Role of the amygdala in antidepressant effects on hippocampal cell proliferation and survival and on depression-like behavior in the rat

Abstract

The stimulation of adult hippocampal neurogenesis by antidepressants has been associated with multiple molecular pathways, but the potential influence exerted by other brain areas has received much less attention. The basolateral complex of the amygdala (BLA), a region involved in anxiety and a site of action of antidepressants, has been implicated in both basal and stress-induced changes in neural plasticity in the dentate gyrus. We investigated here whether the BLA modulates the effects of the SSRI antidepressant fluoxetine on hippocampal cell proliferation and survival in relation to a behavioral index of depression-like behavior (forced swim test). We used a lesion approach targeting the BLA along with a chronic treatment with fluoxetine, and monitored basal anxiety levels given the important role of this behavioral trait in the progress of depression. Chronic fluoxetine treatment had a positive effect on hippocampal cell survival only when the BLA was lesioned. Anxiety was related to hippocampal cell survival in opposite ways in sham- and BLA-lesioned animals (i.e., negatively in sham- and positively in BLA-lesioned animals). Both BLA lesions and low anxiety were critical factors to enable a negative relationship between cell proliferation and depression-like behavior. Therefore, our study highlights a role for the amygdala on fluoxetine-stimulated cell survival and on the establishment of a link between cell proliferation and depression-like behavior. It also reveals an important modulatory role for anxiety on cell proliferation involving both BLA-dependent and -independent mechanisms. Our findings underscore the amygdala as a potential target to modulate antidepressants' action in hippocampal neurogenesis and in their link to depression-like behaviors.

Figure 1. Schematic plan of experimental procedures and timetable.

After handling (H), rats were submitted to stereotaxic surgery for BLA or sham lesions. After recovery, animals were handled again and levels of anxiety were characterized using the Elevated Plus Maze (EPM). Next, chronic fluoxetine treatment was initiated and BrdU was injected after twenty one days of drug administration. After interruption of fluoxetine treatment, depression-like behavior was evaluated using the Forced Swim Test (FST) and then sacrificed.

Figure 2. Effects of chronic treatment with fluoxetine on levels of cell proliferation and survival in the dentate gyrus of the hippocampus and depression-like behavior during the forced swimming test after neurochemical lesions of the basolateral complex of the amygdala (A,B,C) and according to anxiety (D,E,F).

Error bars represent the standard error of the mean. [**p<0.01, *p<0.05 vs. corresponding vehicle group (ANOVA main effect); ++p<0.01, +p<0.05 vs. corresponding vehicle group (ANOVA simple main effect).

Figure 3. Path analysis and fit test for the general model (χ² = 1.21, df = 2, p = 0.751; CFI = 1.00; RMSEA<0.01, p = 0.792).

Significant paths (*p<0.05; **p<0.01) are in black and non significant in gray. The squared multiple correlations (R ²) of the endogenous variables are located in their right inferior corner in gray and italics.

Figure 4. Path analysis for the models according to the lesion groups.

A. Model fit was tested separately for the sham lesion group (χ² = 5.42, df = 2, p = 0.066; CFI = 0.48; RMSEA = 0.21, p = 0.083) and B. for the BLA lesion group (χ² = 0.52, df = 2, p = 0.771; CFI = 1.00; RMSEA<0.01, p = 0.783). Significant paths (p<0.05; **p<0.01) are in black and non significant in gray. The squared multiple correlations (R ²) of the endogenous variables are located in their right inferior corner in gray and italics.

Figure 5. Path analysis for the models according to the anxiety groups.

A. Model fit was tested separately for the low anxiety group (χ² = 0.26, df = 1, p = 0.611; CFI = 1.00; RMSEA<0.01, p = 0.621) and B. for the high anxiety group (χ² = 0.01, df = 1, p = 0.924; CFI = 1.00; RMSEA<0.01, p = 0.927). Significant paths (p<0.05; **p<0.01) are in black and non significant in gray. The squared multiple correlations (R ²) of the endogenous variables are located in their right inferior corner in gray and italics.

Figure 6. Path analysis for the models according to the drug treatment groups.

A. Model fit was tested separately for the vehicle group (χ² = 0.07, df = 1, p = 0.784; CFI = 1.00; RMSEA<0.01, p = 0.791) and B. for the fluoxetine group (χ² = 2.00, df = 1, p = 0.157; CFI = 0.94; RMSEA = 0.17, p = 0.175). Significant paths (p<0.05; **p<0.01) are in black and non significant in gray. The squared multiple correlations (R ²) of the endogenous variables are located in their right inferior corner in gray and italics.