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

Abstract

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.

The Wistar Kyoto Rat: A Model of Depression Traits

“…The possible impaired negative feedback in WKY rats does not appear to be due to a downregulation of glucocorticoid receptors (GRs) [ 81 , 82 ]. In contrast, increased GR staining in the hippocampus of WKY females compared to Wistars, and increased expression of hippocampal Nr3c1 (GR) in WKYs compared to SD, suggest upregulation of GRs in WKYs [ 101 , 102 ]. The upregulation of hippocampal GR in the WKYs parallels the antidepressant effects of glucocorticoid synthesis inhibitors and GR antagonists [ 103 - 105 ], while the findings of GR downregulation could be specific to peripheral cells in major depressive disorder (MDD) individuals [ 99 ].…”

Time of day influences stress hormone response to ketamine

“…This suggests that the significant increase in CORT levels previously seen may be due to hyperactivity of the HPA axis when handling and/or blood sampling. That being said, studies have reported altered density of GRs in the WKY rat 34,35 and decreased GR function contributes to HPA axis hyperactivity and the development of depressive symptoms, 36 which may account for the depressive‐like phenotype seen in these rats.…”