. Zài duì hǎimǎ de yánjiū zhōng,Hari, děng fāxiànle dòngwù zài liǎng yuè líng bèi chǔsǐ shí hǎimǎ yǒu róngliàng jiǎn xiǎo de qūshì, nǎo xiàjiǎo yóuwéi xiǎnzhù, tóngshí bànsuí CAl qūyù shénjīng yuán shùmù jiǎnshǎo. Lèisì de, yěyǒu yánjiū fāxiàn chéngnián dà shǔ nǎo zǔzhīqián'é pízhí V zhuī tǐ shénjīng yuán yǒu suǒ jiǎnshǎo. 4. 2 Shénjīng huàxué shénjīng jiégòu hé gōngnéng yǐngxiàng xué yánjiū fāxiàn, qián'é pízhí shì jīngshén fēnliè zhèng bìngyīn de zhǔyào pízhí zhī yī.Blot K děng zài yánjiū dà shǔ rèn zhī gōngnéng sǔnshāng yǔ pízhí gōngnéng guānxì shí fāxiàn, dān cì zhùshè 0. 1 Mg/kg de MIA-801 kěyǐ yǐnqǐ hǎimǎ-qián'é yè pízhí zhújiàn chǎnshēng de chángchéng fǎnyìng, yǔ cháng shí chéng zēngqiáng de jīzhì xiāngtóng. Dà shǔ gěi yào MIA-801 hòu chūxiàn pízhí dúlì de rèn zhī línghuó xìng sǔnshāng jí hǎimǎ é yè xiāngguān de kōngjiān jìyì sǔnshāng, zhèxiē zuòyòng dōu zài 24 h nèi zhújiàn xuēruò. Jiǎ jiāo děng yánjiū fāxiàn, xīnshēng qī zǔ duàn NMDA shòu tǐ huì yǐnqǐ dà shǔ chéngnián qí hǎimǎ NR1, NR2A de dài cháng xìng zēngjiā, yǐnqǐ qīngchūnqí qián'é yè bù NGF xiàjiàng, yīn'ér rènwéi xīnshēng qī zǔ duàn NMDA shòu tǐ huì yǐnqǐ NGF tiáojié gǎibiàn, gǔ ān suān xìtǒng cháng qī dài cháng. Tángyàméi děng yánjiū fāxiàn, wéi chǎn qí MIA-801 chóngfù chǔlǐ yòudǎo de jīngshén fēnliè zhèng fāyù móxíng dà shǔ mPFC qū hé hǎimǎ SHIT néng dì zhì xìtǒng gōngnéng jiǎntuì, hǎimǎ NE néng dì zhì xìtǒng gōngnéng jiǎntuì. Shénjīng shēngzhǎng yīnzǐ wéi zhòngyào de shénjīng yíngyǎng yīnzǐ, yánjiū [[54] tíshì qí shuǐpíng de gǎibiàn kěnéng cānyù jīngshén fēnliè zhèng de fǎ bìng jīzhì. Wǒguó yī xiàng yánjiū rèndìngle nǎo yuán xìng shénjīng yíngyǎng yīnzǐ zài qián'é yè hé hǎimǎ cúnzài bùtóng de biǎodá móshì. Qiánzhě zài chǎnhòu qí guānchá dào de shēng gāo bùnéng chíxù zhì chéngnián qí huò qīngchūnqí, érhòu zhě zài chéngnián qí hé qīngchūnqí què cúnzài gāo shuǐpíng de biǎodá, dàn zài cǐ zhī qián shì méiyǒu de. Yǒu yánjiū chēng, zài shēngmìng zǎoqí yòng MIA-801 chǔlǐ de dà shǔ chéngnián hòu de gǎibiàn zhǔyào shi yóuyú yǐngxiǎngle zhǔyào de shénjīng dì zhì xìtǒng.Harris L děng Czal xiángxì shuōmíngliǎo NMDA shòu tǐ de NR1 yà xíng zài qiūnǎo bèi cè hé hǎimǎ bèi cè qū cúnzài dī biǎodá, ér zài fù cè qū hé fù cè CA3 qū yǒu guòdù biǎodá. Lìngwài zài pízhí yě fāxiànle NRl biǎodá de zēngjiā. Yī xiàng guānyú dān àn dàixiè de yán jiù bàodào chēng, duōbā'àn dàixiè zài é yè hé wén zhuàng tǐ jūn yǒu suǒ zēngjiā, ér 5 yī qīng sè àn hé qù jiǎ shènshàngxiàn sù jǐn fēnbié zài é pízhí hé wén zhuàng tǐ dàixiè zēngduō duì shénjīng dì zhì de yǐngxiǎng yě shèjíle yā qíng jī dīng suān xìtǒng. Yǒu yánjiū fāxiàn, yǔ duìzhào zǔ dà shǔ xiāng bǐ, chǔlǐ zǔ sǔnshīle jīhū yībàn de qián'é pízhí xiǎo qīng dànbái zhōngjiān shénjīng yuán. Cǐwài yì yǒu yánjiū xiǎnshì,MIA-801 duì yú dànǎo jùyǒu bǎohù zuòyòng. Yuánfènggāng děng 2014 nián de yánjiū fāxiàn,MIA-801 nénggòu yìzhì SD dà shǔ quán nǎo quē xuè/zài guànzhù yǐnqǐ ASIA de S yī yǎ xiāo jī huà, jìn'ér yǐngxiǎng ASIA diāo wáng xìnhào tōnglù, duì shénjīng yuán sǔnshāng qǐ dào bǎohù zuòyòng. Zhōuhóngxiá děng yěyǒu lèisì fāxiàn. Yīncǐ,MK-801 de zuòyòng jīzhì hái yǒudài jìnyībù shēnrù yánjiū. 5 Xiào xìng píngjià jīngshén fēnliè zhèng zuòwéi yī zǔ fùzá de jíbìng, xiǎng yào zài dòngwù móxíng zhōng fùzhì qí cúnzài de quánbù zhèngzhuàng hěn kùnnán, zài mùqián de kēxué jìshù xià jīhū bù kěnéng shíxiàn, yīncǐ xūyào jiànlì yīgè zhǔnzé yòng yú pínggū zhèxiē móxíng. Wèi cǐ, wǒmen tàntǎo MIA-801 gěi yào jiànlì jīngshén fēnliè zhèng dòngwù móxíng shìfǒu hélǐ. Shǒuxiān, tā shì yīgè fābìng jīzhì de móxíng, zhǔyào jīyú NMDA shòu tǐ jiǎshuō, yǐ jīngshén fēnliè zhèng de duōbā'àn néng shénjīng yuán dì zhì chuándì shītiáo wèi jīchǔ. Qícì, chéngnián qí de gǎibiàn yuán yú shēngmìng zǎoqí de bùliáng yīnsù gānrǎo, gāi móxíng yǔ jīngshén fēnliè zhèng de shénjīng fāyù móxíng yīzhì. Cǐwài, xìbāo diāo wáng zēngqiáng yě qiānshè zài jīngshén fēnliè zhèng de fǎ bìng jīlǐ zhōng, yīnwèi tā kěyǐ jiěshì zài sǐ hòu zǔzhī zhōng guānchá dào de xìwéi shénjīngbìng lǐxué biànhuà, rú shénjīng xiānwéi jiǎnshǎo hé wú shénjīng jiāo zhí chūxiàn de xìbāo jiégòu quēxiàn jǐnguǎn zhèngjù xiǎnshì, dòngwù zài shēngmìng zǎoqí jīng MIA-801 chǔlǐ hòu de xíngwéi biǎoxiàn kěyǐ mónǐ jīngshén fēnliè zhèng de bùfèn zhèngzhuàng, dàn réng yǒu zhèngjù xiǎnshì tāmen zhī jiān cúnzài chāyì, yóuqí shì guānyú qián màichōng yìzhì hé zìfā huódòng, yīncǐ zhège móxíng de biǎomiàn xiào dù sìhū bùgòu chōngfèn. Érqiě, bàodào de biànhuà zhǔyào júxiàn yú yángxìng zhèngzhuàng hé rèn zhī sǔnshāng, mùqián fāxiàn de yǔ yīnxìng zhèngzhuàng yǒuguān de biǎoxiàn shàng bù chōngfèn, yīncǐ bùnéng dé chū míngquè de jiélùn. Yīnxìng zhèngzhuàng rú shèhuì gōngnéng quēxiàn, shèhuì tuìsuō shì shǒucì jīngshén jíbìng fāzuò qián de zǎoqí biǎoxiàn zhī yī, shì duì zhìliáo fǎnyìng qiàn jiā de zhèngzhuàng zhī yī, yīncǐ jīngshénbìng xìng zhèngzhuàng huǎnjiě hòu réng xū jiānchí zhìliáo. Yóu cǐ, wǒmen rènwéi, dòngwù móxíng de jiànlì zài zhìliáo yàowù de fǎ xiàn zhōng qǐle zhòngyào de zuòyòng, nénggòu yǐnfā yīnxìng zhèngzhuàng xiāngguān xíngwéi de móxíng huì cúnzài gèng dà jiàzhí. 6 Xiǎojié MIA-801 chǔlǐ xīnshēng dà shǔ dǎozhì NMDA shòu tǐ gōngnéng shītiáo, zài wèi chéngshú dànǎo zhōng jiāsù yǐnfā mímàn xìng xìbāo diāo wáng, zhīhòu chūxiàn xìbāo jiégòu hé tú chù de chóngzǔ. Zhèxiē yìcháng kěnéng yǐ zài shēngmìng wǎnqí chūxiàn jīngshénbìng xìng zhèngzhuàng ér gàozhōng.MIA-801 kěyǐ jiànlì wěndìng de jīngshén fēnliè zhèng yángxìng zhèngzhuàng jí rèn zhī gōngnéng sǔnshāng dòngwù móxíng, jùyǒu hélǐ de jiégòu xiào dù. Yóuyú yīxiē guānchá jiéguǒ de fù xiàn xìng bǐjiào chà, yóuqí zài jīngshén fēnliè zhèng móxíng xíngwéi yánjiū zhōng zuìwéi guǎngfàn de qián màichōng yìzhì hé zìfā huódòng fāngmiàn, yīncǐ tā duì xíngwéi chángqí yǐngxiǎng de yīzhì xìng cúnzài zhēngyì. Érqiě, yǔ yīnxìng zhèngzhuàng yǒuguān de xíngwéi fāxiàn bùzú, zhè fāngmiàn réng xū jìnyībù yánjiū. Cǐwài, yóuyú gěi yào fāngshì, gěi yào jìliàng, dòngwù zhǒnglèi de bùtóng, yánjiū jiéguǒ wǎngwǎng chāyì shéndà. Yīncǐ,MIA-801 gěi yào jiànlì jīngshén fēnliè zhèng dòngwù móxíng mùqián réngrán shì tǎolùn de rèdiǎn zhī yī, wèi bǎozhèng yánjiū jiéguǒ de yīzhì xìng, móxíng jiànlì fāngfǎ hái xūyào jìnyībù tǒngyī huà, nénggòu wánshàn jīngshén fēnliè zhèng yīnxìng zhèngzhuàng de móxíng jiànlì fāngshì hái xū jìnyībù shēnrù yánjiū.

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