精神分裂症,动物模型 z-bo 2020-12-02 487

　　Schizophrenia is a common severe mental illness in psychiatric departments, with an extremely 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 currently 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.

　　 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) 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 unified standard for animal species, dosage and time of administration, so the conclusions of the study are different. 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 stimulus, 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 the 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 permanent damage to PPI, but the latter method works better.

　　 Considering the problem of making reliable prepulse suppression changes, the latest study combines the treatment of new born animals with MIA-801 and isolation to simulate the double-tap 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 treatment or at 4 months of age, so it was concluded that the effect after treatment could not exist for a long time. Also in mice

　　 found that spontaneous movements cannot sustain long-term changes, even though their contact behavior has increased. In the gender study, Guo C et al. [09} found that female mice can increase 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 findings available 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 putting 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 international research express reports 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.

　　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 could be observed during continuous training, the MIA-801 treatment group was more effective in the training phase. The control group still performs poorly Van der Stagy FJ et al. believe that whether it is subcutaneously or intramuscularly, as long as the rodent administration of MIA-801 does not exceed 0.1 mg/kg, it can meet the standards of cognitive impairment models 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 causing 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 and other studies have 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 be sustained into adulthood or adolescence, while the latter has high levels 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 involved in the pathogenesis of schizophrenia, because it can explain the subtle neuropathological changes observed in postmortem tissues, such as decreased nerve fibers and cell structural 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 research 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 research results, the method of model establishment needs to be further unified, which can improve the method of model establishment of negative symptoms of schizophrenia. Further research is needed.