Neuroplastic Correlates in the mPFC Underlying the Impairment of Stress-Coping Ability and Cognitive Flexibility in Adult Rats Exposed to Chronic Mild Stress during Adolescence

Abstract

Using a valid chronic mild stress (CMS) model of depression, we found that adolescent (postnatal days [PND] 28-41) CMS induced transient alterations in anhedonia that did not persist into adulthood after a 3-week recovery period. Previously stressed adult rats exhibited more immobility/despair behaviors in the forced swimming test and a greater number of trials to reach criterion in the set-shifting task, suggesting the impaired ability to cope with stressors and the cognitive flexibility that allows adaptation to dynamic environments during adulthood. In addition, adult rat exposure to adolescent CMS had a relatively inhibited activation in ERK signaling and downstream protein expression of phosphorylated cAMP-response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex. Further correlation analysis demonstrated that immobility and set-shifting performance were positively correlated with the inhibition of ERK signaling. These results indicated adolescent CMS can be used as an effective stressor to model an increased predisposition to adult depression.

Figure 1

Timeline of procedures. We evaluated the effects of chronic mild stress during adolescence on adult behaviors using the following tests: sucrose preference, open field, forced swimming, and attentional set-shifting task.

Figure 2

Effects of adolescent CMS on body weight. The body weights were measured on PND 28 (before the initiation of CMS), PND 42 (1 day after the end of CMS, short-term effect), and PND 63 (3 weeks after the end of CMS, long-term effect). ^∗∗∗p < 0.001 compared to the CON group at the corresponding time points.

Figure 3

Effects of adolescent CMS on sucrose preference (a), horizontal ambulation (b) and number of rearing instances (c) in the open field test and immobility in the FST (d). Behavioral tests were conducted in sequence as follows: the sucrose preference test was performed before, one day after, and 3 weeks after the end of CMS; the open field test was performed one day after each sucrose preference test; the FST was performed one day after the last open field test in adult rats. ^∗p < 0.05 and ^∗∗∗p < 0.001 compared to the CON group at the corresponding time point.

Figure 4

Effects of adolescent CMS on the performance on the AST. Rats were tested 3 weeks after the end of CMS during adulthood. The number of trials to criterion reflected the performance during the 5 stages of the test: simple discrimination (SD), compound discrimination (CD), intradimensional shifting (IDS), reversal learning (RL) and extradimensional set-shifting (EDS). ^∗p < 0.05 compared to the CON group at the corresponding stages.

Figure 5

Effects of adolescent CMS on ERK1/2, pERK1/2, pCREB and BDNF levels in the mPFC of adult rats. (a) pERK1; (b) ERK1; (c) pERK1/ERK1; (d) pERK2; (e) ERK2; (f) pERK2/ERK2; (g) pCREB; (h) BDNF; and (i) representative blots for pERK1/2, ERK1/2, pCREB, BDNF and GAPDH. Rats were decapitated for western blot analysis one day after the behavioral tests. The results were calculated as the intensity of the lane of each transcript relative to the intensity of the corresponding GAPDH band and expressed as the mean ± SEM. ^∗p < 0.05, ^∗∗p < 0.01, ^∗∗∗p < 0.001, compared to the CON group.