Behavioural assays to model cognitive and affective dimensions of depression and anxiety in rats

Abstract

Animal models have been used extensively to investigate neuropsychiatric disorders, such as depression, and their treatment. However, the aetiology and pathophysiology of many such disorders are largely unknown, which makes validation of animal models particularly challenging. Furthermore, many diagnostic symptoms are difficult to define, operationalize and quantify, especially in experimental animals such as rats. Thus, rather than attempting to model complex human syndromes such as depression in their entirety, it can be more productive to define and model components of the illness that may account for clusters of co-varying symptoms, and that may share common underlying neurobiological mechanisms. In preclinical investigations of the neural regulatory mechanisms linking stress to depression and anxiety disorders, as well as the mechanisms by which chronic treatment with antidepressant drugs may exert their beneficial effects in these conditions, we have employed a number of behavioural tests in rats to model specific cognitive and anxiety-like components of depression and anxiety disorders. In the present study, we review the procedures for conducting four such behavioural assays: the attentional set-shifting test, the elevated-plus maze, the social interaction test and the shock-probe defensive burying test. The purpose is to serve as a guide to the utility and limitations of these tools, and as an aid in optimising their use and productivity.

Figure 1

Schematic diagram of the attentional set shifting test arena (dimensions: 40 x 71 x 20 cm, l x w x h). A fixed Plexiglas panel divides the distal third of the arena into two sections, and a digging pot is placed in each section. A removable divider separates the proximal third of the arena from the rest, forming a start box. To begin a trial, a rat is placed in the start box, and the divider lifted. Reprinted, with permission from Elsevier, from (33).

Figure 2

Data from a representative study showing trials to criterion of six consecutive correct responses (expressed as mean ± SEM) for each stage of the AST. Significantly more trials were required to reach criterion during the ED set-shift compared to other tasks (n=6; *p < 0.05 compared to SD, CD, R1, R2 and ID). Abbreviations: SD, simple discrimination; CD, compound discrimination; R1, reversal 1; ID, intradimensional set-shift; R2, reversal 2; ED, extradimensional set-shift; R3, reversal 3. Adapted and reprinted, with permission from Elsevier, from (33).

Figure 3

Schematic diagram of a typical elevated plus-maze apparatus.

Figure 4

Results of a representative experiment showing the anxiogenic effect of acute stress on exploratory behavior in the open arms of the EPM. Acute immobilization stress (5 min), administered 20 min before testing, significantly decreased both OTR for Time (A) and OTR for Entries (B) compared to unstressed controls (*p<0.01, n=5–8). In this study, all rats had been previously implanted bilaterally with guide cannulae aimed at the central nucleus of the amygdala, and all received bilateral vehicle microinjections (0.25 μl/side) 3 min before acute stress exposure, or at an equivalent time (23 min prior to testing) in the unstressed controls. Adapted and reprinted, with permission from Elsevier, from (52).

Figure 5

Results of a representative experiment showing the anxiogenic effect of acute stress on social behavior in the SI test. Acute immobilization stress (5 min), administered 20 min before testing, significantly decreased SI Time compared to unstressed controls (*p<0.01, n=6–8). In this study, all rats were implanted bilaterally with guide cannulae aimed at the central nucleus of the amygdala, and all received bilateral vehicle microinjections (0.25 μl/side) 3 min before acute stress, or at an equivalent time (23 min prior to testing) in the unstressed controls. Adapted and reprinted, with permission from Elsevier, from (52).

Figure 6

Bilateral microinjections, administered into the lateral septum (LS), of either the α₁-adrenergic receptor antagonist benoxathian (2.0 nmole/side), or a cocktail of β₁β₂-receptor antagonists betaxolol + ICI 118,551 (1.0 nmole each/side), attenuated defensive burying behavior and increased immobility on the shock-probe defensive burying test (n=8–18/group; *p<0.05 compared to vehicle control group). Note that in this experiment, because a number of LS-implanted rats did not exhibit any burying behavior, burying time was analyzed non-parametrically; nonetheless, only the reduction caused by benoxathian achieved significance in comparison to vehicle-treated rats in this analysis. By contrast, immobility was normally distributed, and both of the drug treatment effects were significant for this measure. Adapted and reprinted, with permission from Elsevier, from (35).