Adolescent development is marked by many changes in neuroendocrine function, resulting in both immediate and long-term influences on an individual’s physiology and behavior. Stress-induced hormonal responses are one such change, with adolescent animals often showing different patterns of hormonal reactivity following a stressor compared with adults. This review will describe the unique ways in which adolescent animals respond to a variety of stressors and how these adolescent-related changes in hormonal responsiveness can be further modified by the sex and previous experience of the individual. Potential central and peripheral mechanisms that contribute to these developmental shifts in stress reactivity are also discussed. Finally, the short- and long-term programming effects of chronic stress exposure during adolescence on later adult hormonal responsiveness are also examined. Though far from a clear understanding of the neurobehavioral consequences of these adolescent-related shifts in stress reactivity, continued study of developmental changes in stress-induced hormonal responses may shed light on the increased vulnerability to physical and psychological dysfunctions that often accompany a stressful adolescence.

Weight loss is an early manifestation of Alzheimer's disease that can precede the cognitive decline, raising the possibility that amyloid-␤ (A␤) disrupts hypothalamic neurons critical for the regulation of body weight. We previously reported that, in young transgenic mice overexpressing mutated amyloid precursor protein (Tg2576), A␤ causes dysfunction in neuropeptide Y (NPY)-expressing hypothalamic arcuate neurons before plaque formation. In this study, we examined whether A␤ causes arcuate NPY neuronal dysfunction by disrupting intracellular Ca 2ϩ homeostasis. Here, we found that the L-type Ca 2ϩ channel blocker nimodipine could hyperpolarize the membrane potential, decrease the spontaneous activity, and reduce the intracellular Ca 2ϩ levels in arcuate NPY neurons from Tg2576 brain slices. In these neurons, there was a shift from high to low voltage-threshold activated L-type Ca 2ϩ currents, resulting in increased Ca 2ϩ influx closer to the resting membrane potential, an effect recapitulated by A␤ 1-42 and reversed by nimodipine. These low voltage-threshold activated L-type Ca 2ϩ currents were dependent in part on calcium/calmodulin-dependent protein kinase II and IP 3 pathways. Furthermore, the effects on intracellular Ca 2ϩ signaling by both a positive (ghrelin) and negative (leptin) modulator were blunted in these neurons. Nimodipine pretreatment restored the response to ghrelin-mediated feeding in young (3-5 months), but not older (10 months), female Tg2576 mice, suggesting that intracellular Ca 2ϩ dysregulation is only reversible early in A␤ pathology. Collectively, these findings provide evidence for a key role for low-threshold activated voltage gated L-type Ca 2ϩ channels in A␤-mediated neuronal dysfunction and in the regulation of body weight.

During adolescence, the increased susceptibility to stress-related dysfunctions (e.g., anxiety, drug use, obesity) may be influenced by changes in the hormonal stress response mediated by the hypothalamic-pituitary-adrenal (HPA) axis. We have previously reported that restraint stress leads to significantly prolonged HPA responses in pre-adolescent compared to adult rats. Further, pre-adolescent animals exposed to restraint show greater levels of neural activation than adults in the paraventricular nucleus of the hypothalamus (PVN), a key nucleus integrating information from brain regions that coordinate HPA responses. Here, we examined the potential contribution of the noradrenergic A2 region of the nucleus of the solitary tract (NST) as a contributor to these age-dependent shifts in HPA reactivity. Specifically, we used double-labeled immunohistochemistry for FOS and dopamine-β-hydroxylase (DβH) to measure cellular activation and noradrenergic cells, respectively, before or after restraint stress in pre-adolescent (30days old) and adult (70days old) male rats. We also measured the density of DβH-immunoreactive fibers in the PVN as an index of noradrenergic inputs to this area. We found that pre-adolescent animals have a greater number of DβH-positive cells in the A2 region compared to adults, yet the number and percentage of double-labeled DβH/FOS cells were similar between these two ages. We found no differences between the ages in the staining intensity of DβH-immunoreactive fibers in the PVN. These data indicate there are adolescent-related changes in the number of noradrenergic cells in the A2 region, but no clear association between the increased stress reactivity prior to pubertal maturation and activation of A2 noradrenergic afferents to the PVN.