Strain Differences and Effects of Environmental Manipulation on Astrocytes (Glial Fibrillary Acidic Protein), Glucocorticoid Receptor, and Microglia (Iba1) Immunoreactivity between Wistar-Kyoto and Wistar Females.

BACKGROUND: Depression is often associated with an increase in hypothalamic-pituitary-adrenal (HPA) axis reactivity and immune response. To investigate this relationship, we examined the consequences of environmental manipulation on the neural correlates of the HPA axis and immune response in an animal model of depression, the Wistar-Kyoto (WKY) rat. Additionally, female animals are often overlooked in preclinical research because of the hormone fluctuations inherent in the estrous cycle. METHODS: Female rats were randomly assigned to 1 of 3 environments for 30 days: (1) environmental enrichment (EE), (2) standard housing (SH), and (3) isolated housing (IH). Immunoreactivity of astrocytes (glial fibrillary acidic protein [GFAP]), glucocorticoid receptors (GRs), and microglia (Iba1) in the hippocampus and amygdala were measured using immunohistochemistry. RESULTS: WKY animals had significantly more GR staining area and Iba1 staining intensity and area in the CA1 of the hippocampus. In enriched Wistar rats, GFAP staining intensity and area were greater in the CA1. A trend towards a greater percent of area stained with GR was found in WKY animals as compared to that of the Wistar animals. This was due to WKY females in EE having significantly higher GR staining intensity and area in the amygdala as compared to that of animals in SH. DISCUSSION: These strain differences lend support to the use of WKY animals as an animal model of depression. Furthermore, due to the effects of EE on GFAP and GR staining in WKY females, we suggest that EE can be used as an intervention to potentially alleviate the negative effects of depression.

Corticosterone and immune cytokine characterization following environmental manipulation in female WKY rats.

This study investigated the effects of environmental manipulation on female Wistar Kyoto (WKY), an animal model of depression, and female Wistar rats. It explored the function of the hypothalamic-pituitary-adrenal axis (HPA) and immune system, as they have both been implicated in the pathophysiology of depression. A further goal was to characterize the immune cytokine concentrations of female WKY rats as this has, to our knowledge, never been documented. Animals were assigned to enriched, standard, or impoverished housing for four consecutive weeks. Following this, serum was collected at baseline and post-stress periods to measure the concentration of corticosterone, TNF-α, IL-1ß, and IL-10. WKY animals had significantly higher corticosterone levels at the post-stress time-point than their Wistar counterparts. WKY females in isolation tended to have the lowest corticosterone levels which may indicate that they prefer a solitary environment, a symptom of depression. We observed a significant decrease in TNF-α after enrichment in the Wistar strain. A similar decrease in TNF-α was found in the WKY strain, but there was no difference between environmental conditions. There was a significant increase in pre- to post-stress IL-10 level in both Wistar and WKY animals. WKY females had a significantly lower level of IL-1ß as compared to the Wistar animals at both pre- and post-stress time points. Given this strain difference, it is likely that the WKY rats had a dysregulated HPA axis which further influenced their circulating cytokine levels. Further studies are needed to examine how this pattern of findings plays a role in the pathophysiology of depression.

Environmental manipulation affects depressive-like behaviours in female Wistar-Kyoto rats.

While the efficacy of pharmacological interventions to treat depression has been well-studied in animal models, much less work has been done to shed light on how changes in the immediate environment can impact behaviour. Furthermore, most studies have focused on male rodents despite the prevalence of mood disorders in women. In this study, 36 Wistar Kyoto (validated animal model of depression) and 36 Wistar (control) female rats were used to examine the effects of environmental manipulation on depressive- and anxiety-like behaviours. Animals were assigned to one of three groups: standard (3 rats/cage), enriched (6 rats/cage plus physical enrichment), and isolation (1 rat/cage) housing. The elevated plus maze (EPM) and forced swim test (FST) were conducted prior to, and four weeks after environmental assignment to measure anxiety-like and depressive-like behaviours, respectively. Sucrose preference assessed anhedonia both before and after environmental assignment. Weight was measured every week to monitor weight-gain over time. Post-environment sucrose preference was significantly increased in animals in enriched housing as compared to those in isolated housing in both strains. While there were significant differences between strains in measures of open arm duration in the EPM and immobility in the FST, there appeared to be no differences between environmental groups. The results of this study highlight the importance of environmental factors in the expression of anhedonia. Enrichment appears to reduce anhedonia while isolation increases anhedonia. These effects should be studied further to assess whether longer periods of social and physical enrichment alleviate other symptoms of depression.

In utero programming alters adult response to chronic mild stress: part 3 of a longitudinal study.

Exposure to stress before birth may lay the foundation for the development of sensitivities or protection from psychiatric disorders while later stress exposure may trigger either their expression or suppression. This report, part three of a longitudinal study conducted in our laboratory, aimed to examine the interaction between early and adult stress and their effects on measures of anxiety and depression. In parts one and two, we reported the effects of gestational stress (GS) in Long Evans rat dams and their juvenile and young adult offspring. In this third and final installment, we evaluated the effects of GS and chronic mild stress (CMS) in the adult female offspring at 6 month and 12 month time-points. The two by two design included a combination of GS and CMS and the appropriate control groups. Using Hierarchical Linear Modeling, main effects of GS on corticosterone level at the 12 month time-point was found while main effects of CMS were seen in body weight, sucrose preference, and corticosterone, and significant interactions between group at the 6 and 12 month time-points. The GS group had the lowest sucrose preference during CMS at 6 months supporting a cumulative effect of early and later life stress. The GS/CMS group showed lower corticosterone at 12 months than the GS/noCMS group indicating a possible mismatch between prenatal programming and later life stress. These results highlight the importance of early life factors in exerting potentially protective effects in models involving later life stress.

Bisphenol-A: epigenetic reprogramming and effects on reproduction and behavior.

Bisphenol A (BPA) is a synthetic compound used in the production of many polycarbonate plastics and epoxy resins. It is one of the most widely produced chemicals in the world today and is found in most canned goods, plastics, and even household dust. Exposure to BPA is almost universal: most people have measurable amounts of BPA in both urine and serum. BPA is similar in structure to estradiol and can bind to multiple targets both inside and outside the nucleus, in effect acting as an endocrine disruptor. Research on BPA exposure has accelerated in the past decade with findings suggesting that perinatal exposure to BPA can negatively impact both male and female reproduction, create alterations in behavior, and act as a carcinogen. BPA can have both short term and long term effects with the latter typically occurring through epigenetic mechanisms such as DNA methylation. This review will draw on both human and animal studies in an attempt to synthesize the literature and examine the effects of BPA exposure on reproduction, behavior, and carcinogenesis with a focus on the potential epigenetic mechanisms by which it acts.