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 Table of Contents  
Year : 2018  |  Volume : 3  |  Issue : 2  |  Page : 29-30

Mental stress studies in animals

1 China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing, China; Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA
2 Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA

Date of Submission10-Jun-2018
Date of Acceptance11-Jun-2018
Date of Web Publication12-Jul-2018

Correspondence Address:
Dr. Yuchuan Ding
Department of Neurosurgery, Wayne State University School of Medicine, 550 E Canfield, Detroit, MI 48201

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ed.ed_10_18

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How to cite this article:
Guo S, Elmadhoun O, Ding Y. Mental stress studies in animals. Environ Dis 2018;3:29-30

How to cite this URL:
Guo S, Elmadhoun O, Ding Y. Mental stress studies in animals. Environ Dis [serial online] 2018 [cited 2023 Jun 6];3:29-30. Available from: http://www.environmentmed.org/text.asp?2018/3/2/29/236531

Many disturbances including both psychological and physiological are a result of stress. While animal models of social stress cannot mimic those disorders in their entirety, they are essential to uncover the etiology and mechanisms of these disturbances and subsequently develop efficacious treatments.[1] Given the special nature of psychological disorders, the development of relevant animal models has been both a major challenge and focus of research in this field. Several depression-like behavior models have been utilized to study social stress in animals, mostly in rodents.

  Two Types of Model: Chronic and Acute Stress Top

Animal models of psychological stress and depression-like behaviors are divided into acute and chronic stress models. For chronic stress, restraint stress and chronic unpredictable mild stress (CUMS) are often used while repeated social defeat stress (RSDS), forced swim test (FST), tail suspension test (TST), and acute electric foot-shock stress are considered as acute stressor models.

Restraint stress

Restraint stress is a one of the preferred models as it is simple to achieve, mostly painless, and results in no lasting debilitation. Immobilization is a procedural variation of this strategy, and unlike other techniques, it only affects the range of locomotion but does not limit specific limb movement.[2] It typically involves restraining an animal for 1–6 h/day in a restraint device (bag or tube) for a total period of 14–21 days.[3]

Chronic unpredictable mild stress

CUMS is a well-established model, originally started by Katz et al. who developed the three-week chronic unpredictable severe stress protocol.[4],[5] To more accurately mimic the human condition, Willner et al. later replaced severe stressors in Katz's model with mild stressors.[6] This protocol was further modified by Duman's group in the duration, number, and severity of stressors used.[7],[8] Different versions of CUMS are used by different laboratories.[3]

Repeated social defeat stress

RSDS is one of the most frequently used models. During each defeat period, a male C57BL/6J mouse (the intruder) is allowed to interact with an aggressive and large male CD1 mouse for 10 min while the intruder is often rapidly investigated, attacked, and defeated by the resident CD1 mouse. C57BL/6J mice are exposed to different resident aggressors for 10 min/day for 10 consecutive days while being alternated daily rather than removing resident aggressors from their home cage.[9],[10],[11],[12]

Forced swim test

FST is often used to infer “depression-like” behavior. In the FST test, a mouse or rat is placed in an inescapable cylinder of water, and following an initial period of struggling, swimming, and climbing, the animal eventually displays a floating or immobile posture.[13]

Tail suspension test

TST is very similar to FST. Briefly, mice are suspended by their tails for 6 min and the amount of time they spend immobile is recorded.[14] Since water is not required, TST is not confounded by challenges to thermoregulation.[15]

Acute electric foot-shock stress

Acute electric foot-shock stress is another method of inducing stress by the introduction of the rate in a Plexiglas chamber (26 cm × 21 cm × 26 cm), with a grid floor made of stainless steel rods (0.3-cm diameter, spaced 1.0 cm apart). Electrical foot shocks of 0.6-mA intensity of 1-s duration with 30-s intershock interval are delivered for 1 h.[16]

  Our Experience with Chronic Versus Acute Models Top

In our experiments, we used CUMS and RSDS as chronic and acute stress models, respectively, to study the effects of social stress on cerebrovascular disease and atherosclerosis in rats. Based on our experience, the success of using CUMS models appears to be dependent on the interplay among three factors: (i) individual differences in susceptibility to stress, both within and among animal populations, (ii) overall severity of microstressors applied, which need to be intense enough to evoke a stress response and variable to prevent habituation resulted from repeated exposure, and (iii) laboratory practices utilized.[17] In addition, another very important factor is the control group. To increase its validity, animals in this group should be fed in a standard condition and kept undisturbed. This will minimize any stress induced by food and/or living conditions and in turn reduce confounding.

On the other hand, to induce acute stress, three versions of the RSDS model were used in which C57 rats were exposed to a different resident aggressor 10 min/day for 10, 20, or 40 consecutive days. Corticosterone levels appeared to be lower in the 40-day stress group compared with the other groups, an observation that could largely be explained by habituation. This phenomenon occurs when there is a repeated exposure to the same stressor resulting in declining activation of the hypothalamic–pituitary–adrenal axis with repeated exposure.[18]

Animal models are invaluable tools to uncover the devastating impact of social stress. In the present review, we re-explored the main animal stress models to further understand both their utility and drawbacks. Based on our experience, each model has its own limitations that need to be addressed when deciding on the most appropriate protocol to use. For example, it is a challenge to conduct chronic model because of its variability especially in the change seen with corticosterone levels. Additionally, the results of CUMS is dependent on the intensity of the stress method used.[17] In addition, in the mild stress model, results seemed to be largely dependent on many environmental factors which necessitate using strict control groups. Finally, using RSDS for acute stress led to positive results following the standard protocol. However, when this model was modified to establish long-term and chronic stress, results were inconsistent.

Further research is essential to refine animal models for stress and depression-like behaviors. This is a key to maximize our understating of the impacts of stress in hopes of developing efficacious therapies.

Financial support and sponsorship

This work was partially supported by Merit Review Award (I01RX-001964-01) from the US Department of Veterans Affairs Rehabilitation R&D Service.

Conflicts of interest

There are no conflicts of interest.

  References Top

Tamashiro KL, Nguyen MM, Sakai RR. Social stress: From rodents to primates. Front Neuroendocrinol 2005;26:27-40.  Back to cited text no. 1
Buynitsky T, Mostofsky DI. Restraint stress in biobehavioral research: Recent developments. Neurosci Biobehav Rev 2009;33:1089-98.  Back to cited text no. 2
Qiao H, Li MX, Xu C, Chen HB, An SC, Ma XM, et al. Dendritic spines in depression: What we learned from animal models. Neural Plast 2016;2016:8056370.  Back to cited text no. 3
Katz RJ, Roth KA, Carroll BJ. Acute and chronic stress effects on open field activity in the rat: Implications for a model of depression. Neurosci Biobehav Rev 1981;5:247-51.  Back to cited text no. 4
Katz RJ. Animal model of depression: Pharmacological sensitivity of a hedonic deficit. Pharmacol Biochem Behav 1982;16:965-8.  Back to cited text no. 5
Willner P, Towell A, Sampson D, Sophokleous S, Muscat R. Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacology (Berl) 1987;93:358-64.  Back to cited text no. 6
Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 2011;69:754-61.  Back to cited text no. 7
Banasr M, Duman RS. Glial loss in the prefrontal cortex is sufficient to induce depressive-like behaviors. Biol Psychiatry 2008;64:863-70.  Back to cited text no. 8
Chou D, Huang CC, Hsu KS. Brain-derived neurotrophic factor in the amygdala mediates susceptibility to fear conditioning. Exp Neurol 2014;255:19-29.  Back to cited text no. 9
Golden SA, Covington HE 3rd, Berton O, Russo SJ. A standardized protocol for repeated social defeat stress in mice. Nat Protoc 2011;6:1183-91.  Back to cited text no. 10
Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ, et al. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 2006;9:519-25.  Back to cited text no. 11
Krishnan V. Defeating the fear: New insights into the neurobiology of stress susceptibility. Exp Neurol 2014;261:412-6.  Back to cited text no. 12
Porsolt RD, Le Pichon M, Jalfre M. Depression: A new animal model sensitive to antidepressant treatments. Nature 1977;266:730-2.  Back to cited text no. 13
Steru L, Chermat R, Thierry B, Simon P. The tail suspension test: A new method for screening antidepressants in mice. Psychopharmacology (Berl) 1985;85:367-70.  Back to cited text no. 14
Cryan JF, Mombereau C. In search of a depressed mouse: Utility of models for studying depression-related behavior in genetically modified mice. Mol Psychiatry 2004;9:326-57.  Back to cited text no. 15
Kaur A, Bali A, Singh N, Jaggi AS. Investigating the stress attenuating potential of furosemide in immobilization and electric foot-shock stress models in mice. Naunyn Schmiedebergs Arch Pharmacol 2015;388:497-507.  Back to cited text no. 16
Willner P. Reliability of the chronic mild stress model of depression: A user survey. Neurobiol Stress 2017;6:68-77.  Back to cited text no. 17
Grissom N, Bhatnagar S. Habituation to repeated stress: Get used to it. Neurobiol Learn Mem 2009;92:215-24.  Back to cited text no. 18


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