CN111280129A - Construction method of young-stage cynomolgus monkey depression model - Google Patents
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Abstract
The invention discloses a construction method of a green and young cynomolgus monkey depression model, which comprises the steps of selecting 10 adolescent male cynomolgus monkeys, and dividing the cynomolgus monkeys into a chronic unpredictable stimulation group and a control group; carrying out 7-day daily treatment, and carrying out 8-day baseline test after the adaptation is finished; while the chronic unpredictable stimulation group was routinely administered, 5 cycles of the study were performed, including 7 days of chronic unpredictable mild stimulation and 4 days of behavioral observation, the control group was routinely administered throughout the study and 4 days of behavioral observation were performed at the end of each cycle. After the whole experiment period is finished, carrying out apple craving experiment and human invader experiment on the chronic unpredictable stimulation group and the control group, and respectively testing the depression and anxiety behavior of the cynomolgus monkey; collecting hair and blood plasma for testing cortisol content; finally, plasma metabolomics methods were used for comparison with juvenile depressed patients. The model provides reference for potential mechanism research of the adolescent depression in the future.
Description
Technical Field
The invention relates to the field of animal models, in particular to a construction method of a green-juvenile cynomolgus monkey depression model.
Background
Juvenile depression refers specifically to depression occurring in the immature age, a group of common mental diseases mainly manifested by marked and sustained low mood, lack of interest, social withdrawal and decreased ability. Recent epidemiological investigations have indicated that the prevalence of depression in the adolescent phase (13-18 years) is about 4-5%. Major juvenile depression is a common and serious psychiatric disorder with a high risk of suicide and other disorders. Global statistics indicate that suicidal behavior due to depression is peak in the 10-24 year old population.
The contribution of non-human primates to stress provides a good model for the study of the mechanism of depression. The existing research on the pathogenesis of the depression is usually based on an adult animal model, and the basic research for exploring the pathogenesis of the depression of children and teenagers based on the animal model of the depression of the teenagers is quite lacked, so that the pathogenesis of the depression of the children and the teenagers is still unclear until now, and is far away from the research progress of the depression of adults. However, to date, monkey models for juvenile depression are still lacking.
Disclosure of Invention
In order to solve the problem that an animal model of juvenile depression is lacked in the prior art, the invention provides a construction method of a juvenile cynomolgus monkey depression model.
The technical scheme adopted by the invention is as follows: a construction method of a young cynomolgus monkey depression model comprises the following steps:
selecting 10 adolescent male cynomolgus monkeys, and dividing into two groups according to age and weight pairing, wherein the two groups comprise a chronic unpredictable stimulation group and a control group;
daily treatment for 7 days to accommodate indoor conditions, and 8-day baseline testing;
the chronic unpredictable stimulation group was treated daily for 5 cycles, each cycle comprising 7 days of chronic unpredictable mild stress and 4 days of behavioral observation, the control group was treated daily throughout the experiment, 4 days of behavioral observation were also performed at the end of each cycle, and the control group was also behavioral observation.
Further, the daily treatment comprises random water supply, under 12H illumination/dark cycle and standard feeding conditions, the temperature is more than or equal to 18 ℃, the relative humidity is 40-70%, and fresh fruits, vegetables and compound high-nutrition monkey food are fed twice a day.
Further, the chronic unpredictable stimulation group and the control group were each housed in the same side of both rooms.
Further, the baseline test includes a baseline sugar water preference, a baseline weight, and a baseline for capturing basal behavior.
Further, the mild stress comprises noise of 100db,12h, water deprivation of 12h, fasting of 24h, space restriction of 4h, cold stimulation of 10 ℃,10 min, stroboscopic exposure of 12h, and non-evasive foot shock of 6V,10-15 s/wheel and 3-4 wheels.
Further, two different pressures are used during one day, and different pressures are selected during two consecutive days.
In the above protocol, apple craving tests, human intruder tests, and cortisol measurements in hair and blood were also included at the end of the experiment.
By adopting the technical scheme, the invention has the following beneficial effects:
(1) the molding method is simple and convenient, the molding result is stable, the blank of a young cynomolgus monkey depression model is filled, and the method can be well popularized and applied to the research in the field;
(2) the molding method adopts a pairing design, can reduce the sample amount as much as possible, saves the cost and meets the ethical requirement;
(3) the modeling method uses two stimulations every day, and does not use the same stimulation for two consecutive days, thereby simulating unpredictable different types of psychological and physical stimulation experienced by human depression patients in daily life to the maximum extent;
(4) the modeling method uses behavioral observation and sugar water test at the end of each experimental period, and monitors the change of the behavioral in real time;
(5) after the molding method is finished, apple craving test and human invader test are adopted, so that anxiety and depression behaviors can be tested more accurately.
Drawings
FIG. 1 is an overall schedule of the present invention;
FIG. 2 shows the results of the AAT and HIT tests;
FIG. 3 is a volcanic and heat map of differential metabolites between CUMS and CON.
Detailed Description
The invention selects 10 adolescent male cynomolgus monkeys (21-52 months old) and divides the macaques into two groups according to the age and weight pair. Subjects in the chronic unpredictable stimulation group (CUMS, n ═ 5) were exposed to several unpredictable stimuli over 5 cycles. The control group (CON, n-5) was routinely treated daily throughout the experiment. The behavior, body weight and sugar water preferences of all monkeys were measured at baseline and at the end of each stimulation cycle. In addition, apple craving test (AAT), Human Invader Test (HIT), and cortisol levels in hair and blood were also measured at the end of the study.
Therefore, the method comprises the following specific steps:
10 adolescent male cynomolgus monkeys (21-52 months old) were selected and divided into a chronic unpredictable mild stimulation group (designated as CUMS group, n ═ 5) and a control group (designated as CON group, n ═ 5) according to age and weight pairing, and the specific ages and weights of the groups are shown in table 1. All cynomolgus monkeys were housed in a single cage (1.0 m.times.1.5 m, L.times.Wtimes.H). The CUMS group and CON group were housed in the same side of the two rooms, respectively.
TABLE 1 Pair of cynomolgus monkey basic data
Prior to starting the experiment, 10 cynomolgus monkeys were kept in a pre-set monkey house for 7 days to adapt to new indoor feeding conditions (random water supply, feeding fresh fruits, vegetables and complex highly nutritious monkey food twice a day under 12H light/dark cycle and standard feeding conditions (> 18 ℃, 40-70% relative humidity), and baseline tests were performed for 8 days, determining baseline sugar water preference, baseline body weight and taking baseline behavioral baselines.
Then, the CUMS group of cynomolgus monkeys underwent approximately 60 days of experimentation (7 days of chronic unpredictable mild stress and 4 days of behavioral observation for a total of 5 cycles of testing). The pressure source included noise (100db,12h), water deprivation (12h), fasting (24h), space restriction (4h), cold stimulation (10 ℃,10 min), stroboscopic exposure (12h), non-evasive foot shock (6V,10-15 s/round, 3-4 rounds). Two different pressure sources are used during one day and the same pressure source is not selected during two consecutive days. Throughout the experiment, the control group was treated daily as usual. Table S1 provides details of the pressure source and special care for the monkeys during the pressure period. The overall schedule of the experiment is shown in figure 1.
TABLE S1 definition of Chronic unpredictable Mild stimuli
To minimize stress duration, all mild stress programs were performed in the morning 8: 00-12: 00 is completed. We supplied fresh fruits and vegetables daily, except for water deprivation and fasting pressure. Researchers are not allowed to enter the room for the rest of the day. After each stress was completed, the barrier between cynomolgus monkeys was removed for a total of eight hours from 12:00 in the morning to 8:00 in the evening to meet the social contact requirements between non-human primates. Also, toys that can be played with each other, such as blocks, dolls, and rubber balls, are provided.
Cynomolgus monkey breeding bases (Zhongke laboratory animals Co., Ltd., located in the west island of Suzhou, China) provide all breeding conditions and regular nursing and daily cleaning for veterinarians. The animal protocol was approved by the ethical committee of the university of Chongqing medical (approval No.: 20180705;) according to the recommendations of "use of non-human primates in research" and "guidelines for care and use of laboratory animals". Pairing was also designed to minimize the number of subjects while maintaining statistical reliability following the NC3Rs (national center for replacement, reduction and refinement, https:// www.nc3rs.org.uk /) principle.
Behavioral observation and testing
Cynomolgus monkey behaviour was videotaped for 1 hour between baseline and 8:00-10:00 am at the end of each stress cycle. The sony high definition camera is fixed outside the cage, and the observation of the cynomolgus monkey does not have a blind spot, and all researchers are far away from the room to avoid disturbing the monkey. Defining 9 behaviors of cynomolgus monkeys in a single cage environment (curling, movement, stereotypy, reaction to the environment, climbing, self-grooming, playing balls, observing and sitting). These behavioral observations are defined in table S2. In cynomolgus monkeys, a crouch-like behavior (self-hugging of the head towards or below the shoulders in a conscious state) is considered to be a core behavior that shows a depressed mood. In addition, a decrease in activity time is also considered a depressive-like behavior.
TABLE S2 definition of behavior Observation
| Behavior | Definition of |
| Tuck-in-look behavior | Self-hugging head towards or below shoulder in awake state |
| Move | Walk in the cage |
| Pattern cutting behavior | Repetitive motion behavior occurring at least three times in succession in a short time |
| Environmental response | Responsive to environmental stimuli, e.g. eating, drinking, exploring, or the like |
| Climbing device | Climbing in cages |
| Hair-care device | Self-hair-tidying device |
| Playing ball | Played with balls suspended from cages |
| Observation of | Looking or attempting to look outside the cage |
| Resting seat | Sitting or lying on the ground |
At the end of the five stress periods, apple craving test (AAT) and Human Intruder Test (HIT) attempts were also made. In AAT, a reduction in the number of apple attempts is considered to be a lack of pleasure, which is a core symptom in depression patients. In HIT, the sum of stiffness, scratching, yawning and fear ghosting is defined as the anxiety-category behavior. In addition, Sucrose Preference Test (SPT) and body weight were also performed prior to baseline and video recording before the end of each stress cycle. In SPT, monkeys were exposed to pure water or 5% sucrose water for one hour after 12 hours of water deficit.
Apple craving test (AAT) monkeys were given enough apples in cages for 3 days. Then, the apples were suspended outside the cages for 15 minutes for 3 days between 2 pm and 3 pm. The distance between the apple and the cage is such that the arms of the monkey cannot touch (about 0.5 m). The frequency and duration of attempts per day were calculated over 15 minutes.
Human Intruder Test (HIT) HIT comprises four stages, (1) a baseline stage of 10 minutes camera stage; (2) in the lateral shadow stage, an invader enters a room and stands at a position 0.6 m away from the cage body of the subject for 2 minutes; (3) in the staring stage, the invader turns to look straight at the shot object and stares for 2 minutes without leaving the room; (4) and a back stage, namely, the invader directly faces back to the shot object without leaving the room within 2 minutes. After the background phase, the intruder leaves the room and the test is complete. Behavioral analysis scores for the last 2 minutes of the baseline phase and three additional phases. The frequency and duration of 10 actions were recorded, including returning to the cage, pacing, stiffening, fear grimacing, scratching, yawning, shaking the cage, shaking the body, grooming, etc. Anxiety categories include behavioral stiffness, scratching, yawning, and fear grimacing.
And (4) testing syrup preference: an acclimation period of 4 hours per day for a period of 4 days was performed before the first test was performed at baseline. On the first day, the monkeys were deprived of water and had to drink from two pure water bottles of the same size and color. On the next day, two bottles of purified water were exchanged for a 5% sucrose solution. On the third day, purified water was placed on the right side and sucrose water on the left side. On the fourth day, pure water was placed on the left side and sucrose solution was placed on the right side. Then, after 12 hours of water deficit from 8:00PM to 8:00AM on the next day, monkeys were exposed to two pre-weighed bottles filled with pure water or 5% sucrose water for 1 hour. The sugar water preference rate (%) is (sucrose amount/total amount) × 100%.
Determination of hair cortisol: the hair at the back neck was cut with scissors and placed in an aluminum foil pouch. The skilled person is particularly careful not to break the skin of the monkey. Storing in a refrigerator at-80 deg.C for use. Hair Cortisol (Cortisol) levels were determined using a Monkey Cortisol detection kit (Monkey Cortisol RIAJL 21813).
Results
Behavioral results
Results of crunch-like behavior, movements, sugar water preferences and body weight are shown in table S3. At the end of the baseline and third round of stimulation, there were no significant differences in all defined behaviors, body weights and SPTs between the CUMS and CON groups. Compared to the CON group, the CUMS group showed a significantly increased frequency (P-0.0431) and duration of postural contractions (P-0.0431) at the end of the five rounds of stimulation. And showed a significant decrease in duration (P ═ 0.0431) and frequency of motion (P ═ 0.0431). However, the other defined behaviors, body weights and SPT differences between CUMS and CON groups were not significant.
TABLE S3 behavior observations
C is CON group; s is CUMS group; significance results are bolded and underlined.
The results for AAT and HIT are shown in FIG. 2. In AAT (FIG. 2A), CUMS group showed a significant decrease in apple trial time over CON group (P. 0.0431, FIG. 2B), but did not show the frequency of apple trials (FIG. 2C). In HIT (fig. 2D), the CUMS group showed significantly increased anxiety-category behavior at the gaze phase (P-0.0431, fig. 2E), but not the total duration of the other three phases and all four phases (fig. 2F).
Cortisol results
The results for cortisol levels in hair and plasma samples are shown in table S4. Hair cortisol levels were significantly elevated in the CUMS group compared to the CON group (P. 0.0431). However, there was no significant difference in plasma cortisol levels between the CUMS and CON groups (P. 0.8927). Furthermore, there was no significant correlation between cortisol values measured in hair and plasma (r-0.13, P-0.7137).
TABLE S4 Hair and plasma Cortisol concentrations
C is CON group; s is CUMS group; significance results are bolded and underlined.
Plasma metabolomics results
Using LC-MS metabolomic profiling of plasma from the CUMS and CON groups, 145 metabolite components were identified in the positive ion mode and 158 in the negative ion mode. A total of 30 differential metabolites were identified between the CUMS and CON groups according to the criteria of VIP >1 and p <0.05, with up-regulated metabolites and 7 up-regulated metabolites. Fig. 3A and 3B show volcanic and thermal maps of differential metabolites between CUMS and CON. The application of MetabioAnalyst 4.0 revealed the underlying biological processes of 30 different metabolites in CUMS and CON. Pathway analysis revealed that the sulfur metabolic pathway, purine metabolic pathway and glycerolipid metabolic pathway were significantly altered in the CUMS group compared to the CON group (FIG. 3C), and they could be linked by altered metabolites (FIG. 3D).
We reanalyzed the previous adolescent MDD patients' metabolomics data and compared it to the latest metabolomics data from adolescent CUMS monkeys. The alterations in metabolic pathways were integrated in adolescent CUMS monkeys and adolescent MDD patients (figure 3E).
It was concluded that chronic unpredictable mild stress can lead to depressive-like behavior and hypothalamic-pituitary-adrenal axis dysfunction in young cynomolgus monkeys. The model provides reference for potential mechanism research of the adolescent depression in the future.
Claims (10)
1. A construction method of a young cynomolgus monkey depression model is characterized by comprising the following steps:
selecting 10 adolescent male cynomolgus monkeys, and dividing into two groups according to age and weight pairing, wherein the two groups comprise a chronic unpredictable stimulation group and a control group;
carrying out 7-day daily treatment to adapt to indoor conditions, and carrying out 8-day baseline test after the adaptation is finished;
the chronic unpredictable stimulation group was treated daily for 5 cycles, each cycle comprising 7 days of chronic unpredictable mild stimulation and 4 days of behavioral observation, and the control group was treated daily throughout the experiment and 4 days of behavioral observation at the end of each cycle.
2. The method for constructing the green-juvenile cynomolgus monkey depression model according to claim 1, characterized in that: the age of the adolescent male cynomolgus monkey is 21-52 months.
3. The method for constructing the green-juvenile cynomolgus monkey depression model according to claim 1, characterized in that: the cynomolgus monkeys are all raised in a single cage.
4. The method for constructing the green-juvenile cynomolgus monkey depression model according to claim 1, characterized in that: the daily treatment comprises random water supply, under the conditions of 12H illumination/dark cycle and standard feeding conditions, the temperature is more than or equal to 18 ℃, the relative humidity is 40-70%, and fresh fruits, vegetables and compound high-nutrition monkey food are fed twice a day.
5. The method for constructing the green-juvenile cynomolgus monkey depression model according to claim 1, characterized in that: the chronic unpredictable stimulation group and the control group were each housed in the same side of both rooms.
6. The method for constructing the green-juvenile cynomolgus monkey depression model according to claim 1, characterized in that: the baseline test includes baseline sugar water preference, baseline body weight, and baseline for shooting basal behavior.
7. The method for constructing the green-juvenile cynomolgus monkey depression model according to claim 1, characterized in that: the mild stress comprises 100db of noise, 12h of water deprivation, 24h of fasting, 4h of space restriction, 10 ℃ of cold stimulation, 10min of stroboscopic exposure for 12h, 6V of non-evasive foot electric shock, 10-15 s/wheel and 3-4 wheels.
8. The method for constructing the green-juvenile cynomolgus monkey depression model according to claim 7, wherein the method comprises the following steps: two different pressures were used during one day and different pressures were selected during two consecutive days.
9. The method for constructing the model of depression of young cynomolgus monkeys according to any one of claims 1 to 8, wherein: also included were apple craving tests, human intruder tests, and cortisol measurements in hair and blood at the end of the experiment.
10. The method for constructing the green-juvenile cynomolgus monkey depression model according to claim 9, wherein: also included is performing a plasma metabolism analysis.
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Cited By (3)
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|---|---|---|---|---|
| CN114342826A (en) * | 2021-12-09 | 2022-04-15 | 深圳先进技术研究院 | Electric shock device and application |
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| CN114342826A (en) * | 2021-12-09 | 2022-04-15 | 深圳先进技术研究院 | Electric shock device and application |
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| CN115711954A (en) * | 2022-11-18 | 2023-02-24 | 重庆医科大学 | Urine biomarker combination for diagnosing depression of children and teenagers and application thereof |
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