The lonely mouse: verification of a separationinduced model of depression in female mice. Behav Brain Res
Psychology Department and Neuroscience Institute, Dalhousie University, Halifax, Nova Scotia, Canada, B3H 4J1 Behavioural brain research
(Impact Factor: 3.03).
02/2010; 207(1):196-207. DOI: 10.1016/j.bbr.2009.10.006
Animal models of depression seldom test females, even though women are twice as likely as men to suffer from major depressive disorder. Since female mice are sensitive to social isolation, we tested a separation-based model of depression in three experiments. In experiment 1 female C57BL/6J mice were housed in three conditions: isolated (housed individually from 8 weeks of age), separated (housed in groups and then separated and housed individually at 23 weeks of age) and grouped (housed in groups from 8 weeks of age). At 24 weeks of age, there was a significant increase in weight and in immobility in individually housed mice in the forced swim test (FST) and tail suspension test (TST), a reduction in transitions in the L/D box, a reduced startle response and reduced prepulse inhibition, but no differences in cued or context fear conditioning. Experiment 2 showed that fluoxetine treatment administered via drinking water attenuated depressive-like behaviour in the FST and TST in individually housed female C57BL/6J mice, but had no effect on anxiety-like behaviour. Experiment 3 found that group-housed females had higher baseline corticosterone (CORT) levels than isolated females and fluoxetine had no effect on CORT levels. Thus, separation from group housing is a reliable and valid method for inducing depression-like behaviour in female mice. This procedure is both versatile, allowing for the study of genetic and environmental interactions, and accessible, making it useful for studying depression and testing new drugs for its treatment.
Available from: Willem J Kop
- "Psychological distress and its biobehavioral correlates can be systematically studied using animal models that change social and/or environmental factors (e.g.,   for studies in rats). Manipulation of the housing condition is a well-established paradigm to induce distress in rodent models    and can be used to differentiate the effects of social isolation and crowding on biobehavioral and HF-related functional measures compared to the standard condition in which animals are housed in pairs. "
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Heart failure (HF) prognosis is negatively influenced by adverse environmental conditions associated with psychological distress and depression. The underlying mechanisms are not well understood because of insufficient experimental control in prior clinical and epidemiological studies. Using a validated animal model we examined whether distress-producing environmental manipulations (social isolation and crowding) increase HF progression following myocardial infarction (MI).
MI was induced using coronary artery ligation in 8-week old male Wistar rats (N=52) and results were compared to sham surgery (N=24). Housing conditions were randomly assigned at 5days post MI or sham surgery (1/cage=isolation, 2/cage=standard reference condition, or 4/cage=crowding) and continued for 17weeks until the end of observation. The open field test was used to test behavioral responses. Echocardiograms were obtained at weeks 8 and 16, and left ventricular (LV) weight at week 17.
Housing conditions increased behavioral markers of distress (p=0.046) with the strongest effects for the isolated (1/cage) (p=0.022). MI did not increase distress-related behaviors compared to sham. MI-surgery resulted in characteristic HF indices (left ventricular ejection fraction (LVEF) at week 16=46±12% vs. 80±7% in sham, p<0.001). Housing condition was not related to LVEF or LV weight (p>0.10).
Adverse environmental conditions, particularly isolated housing, produce increases in some of the behavioral indicators of distress. No effects of housing were found on post-MI progression of HF. The distress-HF associations observed in humans may therefore reflect common underlying factors rather than an independent causal pathway. Stronger environmental challenges may be needed in future animal research examining distress as related HF progression.
- "The housing environment of mice is often ignored, but differences in the vivarium environment, home cage features, diet, social versus individual housing, and cage enrichment can significantly affect the behavior of mice. In addition, predatory stress of rat to mice (due to long-term housing of rats and mice in the same secondary enclosure) and some housing conditions may induce selective stress among the animals, altering their behavioral performance   . Even changing the mice from social housing to individual housing may be particularly stressful . "
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ABSTRACT: Preclinical studies are essential for translation to disease treatments and effective use in clinical practice. An undue emphasis on single approaches to Alzheimer's disease (AD) appears to have retarded the pace of translation in the field, and there is much frustration in the public about the lack of an effective treatment. We critically reviewed past literature (1990-2014), analyzed numerous data, and discussed key issues at a consensus conference on Brain Ageing and Dementia to identify and overcome roadblocks in studies intended for translation. We highlight various factors that influence the translation of preclinical research and highlight specific preclinical strategies that have failed to demonstrate efficacy in clinical trials. The field has been hindered by the domination of the amyloid hypothesis in AD pathogenesis while the causative pathways in disease pathology are widely considered to be multifactorial. Understanding the causative events and mechanisms in the pathogenesis are equally important for translation. Greater efforts are necessary to fill in the gaps and overcome a variety of confounds in the generation, study design, testing, and evaluation of animal models and the application to future novel anti-dementia drug trials. A greater variety of potential disease mechanisms must be entertained to enhance progress.
- "We next performed a similar experiment but in this case the cells generated one week before training were labeled using a GFP-expressing retrovirus (Table 2, Batch 5, Fig. 2H). Given that the effect of learning on cell survival has been shown to be more pronounced in female rats compared to male (Dalla et al., 2009) and that individual housing (Martin and Brown, 2010) may reduce the ability of the brain to respond to environmental challenges, female C57BL/6J mice housed in groups of 4 were used. Although female mice learned the task (Fig. 7A), dendritic tree measurements revealed no differences between "
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ABSTRACT: New dentate granule cells (GCs) are generated in the hippocampus throughout life. These adult-born neurons are required for spatial learning in the Morris water maze (MWM). In rats, spatial learning shapes the network by regulating their number and dendritic development. Here we explored whether such modulatory effects exist in mice. New GCs were tagged using thymidine analogs or a GFP-expressing retrovirus. Animals were exposed to a reference memory protocol for 10 to 14 days (spaced training) at different times after newborn cells labeling. Cell proliferation, cell survival, cell death, neuronal phenotype and dendritic and spine development were examined using immunohistochemistry. Surprisingly, spatial learning did not modify any of the parameters under scrutiny including cell number and dendritic morphology. These results suggest that although new GCs are required in mice for spatial learning in the MWM, they are, at least for the developmental intervals analyzed here, refractory to behavioral stimuli generated in the course of learning in the MWM. This article is protected by copyright. All rights reserved.
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