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Abstract
Depression is an extremely heterogeneous disorder. Diverse molecular mechanisms have been suggested to underlie its etiology. To understand the molecular mechanisms responsible for this complex disorder, researchers have been using animal models extensively, namely mice from various genetic backgrounds and harboring distinct genetic modifications. The use of numerous mouse models has contributed to enrich our knowledge on depression. However, accumulating data also revealed that the intrinsic characteristics of each mouse strain might influence the experimental outcomes, which may justify some conflicting evidence reported in the literature. To further understand the impact of the genetic background, we performed a multimodal comparative study encompassing the most relevant parameters commonly addressed in depression, in three of the most widely used mouse strains: Balb/c, C57BL/6, and CD-1. Moreover, female mice were selected for this study taken into account the higher prevalence of depression in women and the fewer animal studies using this gender. Our results show that Balb/c mice have a more pronounced anxious-like behavior than CD-1 and C57BL/6 mice, whereas C57BL/6 animals present the strongest depressive-like trait. Furthermore, C57BL/6 mice display the highest rate of proliferating cells and brain-derived neurotrophic factor (Bdnf) expression levels in the hippocampus, while hippocampal dentate granular neurons of Balb/c mice show smaller dendritic lengths and fewer ramifications. Of notice, the expression levels of inducible nitric oxide synthase (iNos) predict 39.5% of the depressive-like behavior index, which suggests a key role of hippocampal iNOS in depression. Overall, this study reveals important interstrain differences in several behavioral dimensions and molecular and cellular parameters that should be considered when preparing and analyzing experiments addressing depression using mouse models. It further contributes to the literature by revealing the predictive value of hippocampal iNos expression levels in depressive-like behavior, irrespectively of the mouse strain.
Highlights
MATERIALS AND METHODSDepression is a heterogeneous disorder which underlying causes are still poorly understood
For the anxious-like behavior, tested using the ratio of distance travaled in the center vs. total distance of the open field test (OFT) [Figure 1C; F(2, 47) = 7.06, p = 0.0021, η2 = 0.23], Balb/c mice showed a more pronounced anxious-like behavior by displaying a lower percentage of distance traveled in the center of the OFT’s arena, in comparison to C57BL/6 mice (p = 0.0014)
In this work we performed a multimodal assessment of the three most widely used mouse strains (CD-1, C57BL/6, and Balb/c) and analyzed behavioral, cellular, and molecular parameters that have been associated with the etiology of depression
Summary
MATERIALS AND METHODSDepression is a heterogeneous disorder which underlying causes are still poorly understood. Balb/c mice were shown to present a marked anxiety trait (Michalikova et al, 2010; An et al, 2011), whereas C57BL/6 animals were shown to display a high immobility time in the forced swimming test (FST) and in the tail suspension test (TST), suggestive of more pronounced depressive-like behavior (Yoshikawa et al, 2002; Miller et al, 2010).
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