Abstract: Depression is a common mental illness that affects people's daily life and health. It mainly includes persistent depression, decreased interest, pessimism, slow thinking, lack of initiative, poor diet and sleep quality, and multiple discomforts in the body. There are even more suicidal thoughts and behaviors, and nearly 15% of suicides in severe depression [1, 2, 3]. World Health Organization research shows that depression has become the second largest disease burden in China. By 2020, depression may become the world's second largest disease after cardiovascular disease [4]. Animal models can help people better understand depression and play a very good role in the treatment of depression. This article describes some commonly used methods of modeling and evaluation of depression.
[Key words] depression depression model brain-derived neurotrophic factor BDNF
Depression is a type of mental disorder that seriously harms people's physical and mental health. Its incidence is very high, with almost 1 in every 7 adults, and there are currently 340 million people with depression in the world, 7 to 8 times the number of people with schizophrenia, and this number is still rising. Depression has also become a hot spot for medical researchers.
1 Establishment of animal models Animal depression models play an important role in the treatment of depression and the development of antidepressants. The main depression models are as follows:
1.1 Drug-induced depression model Reserpine antagonistic, 5-hydroxytryptophan-induced taro behavior, mouse yohimbine-induced lethal test, rat tryptamine convulsion enhancement experiment. These drug-induced models can be used to early evaluate the effects of antidepressants or to pre-screen the pharmacological properties of unknown compounds [5].
1.2 Stress model 1.2.1 Despair model The establishment and evaluation of a rat model of depression is a large, mouse forced swimming ming test model in which rats (or mice) are placed in water. Forced swimming in the annular glass cylinder. Animals are struggling to swim, struggle, and try to escape in the water. It is impossible to escape. They no longer struggle and swim. They only expose their heads to the surface, their limbs float, and maintain a state of inactivity. Called "behaviour despair." This model has been widely used in the screening and evaluation of antidepressants. Domestic Kunming mice and Wistar rats can be used as the first choice for this model [6].
1.2.2 Acquired helpless Seligman et al. established an acquired helpless animal model in 1975 to simulate depression. After the animal is placed in a cage, the animal is given continuous electric shock stimulation so that it cannot escape. After many experiments, even if the animal is placed in an evasive environment, such as shuttle escaping, it appears to be completely incapable or extremely slow. Escape behavior, called “acquired helplessnessâ€, can be used as a representative animal model of endogenous depression [7].
1.2.3 Chronic unpredictable mild stress (CUMS) animal models currently believe that chronic, long-term daily stress is the main cause of depression. In recent years, animal behavior has been abnormal by changing the surrounding environment. The established depression model broadens the thinking for the study of depression.
Therefore, this model is currently widely used. It is a modification of the model of Katz [10] by Willner et al. [9]. Compared with Katz's research, it significantly reduces the intensity of stress factors and measures the lack of pleasure. As the key to the success of the model, the animal model is closer to the mechanism of human depression. The CUMS depression model includes the following different stress factors [11]: 1 black and white reversed 12h/12h; 2 fasted, water-free 24h; 3 litter wet; 4 behavioral restraint; 5 forced swimming; 6 electric shock sole ; 7 high temperature environment; 8 noise interference; 9 strange smell. Several different stress stimuli were applied throughout the experiment, and the sequence was random. The same stimuli could not appear for two consecutive days. Each stress stimuli appeared at most three times during the modeling process, which made the animals unable to predict the occurrence of stimuli.
1.3 Others: such as: resection of the bilateral olfactory bundle, separation of the model, self-brain stimulation.
1.3.1 The behavioral changes caused by the olfactory bulb resection model are similar to depression, which is characterized by decreased passive escape ability, decreased learning and memory ability, increased stress response, altered eating behavior, etc., removal of intracerebral structures and neurotransmitters caused by olfactory bulbs. Changes are similar to the pathophysiological changes in depression [12, 1, 3].
1.3.2 Separation model [14]
The young rats were separated from the female rats before weaning. After 10-12 months of isolation, the animals became irritated due to separation, and the sleep decreased, followed by spontaneous activity, community disorders, loss of appetite, grace, and shrinkage. .
1.3.3 Self-brain stimulation Research shows that there is a very close relationship between depression and the central reward system, and when the latter is inferior, it can be characterized by depression, inferiority and lack of self-confidence. According to this idea, the electrode is buried in the reward area of ​​the rat brain, and the self-stimulation of the pedal is trained, and the influence of the drug is observed by using the pedal frequency and the threshold current intensity as indicators. The credibility of this model has yet to be proved by a wider range of experiments [15].
2 Evaluation of the effectiveness of animal depression model Establishment and evaluation of a rat model of depression 2.1 open-field test
2.1.1 Method: The animal was placed in a box with a wall of 80 cm × 80 cm × 40 cm and the bottom of the box was black, and the bottom surface was composed of 25 equal 16 cm × 16 cm squares, divided by white lines. The animals were placed in the positive central grid and the measurement was started. Each test was performed for 5 minutes. The test procedure was recorded by a camera. Each rat was only tested once for behavior. After the measurement was completed, the stool was cleaned and the bottom of the box was cleaned with 75% alcohol. The next measurement was performed using a single-blind method, once a week, and each group of animals greater than 7 was only statistically significant.
2.1.2 Results We mainly evaluated the degree of depression in the model group from the following aspects. The study found that the following changes occurred in the model group compared to the control group:
2.1.2.1 Reduced horizontal movement, this indicator reflects the reduced activity of animals. The reduction in straight movement reflects the reduced curiosity of the animal to the fresh environment. The activity score is calculated by the number of blocks passing through the bottom area, and the number of uprights is the vertical activity score [16].
2.1.2.2 Decreased weight and food intake indicate a lack of food reward and euphoria in depressed rats.
2.1.2.3 Reduced exercise time and increased immobility time.
31% sucrose preference test (1% sucrose preference test)
Before the measurement, the water was forbidden and fasted for 23 hours. At the 24th hour, the amount of the 1% sucrose solution was measured for 1 hour. The difference in weight of the water bottle before and after the measurement was the amount of 1% sucrose solution consumed by the animal for 1 hour. The 1% sucrose solution consumption was assessed as 1% sucrose consumption / (sum of water, sucrose consumption).
1 was measured weekly, relative to the control group, the ratio decreased in the rat model group, indicating reduced euphoria depression rats, which is one of the core depressive manifestations.
3 other CHL1 , BDNF
3.1 Studies have shown that CHL1 is a biological marker for antidepressant therapy [17] . The close homologue of L1 is an adhesion factor discovered in recent years. It belongs to the adhesion molecule immunoglobulin superfamily and is expressed in the nervous system. It has been shown to be involved in the growth and development of the nervous system and the growth of axons. And the process of synaptic plasticity, and played an important role in learning and memory [18] .
3.2 A large number of clinical studies have indicated that the serum levels of brain-derived neurotrophic factor ( BDNF ) in patients with depression are significantly reduced. In patients receiving antidepressant therapy, the serum BDNF content is greatly increased, not only that, non-drug resistance depression method can effectively improve the content of serum BDNF in patients with depression [19]. These studies indicate that BDNF levels in serum can be a biomarker for the effectiveness of depression and antidepressant therapy [20] . This also suggests that the decline of BDNF in serum may become a standard for animal depression models, which can also be a new direction for everyone's research.
4 Conclusion
In short, these modeling methods have their own advantages and disadvantages. The drug-induced model is mainly used for early evaluation of the efficacy of antidepressants. The desperate model can only be used for the initial screening of depression, and it is relatively realistic to simulate the formation of human depression. It is an unpredictable long-term mild stress model ( CUMS ). Some researchers believe that combining several of these modeling methods may more realistically simulate the formation of human depression.
At present, we are studying the correlation between brain-derived neurotrophic factor BDNF and its precursor proBDNF and depression. It is also the choice of rat CUMS , which plays an important role in our further understanding of depression, but also has certain defects. Some core symptoms such as suicidal tendencies and pessimistic emotions cannot be simulated by animal models, and there is currently no clear biochemical indicator to evaluate their effectiveness, but we believe that with the advancement of technology and researchers The continuous and in-depth study will establish a more complete model and evaluation system.