抑郁症大鼠模型 z-bo 2020-10-14 368

　　Depression is a kind of mental disorder that seriously endangers people's physical and mental health. It has a high incidence, almost 1 in every 7 adults has depression. There are currently 340 million people with depression in the world, which is equivalent to 7 to 8 times that of schizophrenia, and this number is still rising , Depression has also become a research hotspot for medical workers.

　　1 Establishment of animal model

　　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 antagonizes the head shaking behavior induced by 5-hydroxytryptophan, the lethal test induced by yohimbine in mice, and the enhancement test of tryptamine convulsion in rats. These drug-induced models can be used to evaluate the effects of antidepressants early or to screen the pharmacological properties of unknown compounds [5].

　　1.2 Stress model

　　1.2.1 Despair model Establishment and evaluation of depression rat model

　　refers to the forced swimming test model of rats and mice. This model is to put rats (or mice) into a circular glass tank filled with water for forced swimming. The animal first swims, struggles, and tries to escape in the water, and then feels that it is impossible to escape, so it no longer struggles and swims, only its head is exposed to the surface of the water, its limbs are floating, and it maintains a state of immobility. Called "behavior desperate." This model has been widely used in the screening and evaluation of antidepressants. Domestic Kunming mice and Wistar rats can be the first choice animals for this model [6].

　　1.2.2 Acquired helplessness

　　Seligman et al. established an animal model of acquired helplessness in 1975 to simulate depression. After the animal is placed in a cage, the animal is given continuous electric shocks to make it unable to escape. After many experiments, even if the animal is placed in an escapeable environment, such as a shuttle to escape, it will be completely unable or extremely slow The escape behavior is called "acquired helplessness", this model can be used as a representative animal model of endogenous depression [7].

　　1.2.3 Chronic unpredictable mild stress (CUMS) animal model

　　It is currently believed that chronic, long-term daily stress is the main cause of depression. In recent years, the depression model established by changing the surrounding environment to make animals behave abnormally has broadened the thinking for the study of depression.

　　Therefore, this model is currently widely used. It is an improvement of Willner et al. [9], an improvement of Katz et al.'s model. Compared with Katz’s research, it significantly reduces the intensity of stress factors and is a measure of anhedonia. As the key to the success of the model, the animal model is closer to the mechanism of human depression. The production of the CUMS depression model includes the following different stress factors [11]: ① black and white are reversed for 12h/12h; ②fasting and water-free for 24h; ③wet litter; ④behavior restraint; ⑤forced swimming; ⑥electrical foot sole ;⑦High temperature environment;⑧noise interference;⑨unfamiliar smell. Several different stress stimuli were applied throughout the experiment in random order. The same stimulus could not appear for two consecutive days. Each stress stimulus appeared at most three times during the modeling process, which made the animals unpredictable.

　　1.3 Others: such as: removal of bilateral olfactory tracts, separation of models, self-brain stimulation.

　　1.3.1 The behavioral changes caused by the olfactory bulb resection model are similar to those of depression, manifested as decreased passive avoidance ability, decreased learning and memory ability, increased stress response, changes in eating behavior, etc., the structure and neurotransmitters in the brain caused by removal of the olfactory bulb The changes are similar to the pathophysiological changes of depression [12, 1, 3].

　　1.3.2 Separation model [14]

　　Separate the juvenile rat from the mother rat before weaning. After 10-12 months of isolation and feeding, the animal will become irritable and sleep less due to the separation, followed by decreased spontaneous activity, social disorder, decreased appetite, sadness, and atrophy. .

　　1.3.3 Self-brain stimulation

　　Research has shown that there is a very close relationship between depression and the central reward system, and when the latter function is low, it can be manifested as depression, strong inferiority complex and insufficient self-confidence. According to this idea, the electrodes are buried in the reward area of the mouse brain, and the pedals are trained to self-stimulate. The pedal frequency and threshold current intensity are used as indicators to observe the effects of drugs. The credibility of this model has yet to be proved by more extensive experiments [15].

　　2 Evaluation of the effectiveness of animal depression models Establishment and evaluation of depression rat models

　　2.1 open-field test

　　2.1.1 Method: Put the animal in a box with a peripheral wall of 80cm×80cm×40cm and a black bottom, and the bottom surface is composed of 25 equal 16cm×16cm squares, divided by white lines. Put the animal in the center grid and start the measurement. Each measurement is 5 minutes. The test process is recorded by a video camera. Each rat only conducts a behavior measurement. After the measurement is completed, the feces are cleaned, and the bottom of the box is wiped with 75% alcohol. For the next determination, a single-blind method was used to determine once a week. It is only statistically significant for animals in each group to be greater than 7.

　　2.1.2 Results

　　We mainly evaluate the depression degree of the model group from the following aspects. The study found that compared with the control group, the following changes will occur in the model group:

　　2.1.2.1 Decrease in horizontal movement, this indicator reflects the decrease in animal activity. Straight movement is reduced, which reflects the decrease in the animal's curiosity about the fresh environment. The number of blocks that cross the bottom area is the horizontal activity score, and the number of uprights is the vertical activity score [16].

　　2.1.2.2 The decrease in body weight and food intake indicates the lack of food reward and euphoria in depressed rats.

　　2.1.2.3 Exercise time decreases and immobility time increases.

　　31% sucrose preference test (1% sucrose preference test)

　　Before the measurement, water and fasting for 23 hours were carried out. At the 24th hour, the amount of 1% sucrose solution consumed by the animals in 1 hour was measured. The weight difference of the water bottle before and after the measurement is the amount of the animal drinking 1% sucrose solution in 1 hour. The consumption of 1% sucrose solution is evaluated as 1% sucrose consumption/(sum of water and sucrose consumption).

　　is measured once a week. Compared with the control group, the ratio is significantly decreased in the model rat group, indicating that the euphoria of the depression group is reduced, which is one of the core manifestations of depression.

　　3 Other CHL1, BDNF

　　3.1 Studies have shown that CHL1 is a biological marker for antidepressant therapy [17]. Nerve cell adhesion molecule CHL1 (close homologue of L1) is an adhesion factor discovered in recent years. It belongs to the immunoglobulin superfamily of adhesion molecules and is concentrated in the nervous system. Studies have shown that it participates in the growth and development of the nervous system and the growth of axons. And synaptic plasticity and other processes, and play an important role in learning and memory [18].

　　3.2 A large number of clinical studies have pointed out that the content of brain-derived neurotrophic factor (BDNF) in the serum of patients with depression is significantly reduced, and the content of BDNF in the serum of patients receiving antidepressant treatment is greatly increased. Not only that, but non-drug resistance Depression methods can also effectively increase the content of BDNF in the serum of patients with depression [19]. These studies point out that the BDNF content in serum can be a biological marker of the effectiveness of depression and antidepressant treatments [20]. This also reminds us that the decrease of BDNF in serum may become a standard of animal depression model, 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, and the despair model can only be used for the initial screening of depression, and is relatively a model that can simulate the formation of human depression more realistically 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 depression in humans.

　　At present, we are studying the correlation between brain-derived neurotrophic factor BDNF and its precursor proBDNF and depression, and we also choose rat CUMS. It has played an important role in further understanding of depression, but it also has certain defects. Some core symptoms such as suicidal tendencies, pessimistic and depressed emotions cannot be simulated by animal models, and there is currently no clear biochemical index to evaluate its effectiveness, but we believe that with the advancement of technology and researchers Continuous in-depth research will establish a more complete model building and evaluation system.