Early Life Stress Increases Metabolic Risk, HPA Axis Reactivity, and Depressive-Like Behavior When Combined with Postweaning Social Isolation in Rats

Abstract

Early-life stress is associated with depression and metabolic abnormalities that increase the risk of cardiovascular disease and diabetes. Such associations could be due to increased glucocorticoid levels. Periodic maternal separation in the neonate and rearing in social isolation are potent stressors that increase hypothalamus-pituitary-adrenal axis activity. Moreover, social isolation promotes feed intake and body weight gain in rats subjected to periodic maternal separation; however, its effects on metabolic risks have not been described. In the present study, we evaluated whether periodic maternal separation, social isolation rearing, and a combination of these two stressors (periodic maternal separation + social isolation rearing) impair glucose homeostasis and its relation to the hypothalamus-pituitary-adrenal axis and depressive-like behavior. Periodic maternal separation increased basal corticosterone levels, induced a passive coping strategy in the forced swimming test, and was associated with a mild (24%) increase in fasting glucose, insulin resistance, and dyslipidemia. Rearing in social isolation increased stress reactivity in comparison to both controls and in combination with periodic maternal separation, without affecting the coping strategy associated with the forced swimming test. However, social isolation also increased body weight gain, fasting glucose (120%), and insulin levels in rats subjected to periodic maternal separation. Correlation analyses showed that stress-induced effects on coping strategy on the forced swimming test (but not on metabolic risk markers) are associated with basal corticosterone levels. These findings suggest that maternal separation and postweaning social isolation affect stress and metabolic vulnerability differentially and that early-life stress-related effects on metabolism are not directly dependent on glucocorticoid levels. In conclusion, our study supports the cumulative stress hypothesis, which suggests that metabolic risk markers arise when vulnerable individuals are exposed to social challenges later in life.

Effect of early life stress on anxiety and depressive behaviors in adolescent mice

“…Some works indicated that additional stress in adolescence or adulthood is needed to manifest the effect of MS (Hill et al, ; Marais, van Rensburg, van Zyl, Stein, & Daniels, ; Vargas, Junco, Gomez, & Lajud, ). In our study, RS in adolescence increased depression‐like behavior only in males but not females.…”

Disruption of behavior and brain metabolism in artificially reared rats

“…However, some neurotransmitters can increase its release (Yorgason et al, ). The hypothalamus–pituitary axis (HPA) seems particularly sensitive to this kind of stress and modifications include reduction in the HPA axis activity (Sanchez et al, ; Pournajafi‐Nazarloo et al, ; Cinini et al, 2014; Vargas et al, ). Affected brain areas are mainly hippocampus, amygdala, nucleus accumbens, thalamus, and medial prefrontal cortex (Sanchez et al, ; Silva‐Gómez et al, ; Lukkes et al, ; Ahern et al, ; Murínová et al, ).…”

“…As in the case of postweaning separation, the observed effects are anxiety as the dominant one, and reductions in neuronal activity (Gonzalez and Fleming, ; Cirulli et al, ; Braun et al, ; Toda et al, ), neurogenesis (Wang and Gondré‐Lewis, ), neurotransmitters release (León‐Rodríguez and Dueñas, ; Toda et al, ; Wang et al, ), growth factors production or expression (Cirulli et al, ; Wang et al, ), and deterioration of the HPA axis. Some authors report a decrease in corticosterone levels (Meagher et al, ), and HPA axis reactivity while others find the opposite (Vargas et al, ) despite the fact that both researchers performed the same protocol (3 h) during the same interval of development. Once again, all these authors find changes mainly in hippocampus and amygdala, although in this case, the thalamus and medial prefrontal cortex (PFC) is also altered.…”

Adolescent Ethanol Exposure Leads to Stimulus-Specific Changes in Cytokine Reactivity and Hypothalamic-Pituitary-Adrenal Axis Sensitivity in Adulthood

“…Because early life shipping can produce variations in stress history and thereby influence stress reactivity (Laroche et al, 2009a,b; Vargas et al, 2016), rats for Experiment 4 were bred in house. Thus, in Experiment 4, rats ( n = 6–8 per group; N = 30) were given four cycles of vehicle or ethanol intubations utilizing the procedure described above.…”