Estrous Cycle Phase-Dependent Changes in Anxiety- and Depression-Like Profiles in the Late Adolescent Wistar-Kyoto Rat

Abstract

Background: Depression often manifests during adolescence when the development and networking of social and emotional brain areas is being influenced by hormones. The Wistar Kyoto (WKY) rat has been proposed as an animal model of adolescent depression with various face, construct, and predictive validities for clinical depression having been established.

Purpose: The influence of the estrous cycle on anxiety- and depression-like behaviors in female adolescents may be tested out further using this model.

Methods: Female adolescent WKY rats were tested for anxiety- and depression-like behaviors in the elevated plus maze and forced swim test (FST) during different phases of the estrous cycle with inbred, age-, and phase-matched Wistar rats as controls.

Results: Wistars in proestrus-estrus demonstrated reduced anxiety levels. WKY also demonstrated increased open arm time and entries and closed arm time, but less than Wistars, and as closed arm entries remained unaffected, it did not translate into a lowering of the anxiety levels. Risk taking and risk assessment behaviors were not affected by estrous phases in WKY, though exploratory behavior was reduced in proestrus-estrus. In Wistars, increased risk taking and decreased risk assessment behaviors were observed during proestrus-estrus. Increased immobility in the FST, indicative of learned helplessness was not influenced by phase in the WKY, which was at variance with Wistars that demonstrated phase-specific differences.

Conclusion: Results indicate a masking effect of indicative hormones in this putative model of adolescent depression, with implications for an unravelling of the steroid milieu in predisposed adolescent depression and for taking phase-specific time windows into account for therapeutic interventions.

Keywords: Elevated plus maze; Females; Forced swim test; Puberty.

Fig. 1

Photomicrographs of stages of the estrous cycle: a metestrus or diestrus 1; b diestrus 2; c proestrus; d estrus. Long arrows point to leucocytes; short arrows point to cornified cells; open long arrows point to nucleated epithelial cells.

Fig. 2

Anxiety-related behaviors in EPM of Wistar (WIS) and Wistar Kyoto (WKY) female rats at P 60 during diestrus (D1 + D2) and proestrus-estrus phases (P + E) of estrous cycle. a Open arm duration. ** Significant differences between WIS and WKY during proestrus-estrus phases (P + E) of estrous cycle, p < 0.01, t = 3.374. ^$$$ Significant difference in Wistars during diestrus (D1 + D2) and proestrus-estrus phase (P + E) − p < 0.001, t = 6.142. b Open arm entries. * Significant differences between WIS and WKY during proestrus-estrus phases (P + E) of estrous cycle, p < 0.05, t = 3.093. ^$$ Significant difference in Wistars during diestrus (D1 + D2) and proestrus-estrus phase (P + E) − p < 0.01, t = 3.214.

Fig. 3

Depression-like behaviors of Wistar (WIS) and Wistar Kyoto (WKY) female rats at P60 during diestrus (D1 + D2) and proestrus-estrus phases (P + E) of estrous cycle in FST. a Immobility duration. * Significant difference between WIS and WKY during proestrus-estrus phases (P + E) of estrous cycle, t = 2.956; p < 0.05. ^$ Significant difference in Wistar during diestrus (D1 + D2) and proestrus-estrus phase (P + E), t = 3.237; p < 0.05. b Latency to immobility. ** Significant difference between WIS and WKY during proestrus-estrus phases (P + E) of estrous cycle, p < 0.01, t = 3.799. ^$$$ Significant difference in Wistar during diestrus (D1 + D2) and proestrus-estrus phase (P + E), t = 8.342; p < 0.001. ^$$ Significant difference in WKYs during diestrus (D1 + D2) and proestrus-estrus phase (P + E), t = 3.716; p < 0.01.