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Update in the methodology of the chronic stress paradigm: internal control matters.

Strekalova T, Couch Y, Kholod N, Boyks M, Malin D, Leprince P, Steinbusch HM - Behav Brain Funct (2011)

Bottom Line: Here, we discuss a variant of the standard stress paradigm, which results in anhedonia.This anhedonic state was defined by a decrease in sucrose preference that was not exhibited by all animals.This is illustrated, for instance, by distinct physiological and molecular profiles in anhedonic and non-anhedonic groups subjected to stress.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, Netherlands. t.strekalova@maastrichtuniversity.nl

ABSTRACT
To date, the reliability of induction of a depressive-like state using chronic stress models is confronted by many methodological limitations. We believe that the modifications to the stress paradigm in mice proposed herein allow some of these limitations to be overcome. Here, we discuss a variant of the standard stress paradigm, which results in anhedonia. This anhedonic state was defined by a decrease in sucrose preference that was not exhibited by all animals. As such, we propose the use of non-anhedonic, stressed mice as an internal control in experimental mouse models of depression. The application of an internal control for the effects of stress, along with optimized behavioural testing, can enable the analysis of biological correlates of stress-induced anhedonia versus the consequences of stress alone in a chronic-stress depression model. This is illustrated, for instance, by distinct physiological and molecular profiles in anhedonic and non-anhedonic groups subjected to stress. These results argue for the use of a subgroup of individuals who are negative for the induction of a depressive phenotype during experimental paradigms of depression as an internal control, for more refined modeling of this disorder in animals.

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Differential stress-induced changes in the sucrose test parameters in anhedonic and non-anhedonic mice. (A) Sucrose preference in the anhedonic group is significantly lower than in non-anhedonic and control mice after 2.5, 3.5 and 4 weeks of stress. (B) Sucrose intake in the anhedonic group is significantly increased after 2.5 weeks of stress and significantly decreased after 3.5 weeks of stress (vs. non-anhedonic group) and after 4 weeks of stress (vs. control and non-anhedonic group). Non-anhedonic mice show elevated sucrose intake after 2.5 and 3.5 weeks of stress. (C) Water intake is elevated in the anhedonic animals after 2.5 - 4 weeks of stress (vs. control and non-anhedonic group). In the non-anhedonic group; water intake is increased after 2.5 weeks of stress as compared to control. (D) Total liquid intake is elevated both in the anhedonic and in non-anhedonic animals after 2.5 and 3.5 weeks of stress (vs. control group). After 2.5 weeks, anhedonic mice show significantly higher total liquid intake than non-anhedonic mice. Parameters of the sucrose test are expressed as a percentage of the mean values of the control group, and compared between anhedonic (dashed line) and non-anhedonic (plain line) groups during a 4-week stress procedure as mean ± (SEM) (*p < 0.05 vs. control group; #p < 0.05 vs. non-anhedonic group; Mann-Whitney).
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Figure 2: Differential stress-induced changes in the sucrose test parameters in anhedonic and non-anhedonic mice. (A) Sucrose preference in the anhedonic group is significantly lower than in non-anhedonic and control mice after 2.5, 3.5 and 4 weeks of stress. (B) Sucrose intake in the anhedonic group is significantly increased after 2.5 weeks of stress and significantly decreased after 3.5 weeks of stress (vs. non-anhedonic group) and after 4 weeks of stress (vs. control and non-anhedonic group). Non-anhedonic mice show elevated sucrose intake after 2.5 and 3.5 weeks of stress. (C) Water intake is elevated in the anhedonic animals after 2.5 - 4 weeks of stress (vs. control and non-anhedonic group). In the non-anhedonic group; water intake is increased after 2.5 weeks of stress as compared to control. (D) Total liquid intake is elevated both in the anhedonic and in non-anhedonic animals after 2.5 and 3.5 weeks of stress (vs. control group). After 2.5 weeks, anhedonic mice show significantly higher total liquid intake than non-anhedonic mice. Parameters of the sucrose test are expressed as a percentage of the mean values of the control group, and compared between anhedonic (dashed line) and non-anhedonic (plain line) groups during a 4-week stress procedure as mean ± (SEM) (*p < 0.05 vs. control group; #p < 0.05 vs. non-anhedonic group; Mann-Whitney).

Mentions: Interestingly, in populations with an initially low percentage of submissive animals (15-20%), all submissive mice develop anhedonia. In populations with a high percentage of submissive individuals (>50%), the percentage of non-submissive (dominant or aggressive) animals susceptible to anhedonia is significantly lower in comparison to a submissive cohort of mice. Remarkably, social characteristics of animal batches, such as a percentage of aggressive mice, were found to be related to behavioural patterns during stress. For example, changes in parameters such as sucrose intake and preference, and total liquid intake during different phases of the course of stress exposure were observed over a several years in our lab, under identical experimental conditions [39,47]. For instance, in populations with an initially low percentage of submissive animals, statistically significant decreases in sucrose preference in the stressed group occur at 3.5 weeks after introduction of the stressor. Interestingly, in these animals, stress exposure causes an increase in sucrose intake and preference at the beginning of the stress procedure, and leads to a slight elevation of water intake. In contrast, in experimental groups containing high percentage of submissive individuals (>50%) the drop in sucrose preference is detected much earlier, after 2.5 weeks of stress; these animals demonstrate an increase in sucrose intake and sharp elevation of water consumption [Figures 1 and 2B; [44,48]]. Over our 6 years of studying them, the C57BL/6N strain of mice have shown a remarkable range, from 15-85%, in the proportion of individuals with submissive social characteristics.


Update in the methodology of the chronic stress paradigm: internal control matters.

Strekalova T, Couch Y, Kholod N, Boyks M, Malin D, Leprince P, Steinbusch HM - Behav Brain Funct (2011)

Differential stress-induced changes in the sucrose test parameters in anhedonic and non-anhedonic mice. (A) Sucrose preference in the anhedonic group is significantly lower than in non-anhedonic and control mice after 2.5, 3.5 and 4 weeks of stress. (B) Sucrose intake in the anhedonic group is significantly increased after 2.5 weeks of stress and significantly decreased after 3.5 weeks of stress (vs. non-anhedonic group) and after 4 weeks of stress (vs. control and non-anhedonic group). Non-anhedonic mice show elevated sucrose intake after 2.5 and 3.5 weeks of stress. (C) Water intake is elevated in the anhedonic animals after 2.5 - 4 weeks of stress (vs. control and non-anhedonic group). In the non-anhedonic group; water intake is increased after 2.5 weeks of stress as compared to control. (D) Total liquid intake is elevated both in the anhedonic and in non-anhedonic animals after 2.5 and 3.5 weeks of stress (vs. control group). After 2.5 weeks, anhedonic mice show significantly higher total liquid intake than non-anhedonic mice. Parameters of the sucrose test are expressed as a percentage of the mean values of the control group, and compared between anhedonic (dashed line) and non-anhedonic (plain line) groups during a 4-week stress procedure as mean ± (SEM) (*p < 0.05 vs. control group; #p < 0.05 vs. non-anhedonic group; Mann-Whitney).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3111355&req=5

Figure 2: Differential stress-induced changes in the sucrose test parameters in anhedonic and non-anhedonic mice. (A) Sucrose preference in the anhedonic group is significantly lower than in non-anhedonic and control mice after 2.5, 3.5 and 4 weeks of stress. (B) Sucrose intake in the anhedonic group is significantly increased after 2.5 weeks of stress and significantly decreased after 3.5 weeks of stress (vs. non-anhedonic group) and after 4 weeks of stress (vs. control and non-anhedonic group). Non-anhedonic mice show elevated sucrose intake after 2.5 and 3.5 weeks of stress. (C) Water intake is elevated in the anhedonic animals after 2.5 - 4 weeks of stress (vs. control and non-anhedonic group). In the non-anhedonic group; water intake is increased after 2.5 weeks of stress as compared to control. (D) Total liquid intake is elevated both in the anhedonic and in non-anhedonic animals after 2.5 and 3.5 weeks of stress (vs. control group). After 2.5 weeks, anhedonic mice show significantly higher total liquid intake than non-anhedonic mice. Parameters of the sucrose test are expressed as a percentage of the mean values of the control group, and compared between anhedonic (dashed line) and non-anhedonic (plain line) groups during a 4-week stress procedure as mean ± (SEM) (*p < 0.05 vs. control group; #p < 0.05 vs. non-anhedonic group; Mann-Whitney).
Mentions: Interestingly, in populations with an initially low percentage of submissive animals (15-20%), all submissive mice develop anhedonia. In populations with a high percentage of submissive individuals (>50%), the percentage of non-submissive (dominant or aggressive) animals susceptible to anhedonia is significantly lower in comparison to a submissive cohort of mice. Remarkably, social characteristics of animal batches, such as a percentage of aggressive mice, were found to be related to behavioural patterns during stress. For example, changes in parameters such as sucrose intake and preference, and total liquid intake during different phases of the course of stress exposure were observed over a several years in our lab, under identical experimental conditions [39,47]. For instance, in populations with an initially low percentage of submissive animals, statistically significant decreases in sucrose preference in the stressed group occur at 3.5 weeks after introduction of the stressor. Interestingly, in these animals, stress exposure causes an increase in sucrose intake and preference at the beginning of the stress procedure, and leads to a slight elevation of water intake. In contrast, in experimental groups containing high percentage of submissive individuals (>50%) the drop in sucrose preference is detected much earlier, after 2.5 weeks of stress; these animals demonstrate an increase in sucrose intake and sharp elevation of water consumption [Figures 1 and 2B; [44,48]]. Over our 6 years of studying them, the C57BL/6N strain of mice have shown a remarkable range, from 15-85%, in the proportion of individuals with submissive social characteristics.

Bottom Line: Here, we discuss a variant of the standard stress paradigm, which results in anhedonia.This anhedonic state was defined by a decrease in sucrose preference that was not exhibited by all animals.This is illustrated, for instance, by distinct physiological and molecular profiles in anhedonic and non-anhedonic groups subjected to stress.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, Netherlands. t.strekalova@maastrichtuniversity.nl

ABSTRACT
To date, the reliability of induction of a depressive-like state using chronic stress models is confronted by many methodological limitations. We believe that the modifications to the stress paradigm in mice proposed herein allow some of these limitations to be overcome. Here, we discuss a variant of the standard stress paradigm, which results in anhedonia. This anhedonic state was defined by a decrease in sucrose preference that was not exhibited by all animals. As such, we propose the use of non-anhedonic, stressed mice as an internal control in experimental mouse models of depression. The application of an internal control for the effects of stress, along with optimized behavioural testing, can enable the analysis of biological correlates of stress-induced anhedonia versus the consequences of stress alone in a chronic-stress depression model. This is illustrated, for instance, by distinct physiological and molecular profiles in anhedonic and non-anhedonic groups subjected to stress. These results argue for the use of a subgroup of individuals who are negative for the induction of a depressive phenotype during experimental paradigms of depression as an internal control, for more refined modeling of this disorder in animals.

Show MeSH
Related in: MedlinePlus