Orexins actions in adolescence

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SUMMARY Habituation is the progressive decline in responses to repeated exposure to the same, homotypic stressor. It is highly conserved and observed in species ranging from humans to rodents. Habituation is adaptive because it allows animals to filter out irrelevant stimuli and focus selectively on important stimuli, thereby facilitating optimal responding in a complex and changing environment. The ability to habituate to repeated cognitive stressors is disrupted in several psychiatric disorders including post-traumatic stress disorder post-traumatic stress disorder (PTSD). In previous work, we identified sex differences in habituation in adult rats. While male rats habituate to 5 days of 30min restraint/day, as indicated by reductions in hypothalamic-pituitary-adrenal (HPA) activity and behavior on the 5th compared to the 1st day, female rats do not habituate to 5 days of restraint. We showed that elevations in orexinergic expression and activity in adult females compared to adult males contribute to this disrupted habituation in females. The elevations in orexin mRNA in adult females are dependent on glucocorticoid receptor (GR) binding at the prepro-orexin promoter. However, little is known about orexin functions in adolescence. In preliminary data, we show that adolescent male and female rats do not habituate to 5 days of repeated restraint and that male adolescents exhibit higher basal circulating glucocorticoids than adult males. They also exhibit higher orexin expression that do adult males. Together, the findings in adult and adolescent rats suggest that higher orexin expression and activity in adolescent males and females may be promoted by elevated glucocorticoids and lead to disrupted habituation. The posterior paraventricular thalamus (pPVT) is an important site mediating habituation, is densely innervated by orexins and orexins act in the pPVT to regulate responses to chronic stress such as facilitation. These data lead to the central hypothesis that elevations in orexin expression and activity in both adolescent males and females are promoted by glucocorticoids and that elevations in orexin neurotransmission in the pPVT disrupt habituation in adolescence. Specific Aim 1 will test the hypothesis that increased GR binding at the prepro-orexin promoter in adolescent males and females elevates orexin expression. Specific Aim 2 will test the hypothesis that elevations in orexin activity in the pPVT of adolescent male and female rats disrupt neuroendocrine and behavioral habituation. Experiments will use DREADDs or virally-mediated knockdown of orexin receptors to inhibit orexin activity in the pPVT. We expect that inhibition of orexin activity in the pPVT will promote habituation in both male and female adolescent rats. Together, the experiments will provide the first information on orexin activity and functions during adolescence and provide mechanistic insights as to why habituation is not observed in adolescence.