Research reportCorrelations between behaviours in the elevated plus-maze and sensitivity to unpredictable subchronic mild stress: evidence from inbred strains of mice
Introduction
Over the past decades, many patients have been shown to exhibit both anxiety and depressive symptoms, raising questions about comorbidity between anxiety and mood disorders [3], [4], [36], [62]. Different hypothesises have been proposed as to this relationship. First, anxiety and depression have been described as distinct disorders that would often co-occur. Second, this comorbidity was explained by a sequential relationship, high anxiety may being a risk factor for the occurrence of mood disorders [21], [28], [44]. Third, some authors [3], [52], [53] supported the concept of a mixed anxiety–depression disorder, a pathology that was incorporated in the International Classification of Disease (ICD-10) [61]. Finally, Clark and Watson [13] proposed a tripartite model based upon a dimensional construct including components shared by anxiety and depression (negative affects, general distress) and specific features (autonomic hyperarousal and somatic tension for anxiety and absence of positive affect for depression). When experiencing negative affect, individuals may select preferentially the negative component of a given event thus amplifying the perception of threat [10], [12], [17]. In sum, the mechanisms underlying the comorbidity of depression and anxiety remain rather obscure and require further investigation. Animal models remain indispensable tools for this.
Several procedures have been used to study depressive-like behaviours or the efficacy of antidepressive treatments in animals, including the forced swim test and the unpredictable chronic mild stress. The former was proposed by Porsolt et al. for the study of the effectiveness of antidepressant treatments both in rats and in mice [45], [46]. It is mainly based upon the antidepressant-induced decrease of immobility exhibited by rodents introduced in a water tank [16], [34]. The chronic mild stress was introduced by Willner et al. [58] and described as a procedure mimicking some aspects of the etiology of human depression. Rats subjected to this procedure display a loss of sucrose preference interpreted as “anhedonia”, a core symptom of major depression [29], [30], [39], [41], [63]. This is reversed by chronic treatment with antidepressants [38], [43], [59], [60]. These two tests are different in many aspects, the forced swim test being rather considered as a bio-assay for antidepressants and the chronic mild stress as an animal model of depression. Indeed, contrarily to the chronic mild stress, the forced swim test does not mimic the causal or the phenomenological features of major depression.
A large inter-individual variability can be observed in the response of rodents confronted to the forced swim test [35], [54] as well as to the chronic stress [42]. This variability can be related to strain differences. In the forced swim test, different reactions have been observed according to the strain used [2], [33]. Variability may also be related to inter-individual differences in the reaction to threat stimuli. Some authors have investigated this relationship [1], [26] using the forced swim test and the elevated plus-maze without finding any relationship. However, this study did not use chronic mild stress.
The present study was aimed at investigating whether anxiety of animals may predict their further susceptibility to a depressive-like situation such as the forced swim test or an unpredictable subchronic mild stress (USMS), a new version of the chronic mild stress. In order to obtain inter-strain variability, we used eight different strains of mice. Indeed, strain differences in anxiety tests have been largely studied in this species in various situations [7], [8], [11], [14], [24], [35], [55] and some data are also available on strain differences in the forced swim test [33], [35] and in sensitivity to USMS [19], [38].
Anxiety-like behaviour was assessed in two tests: the elevated plus-maze [31] and the free exploratory paradigm [6], [23]. These situations have been proposed to model state and trait anxiety, respectively [5]. In the former, mice are forced to enter in a new area, a procedure described to be very stressful in this species. In the later, mice have free access to a new area, which is less stressful, as no raise in corticosterone level is observed in such conditions [39]. After anxiety-like behaviour assessment, mice were exposed to the forced swim test and then subjected to a 2-week chronic USMS procedure. In this last situation, USMS-induced sucrose preference changes, body weight changes and state of the fur changes were recorded. Indeed, when subjected to USMS, mice display soiled fur and piloerection [19], [37] that is reversed by chronic antidepressants [18], [25], [50]. The responses obtained in these two paradigms were then related to the initial anxiety to determine potential relationships.
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Animals
Eight inbred strains of male mice, aged of 6 weeks at their arrival in our lab, were used: BALB/c ByJ, C57BL/6 J, DBA/2 J, C3H/He J, CBA J (obtained from Centre d’Elevage Janvier, Le Genest Saint Isle, France), FVB/NA and 129/Sv J (from the CDTA of Orleans, France), BA (reared in the Laboratory, originally from the Institut de Transgénose, Orleans) (N = 12 for each group). Animals were kept under standard laboratory conditions with food and water ad libitum. Experimental room was maintained on
Anxiety-like behaviours in the eight strains
Over all strains, there were significant differences in the elevated plus-maze for rearing (F[7, 88] = 8.9, P < 0.01), protected head-dips (F[7, 87] = 4.2, P < 0.01), unprotected head-dips (F[7, 87] = 3, P < 0.01), unprotected stretched postures (F[7, 87] = 2.3, P < 0.05), closed arms returns (F[7, 87] = 2.7, P < 0.01) and open arms avoidance (F[7, 87] = 2, P < 0.05). No differences were seen for percent of open arms entries (F[7, 87] = 1.9, P = 0.08) and for protected stretched postures (F[7,
Discussion
In the present study, we found strain differences in both anxiety tests and depression-like tests. Anxiety-like behaviour was significantly associated with the behaviour in the forced swim test and the sensitivity to the subchronic unpredictable mild stress. However, this association, even if significant, is a modest one (contributions ranging from 14 to 31%).
The strain variability recorded in the two anxiety tests confirms previous data [7], [14], [24]. In the elevated plus-maze, the manner
Acknowledgements
This study was supported by the Post-Genome Grant from French Ministere de l’Industrie. Authors also greatly acknowledge Raymond Jegat who built the experimental apparatus and Hugo Bourne and Anna Malbos for helping in English text. Further, we thank Wim Crusio who advised us in the choice of the different strains.
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2019, Applied Animal Behaviour ScienceCitation Excerpt :All these data consistently pointed out to a much higher level of anxiety in BALB/cJ dams and of locomotion and exploratory behavior in Swiss Webster dams. In fact, anxiety is a complex trait, but has a strong genetic basis (Clément et al., 2002; Ducottet and Belzung, 2005) and BALB/cJ mice have shown higher levels of anxiety compared to other inbred strains (Okva et al., 2013), to the point of being recommended as a model for “pathological” anxiety (Belzung and Griebel, 2001). Increased head scanning time, combined with decreased time on closed arms, were observed in pregnant BALB/cJ dams, compared to their non-pregnant counterparts.