RESUMO
Exposure to adversity during early life can have profound influences on brain function and behavior later in life. The peripubertal period is emerging as an important time-window of susceptibility to stress, with substantial evidence documenting long-term consequences in the emotional and social domains. However, little is known about how stress during this period impacts subsequent cognitive functioning. Here, we assessed potential long-term effects of peripubertal stress on spatial learning and memory using the water maze task. In addition, we interrogated whether individual differences in stress-induced behavioral and endocrine changes are related to the degree of adaptation of the corticosterone response to repeated stressor exposure during the peripubertal period. We found that, when tested at adulthood, peripubertally stressed animals displayed a slower learning rate. Strikingly, the level of spatial orientation in the water maze completed on the last training day was predicted by the degree of adaptation of the recovery -and not the peak-of the corticosterone response to stressor exposure (i.e., plasma levels at 60 min post-stressor) across the peripubertal stress period. In addition, peripubertal stress led to changes in emotional and glucocorticoid reactivity to novelty exposure, as well as in the expression levels of the plasticity molecule PSA-NCAM in the hippocampus. Importantly, by assessing the same endpoints in another peripubertally stressed cohort tested during adolescence, we show that the observed effects at adulthood are the result of a delayed programming manifested at adulthood and not protracted effects of stress. Altogether, our results support the view that the degree of stress-induced adaptation of the hypothalamus-pituitary-adrenal axis responsiveness at the important transitional period of puberty relates to the long-term programming of cognition, behavior and endocrine reactivity.
RESUMO
Early-life stress is a critical risk factor for developing psychopathological alterations later in life. This early adverse environment has been modeled in rats by exposure to stress during the peripubertal period-that is, corresponding to childhood and puberty-and has been shown to lead to increased emotionality, decreased sociability and pathological aggression. The amygdala, particularly its central nucleus (CeA), is hyperactivated in this model, consistent with evidence implicating this nucleus in the regulation of social and aggressive behaviors. Here, we investigated potential changes in the gene expression of molecular markers of excitatory and inhibitory neurotransmission in the CeA. We found that peripubertal stress led to an increase in the expression of mRNA encoding NR1 (the obligatory subunit of the N-methyl D-aspartate (NMDA) receptor) but to a reduction in the level of mRNA encoding glutamic acid decarboxylase 67 (GAD67), an enzyme that is critically involved in the activity-dependent synthesis of GABA, and to an increase in the vesicular glutamate transporter 1 (VGLUT1)/vesicular GABA transporter (VGAT) ratio in the CeA. These molecular alterations were present in addition to increased novelty reactivity, sociability deficits and increased aggression. Our results also showed that the full extent of the peripubertal protocol was required for the observed behavioral and neurobiological effects because exposure during only the childhood/prepubertal period (Juvenile Stress) or the male pubertal period (Puberty Stress) was insufficient to elicit the same effects. These findings highlight peripuberty as a period in which stress can lead to long-term programming of the genes involved in excitatory and inhibitory neurotransmission in the CeA.
