The Wistar Kyoto Rat: A Model of Depression Traits

Abstract

There is an ongoing debate about the value of animal research in psychiatry with valid lines of reasoning stating the limits of individual animal models compared to human psychiatric illnesses. Human depression is not a homogenous disorder; therefore, one cannot expect a single animal model to reflect depression heterogeneity. This limited review presents arguments that the Wistar Kyoto (WKY) rats show intrinsic depression traits. The phenotypes of WKY do not completely mirror those of human depression but clearly indicate characteristics that are common with it. WKYs present despair-like behavior, passive coping with stress, comorbid anxiety, and enhanced drug use compared to other routinely used inbred or outbred strains of rats. The commonly used tests identifying these phenotypes reflect exploratory, escape-oriented, and withdrawal-like behaviors. The WKYs consistently choose withdrawal or avoidance in novel environments and freezing behaviors in response to a challenge in these tests. The physiological response to a stressful environment is exaggerated in WKYs. Selective breeding generated two WKY substrains that are nearly isogenic but show clear behavioral differences, including that of depression-like behavior. WKY and its substrains may compare characteristics of subgroups of depressed individuals with social withdrawal, low energy, weight loss, sleep disturbances, and specific cognitive dysfunction. The genomes of the WKY and WKY substrains contain variations that impact the function of many genes identified in recent human genetic studies of depression. Thus, these strains of rats share characteristics of human depression at both phenotypic and genetic levels, making them a model of depression traits.

Chronic stress from adolescence to adulthood increases adiposity and anxiety in rats with decreased expression of Krtcap3

“…We also found that immobility in the FST increased in stress-exposed KO rats from Day 1 to Day 2 of the test, with minimal changes between days in stress-exposed WT rats. This suggests a greater passive coping response ( Commons et al, 2017 ; Molendijk and de Kloet, 2019 ) or greater depressive-like behavior ( Redei et al, 2022 ) in KO rats following early life stress. As the WKY rat is hyper-sensitive to stress ( Redei et al, 2022 ), these findings support that WT rats may have been unable to distinguish between the stress of the study design (control rats) and the chronic stress procedures (stress-exposed rats): it is possible that both groups of rats were chronically stressed.…”

“…Given the literature supporting early mild stress as potentially protective and that WKY rats are known to be stress-sensitive ( Redei et al, 2022 ), it is likely a combination of both. Upcoming work from the Redei lab also suggests that WKY rats are chronically stressed when administered multiple behavioral tests despite long periods of rest in between (personal communication).…”

“…Three days after the NSF, rats participated in a FST to measure passive coping to stress ( Commons et al, 2017 ) and/or depressive-like behavior ( Redei et al, 2022 ). Rats were placed in a tank of water (25°C ± 2, diameter 28.8 cm, height 49.8 cm, water depth 39 cm) for 15 min on Day 1 and 5 min on Day 2 as previously described ( Solberg et al, 2004 ).…”

“…Video recording of the first 5 min of Day 1 and the full 5 min of Day 2 were used to manually score movements made by the rat at 5 s intervals: immobility (floating or bracing) and mobility (swimming, climbing, or diving). Increased immobility is associated with increased passive coping ( Commons et al, 2017 ) and/or depressive-like behavior ( Redei et al, 2022 ).…”

Changes in Environmental Stress over COVID-19 Pandemic Likely Contributed to Failure to Replicate Adiposity Phenotype Associated withKrtcap3

“…We initially presumed this was evidence of chronic stress altering CORT secretion in response to acute stress in the Study 1 WT rats [28, 32, 33], but replicating this pattern in Study 2 rats indicated the effect was not related to environment. We propose that Krtcap3- KO rats exhibit low basal CORT and are relatively unaffected by low-grade chronic environmental stress relative to the stress-responsive WKY rat [36] but exhibit a heightened response to acute social stress relative to WT rats. Studies in rodents have previously shown strain-specific differences in CORT response following restraint stress plus differences in glucocorticoid receptor (GR) expression [37–39], supporting a role of genetics in basal CORT levels and stress response.…”