Research progress on depression models of different strains of rats and mice

WEN Xiao-yu, SUN Yu-hao, LI Zhuo-xian, XIA Meng

1. School of Basic Medical Sciences, Guangxi University of Traditional Chinese Medicine, Nanning 530000, China

Keywords:

ABSTRACT

1. Introduction

In recent years, it has been found that the prevalence of depression in the world is 20%, its incidence has the characteristics of universalization and rejuvenation, and the health problems of depression have gradually developed into one of the our society. It is not conducive to the stable development of society[1].Depression,as a common psychological and mental illness, the increased suicide rate year by year seriously affects the physical and mental health and social stability of Chinese residents. The cause of patients' suicide is mainly related to the extreme sadness, depression and anxiety of the illness[2,3].According to the clinical symptoms of depression,it can be classified as the category of "emotional disease" and"depression syndrome" in traditional Chinese medicine, and the core of traditional Chinese medicine treatment is dialectical treatment of,by grasping the etiology and pathogenesis of the disease [4].In the study of diseases, Chinese medicine has played many advantages in the treatment of "emotional disease" and accumulated rich experience. With the development of basic medicine of traditional Chinese medicine, the basic research of depression, depression with the model of Chinese medicine has become the hot research,"disease" "certificate" combined research also involves many aspects, build fit medical animal model, on the characteristics of western medicine, provide an important basis for our more objective understanding of disease[5].Liver depression and spleen deficiency type depression is the main common syndrome type one-way depression. Its main pathogenesis is liver can not be released, the spleen can not be healthy, Qi and blood disorders. On the basis of emotional depression, it is easy to appear less qi and lazy words, do not want to eat, diarrhea and other symptoms[6].Therefore, on the basis of constructing a single animal model of depression mice, it is necessary to combine various means to simulate the characteristics of human pathogenesis and explore the principle of inducing pathogenesis to achieve the stability and reliability of syndrome animal model[7].It can be seen that the animal model is established and widely used and will effectively serve the development of TCM antidepress ants .At present, the traditional mold making method does not fully reflect the syndrome characteristics of traditional Chinese medicine by chronic stress stimulation (CUMS), chronic binding stress (CRS), suspension (clip) tail and other ways, and there are still quite different animal molding results between different products . In addition, some scholars have proposed that the suspension experimental model fits the TCM liver stagnation and air stagnation, while the blood level induction model is the heart and spleen deficiency type, and the scientific and objective establishment and test syndrome model is the key to the study of TCM depression. The following review of the characteristics of mice suitable for different strains of depression models is conducted to provide the basis for the further development of qualified mouse models of depression .

2. Rat Model of Syndrome of Depression with Liver Depression and Spleen Deficiency

Rodents have the advantages of similar human kinship, and therefore are stable as monitoring targets in many experiments .In the construction of animal syndrome model, the relevant test standards can also meet the characteristics of TCM syndrome syndrome. In addition, because of different characteristics, there have different requirements and attention in the selection of depression. Based on the large differences in behavioral, endocrine metabolism, genetics, and social psychological levels, considering the accuracy of reasonably matching experimental animal types, the formulation of relevant monitoring standards, which is the key to the effective and scientific evaluation of depressed animal models .Mature and reliable experimental animal models can better achieve the experimental effect and experimental data . Therefore, it can be seen that when using mice as the research object, the detailed types of different characteristics can be more suitable for the experiment,better serve the researchers, there are differences in the maximum possible reduction experiment, to ensure the scientific nature of the experimental data .

2.1 Depressive model of different strains of mice

Mice of different strains have unique phenotypes and are the most widely used animal models in disease research at present. They have unparalleled advantages such as small size, low price, free access to genome sequencing maps from the Internet, and convenient use of genetic engineering technology to induce mouse model building[8].As an excellent strain in the mouse model of depression, C57BL/6 mice showed the characteristics of small individual difference and high stability, and were generally considered to be the first choice for making stress models[9].The most common common mouse depression is one of the classic depression models of chronic stress stimulation (CUMS), when suspended, struggling to overcome abnormal posture will produce desperate static behavior, although the cause of depression and more close to humans, but it is difficult to maintain the depression state, is not conducive to the long - term type of depression research[10,11].To master the characteristics and advantages of different strains of mice can help to select appropriate modeling methods to build a long-term and stable depression mouse model with traditional Chinese medicine syndrome, which greatly ensures the scientific nature of the experimental research. There are also Kunming mouse model, BALB/C mouse, ICR mouse model and FST、TST、CUMS、CRS mouse model of different strains.

2.1.1 Chinese Kunming KM Mouse Model

Zhang Zhongqi[12]Citing the influence of the time of modeling on the use of Kunming (KM) mice, high fixed time values during forced swimming at April ～ September, the reason may be affected by the biological clock and biological cycle of animals. While KM mice have greater individual differences than Wistar rats, But from the experiment, KM mice were used only once, The effect of dosage and cost on model making was significantly lower than that of many rats, And when designing compulsive swimming to study the antidepressant effects of drugs, KM mice should be preferred, Because the individual behavior difference is obvious, It is easier to study the experimental study with no significant contrast difference. The study also found that the changes of miRNA-132 and miRNA-134 levels in hippocampus of KM mice were closely related to depression in 3 weeks after the intervention. At the same time, detailed research reports that, Abnormal levels of miRNAs also occur in the hippocampus of mentally ill patients, Perhaps because miRNA-132 can significantly inhibit the expression of brain-derived neurotrophic factor (BDNF) in humans, To induce mental illness[13,14].Recent studies have reported that the use of CUMS modeling in male and female KM mice, female KM mice,in addition to emotional stress changes, can also cause related reproductive dysfunction, for the observation of gender differences in mental experiments, performance is more effective, operational and reproducible characteristics. At the same time, male Kunming mice with relatively good retest reliability were recommended in the study of compound pharmacodynamics evaluation[15,16].

2.1.2 BALB/C Mouse Depression Model

As an experimental object, mice have the sensitivity, validity and reliability suitable for depression modeling, which can provide feasible experimental reference and establish relevant standards to a great extent. Under the same feeding conditions, the forced swimming behavior of KM mice and BALB/C mice of similar individual quality changed in different water temperature and circadian rhythm environment [17]. Meanwhile, the immobility time of Kunming mice during the day was significantly less than that of BALB/C mice, and the immobility time of BALB/C mice at night was shorter than that of the day. The further study found that the number of positive results in BALB/C mice was significantly higher than that in KM mice, and the degree of gender influence in mice was not high. This type of mice were more likely to develop depressive behavior in 22℃ of water temperature, and when chronic unpredictable stress (CUMS) and subcutaneous injection of corticosterone were performed, BALB/C strain mice also developed significant and stable qi deficiency syndromes. At the same time,the strain mice also developed Qi deficiency syndrome after social frustration stress test [18,19].Binding and noise stress for 5 days can obviously prolong the rest time of forced swimming in mice. BALB/C mice are commonly used inbred line mice, which have lower social performance and better copy some models of psychosomatic diseases of human beings. More in line with the characteristics of syndromes [20].

2.1.3 male C57BL/6 mouse model of depression

C57BL/6 strain mice are suitable for the construction of a new long-term depression LTD model with chronic stress after weaning because they are separated by early mother and child.Compared with traditional CUMS、ELS mice, this model can show obvious degenerative degeneration in the CA1 and CA3 areas of hippocampus of LTD mice, Li Liangping [21].The results showed that C57BL/6 strain mice were more likely to exhibit depressionlike behavior than NIH Swiss mice in the observation of open field experiments under acute stress, and speculated that behavioral performance might be affected by genetic factors. C57BL/6 mice also had long-term depressive behavior and showed long-term psychological stress, so it was suitable to study the long-term changes and differences of simulated depression[22,23]. Moreover,it is pointed out that C57BL/6 mice showed significant sensitivity to weight, sugar water preference, open field and vertical motion after CUMS modeling, so it is considered that C57BL/6 mice are suitable for animal models of depression constructed by traditional modeling[24]. Based on the characteristics of low spontaneous activity and poor ability to explore novel environment in C57BL/6 mice, it is easier to form this state in behavioral despair. To sum up,the strain mice can not only be used as a slow acute stress depression model, but also have the potential to become a variety of forms of stress modeling.

2.1.4 ICR Mouse Depression Model

Li Tengfei [25]said the total dynamic distance, movement speed and movement time of ICR and KM mice were significantly higher than that of C57BL/6 mice, and the number of standing times ICR mice were also more significant than that of C57BL/6 mice. The individual differences of ICR mice in the population and the polymorphism at some loci were more in line with the characteristics of distant animals. Under chronic restraint stress ICR the body weight growth rate of the mice showed a decreasing trend, and the activity distance, vertical standing times and hair management times of the open field experiment were significantly reduced. When the incubation period of ICR mice was shortened, the ratio of original crossing times and original platform quadrant time increased significantly. The experiment showed that chronic restraint stress could cause depression-like behavior of ICR mice, but it promoted the spatial learning and memory ability of ICR mice [26,27].Fibroblast growth factor can affect the growth and differentiation of neurons to regulate the occurrence of the disease, FGF2 the content in the cerebral cortex, hippocampus and cerebellum of depressed patients is decreased, while the FGF9 is significantly upregulated. FGF2/FGF9 can regulate the occurrence of depression in the occurrence of depression has a corresponding regulatory effect.The increase of lipopolysaccharide FGF2 content in the rat brain can improve the depressive behavior of rats, while the injection of FGF9 in the mouse ventricle can cause depressive behavior[28].

2.1.5 FST、TST、CUMS、CRS mouse model regardless of strain

FST models in animal models of depression have the advantages of low cost, simplicity, high efficiency and reliability. They are widely used in the screening of antidepressants or the evaluation of behavioral changes in other models of depression, Porsolt 1977[29]. A more mature mouse depression model was constructed by et al. This method can only understand the depression state of mice by influencing the changes of external behavior, so it is difficult to reflect the changes of some internal core symptoms in patients with depression. Therefore, a mouse tail suspension experiment (TST),first proposed by Steru L et al. in 1985, TST has the characteristics of simplicity, speed and sensitivity. Wang Jiannan [30]. Think TST can be used in combination with FST while building depression models, At the same time, rapid screening of antidepressants and evaluation of behavioral changes in other depression models. Mice of this type have obvious advantages in cost saving and aging,Therefore, it is also widely used. Chronic restraint stress (CRS) and chronic mild non-preparatory stimulation (CUMS) are commonly used in animal models of depression, CUMS mold making mode is CRS mild, CRS is usually a single-factor stressor, CUMS is a multi-factor stressor[31]. CUMS model mice compared to CRS model mice, In the experiment of forced swimming and open field,the distance of activity decreased obviously, and the rest time was long, And the number of activities significantly decreased, FGF2 in the hippocampus of mice decreased significantly, The depression tendency and central nervous inhibition effect of CUMS model mice were better than that of CRS model mice [32] .

2.2 Depressive model of different strains of rats

Weight change and behavioral observation data of rats in depression modeling experiment are very sensitive indexes to evaluate antidepressant effect[33]. In chronic forced water swimming experiments, the hippocampus cor id levels caused the increased activity of 5 - HT and DA in the brain, causing the body mass growth and the significant decrease in food intake rate in rats, which has more research value and significance compared with mice[34].Among them, the most representative is the SD rat and Wistar rats,both as distant close group of white rats, is the preferred object of clinical experimental study and mechanism at home and abroad, can better simulate the condition of depression under stress in chronic binding stress in the two rats, in addition to the non - spatial learning and memory damage is more significant[35,36]. In addition to the common rat models of the above two strains, there are WKY、FH/Wjd and other different strains of rats in the study of depression as the research object, but as the research object of TCM syndrome may be slightly inferior to SD rats and Wistar rats.

2.2.1 Rat model of liver depression SD spleen deficiency depression

By stress induced by ischemic stroke, there is no obvious damaging stimulation to the body of rats, which is similar to the process of depression . The principle of the CIS model rats from the angry state liver gas stagnation to depression, and gradually have spleen deficiency fatigue, fatigue, loose stool, in line with the " liver wooden soil " mechanism, so this model is widely recognized by the Chinese medicine syndrome researchers [37]. Chen Xiaomei[38]used electric shocks to the plantar, ice water swimming, 24 h water ban,24 h fasting, restraint (4 h), tail clamping (2 min), exchange cage objects, Random stimulation every day, build chronic unpredictable stress models. In the midst of external stress, According to TCM theory, the main cause of depression is liver depression, Combined with behavioral, dietary intake, defecation and weight changes, It is consistent with the symptoms of spleen deficiency such as loss of appetite, fullness, fatigue and loose stools in TCM syndromes. Yang Lijing[39] found significant differences in weight gain, sugar water preference and forced swimming after chronic social frustration stress (CSDS) modeling SD rats (P＜0.05), There was no statistical difference in the number and time of opening/closing arm between open field experiment and elevated experiment, And it suggests that SD rats have obvious depressive characteristics, At the same time, the anxiety was not obvious, to ensure that the animal model appears more in line with the characteristics of depression, Better as a research model for depression.

2.2.2 Wistar Male Depressed Rat Model

After 21 days of modeling Wistar male rats using chronic unpredictable stress, For forced swimming test, open field test,Modelling using 4℃ of ice water swimming, light and dark upside down 24 h、 fasting water 24 h、 tail 3 min、 electric shock plantar 5, wet cushion 10 h, Open field tests were performed before and after ketamine injection 1 h、2 h、6 h、1 d、4 d and 7 d, The horizontal and vertical movements of rats were observed and recorded. To build a rat model Wistar depression through CUMS, Detection of NF-κB signaling pathway activity in hippocampus of rats with depression showed a significant increase, Meanwhile, the number of neurons in the DG, CA1 and CA3 regions of hippocampus decreased [].Wistar rats showed different levels of high blood viscosity in the condition of liver stagnation and spleen deficiency, while the high blood viscosity in the model rats was mainly related to the changes of platelets and other macromolecular components[41]. Some scholars believe that Chinese medicine believes that "Qi moves while blood moves" in line with modern medicine that Qi can promote the operation of blood and prevent abnormal blood stagnation.

2.2.3 WKY Rat depression model

Wistar Kyoto (WKY) rats are inbred lines of Wistar rats with high levels of endogenous depressive-like behavior[42].WKY rats were discovered in 1963 by OKAMOTOK and validated by Pare WP as an experimental animal of depression model. WKY rats were prone to acquired helplessness in the process of modeling, the level of static despair in forced water swimming experiment was very high and the duration was long. The results showed that the molecular mechanisms of WKY rats were different from those of Wistar rats with chronic stress depression. This suggests that different molecular mechanisms of WKY rats are expected to be the target of new drugs[43,44].WKY rats are more prone to depression-like behaviors such as increased resting time and loss of pleasure in forced swimming experiments, and the density of dendritic spines in the hippocampus and prefrontal cortex decreases significantly as a result Wistar stress-sensitive rats and abnormal regulation of the HPA axis,which most researchers apply to anxiety disorders[45-48].

2.2.4 FH/Wjd rat model

FH/Wjd (Fawn-Hooded) rats are inbred Wistar to the 19th generation of inbred rats, has 5-hydroxytryptamine, the difference is obvious, the behavior despair is obvious, And their depressive characteristics have been identified, is an ideal animal model of depression . Previous studies have found, FH/Wjd rats were at rest during the forced swimming experiment, Compared with SD rats,And in the water maze, significantly with depression characteristics such as lack of pleasure, low learning and memory, poor fatigue endurance, and behavioral despair[49-51]. Xiong Tingwang[52] in the study confirmed that FH/Wjd rats have obvious anxiety behavior and high activity mechanism may be associated with low DA、5-HT content, hypermetabolism, Neuropsychiatric diseases associated with hyperaxial HPA, Its mechanism is clear characteristic as depression research object, Also has the more trustworthy characteristic.

2.2.5 FSL and CUMS rat models of depression regardless of pedigree

Overstreet and Wegener first proposed FSL rat mode, but then found that the model animals showed prolonged REM sleep and prolonged rest time in forced water swimming, and these behavioral changes could be reversed by antidepressants. At the same time, the two men found antidepressant-like behavior in FSL rats 14 days after antidepressant treatment. A remarkable feature of FSL rats is that they are very sensitive to many drugs with different pharmacological mechanisms. As a result FSL rats can be used as a genetic animal model for depression [53,54].The content of BDNF neurotrophic factor in the brain plays an important role in the pathogenesis of depression, and there will be a BDNF decline in the brain of CUMS model rats after modeling. Dandekar found that the contents of BDNF in hippocampus and cerebrospinal fluid of model rats were significantly decreased, and the contents of interleukin family IL-2、IL-5、IL-7 in hippocampus of CUMS model rats were significantly increased.However, CUMS model rats showed abnormal intestinal metabolism, butyric acid and sodium propionate in feces metabolism were dysregulated[55].

3. Discussion

Depression belongs to the category of "depression syndrome" in traditional Chinese medicine. The main cause and pathogenesis of depression are the involvement of liver, heart and spleen spleen involvement and qi and blood disorders. At present, environmental stress modeling method and corresponding behavioral measurement are used as one of the classical animal depression models [56].According to literature retrieval and data collection, in addition to chronic stress models, there are acquired helpless models, chronic social failure models, single physical stress model, chronic forced swimming stress, ha em pine, lip opol ys accharide, glucocortico id induced molding, surgical molding and genetic knockout[57].This paper analyzes the differences and advantages of behavioral experiment, sugar and water consumption experiment, weight change and so on, and discusses the mouse model lines which are most suitable for depression model. By using the key words "mouse"or "rat" plus "depression" model "to search for depression research papers on the CNKI of nearly ten years, 793 papers were used in mouse models, and 1401 in rats. It is suggested that the use of depression model in rats is higher than that in mice, meanwhile,Zhao Qian [58]believed that the disease occurrence and expression caused by the rat CUMS model can better simulate the human depression symptoms and a series of biochemical changes caused by human depression. The effectiveness of mood disorder drugs can fully reflect, which meets the evaluation standards of the surface validity,structural validity and prediction validity of mood disorder animal models, so it is widely used in the field of depression research .

To explore the best models for the depression model of mice that fit the syndrome by making models of different strains of mice,analyzing the differences and advantages of open field experiment,sugar water consumption experiment and weight change. By using the key words "mouse" or "rat" plus "depression" model "to search for depression research papers on the CNKI of nearly ten years,793 papers were used in mouse models, and 1401 in rats. At the same time, Zhao Qian thinks that the disease occurrence and manifestation caused by rat CUMS model can simulate human depression symptoms and biochemical changes caused by a series of human depression. The effectiveness of emotional disorder drugs can be fully reflected, that is, meet the evaluation criteria of surface validity, structural validity and predictive validity of animal model of emotional disorder, so it is widely used in the field of depression research.

As a result of the lack of standardized standards for animal models that fit the symptoms of liver depression and spleen deficiency,Sun Xiaoqian[59] and others, in order to try to solve this problem,according to the characteristics of human diseases, such as hypochondriac pain, abdominal distension, food loss, loose stools,pale red tongue or light tongue, by observing the shape of the model animals, such as mental state, tongue, eyes, tail ecchymosis, diet,feces, hair and so on, to develop a scoring table of animal models that meet the symptoms, so that the animal models can grasp the symptoms more accurately.Syndrome recognition is the core of TCM syndrome differentiation and treatment. In animal experimental research, the establishment of syndrome model is the key to study the material basis of TCM drugs. It can not prove the reliability of modeling method, so the research on syndrome model establishment and test still needs to be further improved[60].

4. outlook

According to the above content, the relevant literature summary found that the modern depression animal modeling at home and abroad mainly take stress molding, drug molding, surgical molding,and gene knockout as common methods[61-64].

The establishment of depression animal model is of great significance to the pathogenesis of depression . Using mono amine neuro transmitter is the only criterion for model evaluation, it lacks the combination of syndrome differentiation, which is not conducive to the construction of qualified experimental animal model .Meet the research needs to choose the corresponding animal model, can grasp the advantages of different animals, so as to accurately select the model of the animal products, using the correct mold making,with more appropriate certification waiting scoring and diagnosis standards, to improve the quality of experiment and better complete the experimental animal model construction .The author believes that if we want to simulate depression for a long time and can better achieve the experimental purpose of depression syndrome research and syndrome type research, we can use chronic mild nonpretimulatory (CUMS) modeling to Wistar rats or SD male rats.With the wide application of molecular biology technology in the field of mental illness and mental medicine, new techniques, new methods and new ideas based on genetic science have reached the embodiment of simulating the state of depression from the angles of biology and genetics[60].Syndromes are the key points in TCM syndrome differentiation and treatment, and the research mode of combination of disease and syndrome has gradually developed into the mainstream of TCM research. Because TCM emphasizes the whole concept, it can also consider using modern system biology means, which is represented by metabolomics, proteomics and genomics, proteomics and genomics, and tries to ensure the construction of TCM animal model with comprehensive and accurate biological material basis of syndrome from "macro" to "micro"[].Although the characteristics of the current mouse strain model can meet most of our experimental requirements, we still need to study and develop new animal models of depression. To build a highly suitable animal model of traditional Chinese medicine syndrome,standardized experimental animal modeling, for the future in-depth study of TCM pathogenesis and syndrome to provide more valuable research ideas.