Neuropeptide Y mediates the initial hypothalamic-pituitary-adrenal response to maternal separation in the neonatal mouse.

The function of the hypothalamic-pituitary-adrenal (HPA) axis of the neonatal mouse or rat is characterized by a period of quiescence, where mild stimuli are unable to elicit a pronounced increase in circulating corticosterone. A disruption of this period by maternal separation has been shown to result in a variety of long-term consequences, including neuroendocrine and behavioral disturbances. We have recently shown that peripheral metabolic markers like glucose or ghrelin are altered by maternal separation and that these changes precede the effects on corticosterone secretion. In the current study, we investigated whether the initial activation of the HPA axis is mediated via neuropeptide Y (NPY). To test this hypothesis, we studied the effects of an 8 h maternal separation in NPY-deficient mice. In addition, we compared the effect of the genotype with the previously described pharmacological effect of a ghrelin receptor antagonist. We could show that the peripheral response to maternal separation is decreased in NPY heterozygous and homozygous animals. In addition, maternal separation effects on corticotropin releasing hormone and glucocorticoid receptor expression in the brain were prevented in NPY-deficient pups. These effects were similar to a pharmacological ghrelin receptor blockade. We conclude that metabolic signals via an NPY-mediated pathway play a crucial role in activating the stress system of the neonatal mouse.

Long-term behavioral and neuroendocrine alterations following chronic social stress in mice: implications for stress-related disorders.

The period of adolescence is characterized by a high vulnerability to stress and trauma, which might result in long-lasting consequences and an increased risk to develop psychiatric disorders. Using a recently developed mouse model for chronic social stress during adolescence, we studied persistent neuroendocrine and behavioral effects of chronic social stress obtained 12 months after cessation of the stressor. As a reference, we investigated immediate effects of chronic stress exposure obtained at the end of the chronic stress period. Immediately after the 7 week chronic stress period stressed animals show significantly increased adrenal weights, decreased thymus weight, increased basal corticosterone secretion and a flattened circadian rhythm. Furthermore, stressed animals display an increased anxiety-like behavior in the elevated plus maze and the novelty-induced suppression of feeding test. Hippocampal mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) mRNA levels were significantly decreased. To investigate persistent consequences of this early stressful experience, the same parameters were assessed in aged mice 12 months after the cessation of the stressor. Interestingly, we still found differences between formerly stressed and control mice in important stress-related parameters. MR expression levels were significantly lower in stressed animals, suggesting lasting, possibly epigenetic alterations in gene expression regulation. Furthermore, we observed long-term behavioral alterations in animals stressed during adolescence. Thus, we could demonstrate that chronic stress exposure during a crucial developmental time period results in long-term, persistent effects on physiological and behavioral parameters throughout life, which may contribute to an enhanced vulnerability to stress-induced diseases.