Orexins actions in adolescence

摘要 习惯化是对反复暴露于相同的同型应激源的反应的进行性下降。它 是高度保守的，在从人类到啮齿动物的各种物种中都能观察到。习惯化是适应性的，因为 它允许动物过滤掉不相关的刺激，有选择地专注于重要的刺激，从而促进 在复杂多变的环境中实现最佳响应。习惯重复认知的能力 应激源在几种精神障碍中被破坏，包括创伤后应激障碍 应激障碍(PTSD)。在之前的工作中，我们确定了成年大鼠习惯化的性别差异。而男性 大鼠习惯于每天束缚5天，表现为下丘脑-垂体-肾上腺皮质的减少 (HPA)5日的活动和行为与第1天相比，雌性大鼠没有习服到第5天 克制。我们发现，与成年女性相比，成年女性的食欲素能表达和活性升高 男性促成了女性这种被打乱的习性。成年女性食欲素mRNA的升高是 依赖于前增食欲素原启动子上的糖皮质激素受体(GR)结合。然而，人们对此知之甚少 关于食欲素在青春期的作用。在初步数据中，我们表明，青春期的雄性和雌性大鼠 不要习惯于5天的反复限制，男性青少年表现出更高的基础循环 糖皮质激素的比例高于成年男性。它们也表现出比成年雄性更高的食欲素表达。一起， 在成年和青春期大鼠的研究结果表明，青春期大鼠的增食欲素表达和活性更高 男性和女性可能会因糖皮质激素升高而促进，并导致习惯化中断。这个 丘脑室旁后核(PPVT)是调节习惯化的重要部位，分布密集 通过食欲素和食欲素在pPVT中起作用，调节对慢性应激的反应，如易化。这些 数据导致了一个中心假设，即食欲素的表达和活动在两个青少年中都有所上升 糖皮质激素和增食欲素神经传递的升高促进了男性和女性 在pPVT中打乱青春期的习惯化。特定目标1将检验增加GR的假设 在青春期男性和女性中，与食欲素前体启动子的结合可以提高食欲素的表达。特定的 目的2验证青春期男性和女性pPVT中增食欲素活性升高的假设 老鼠会扰乱神经内分泌和行为习惯。实验将使用DREADD或病毒媒介 阻断增食欲素受体以抑制pPVT中的增食欲素活性。我们预计食欲素活性的抑制 PPVT将促进雄性和雌性青春期大鼠的习惯化。总之，这些实验将 提供有关食欲素在青春期的活动和功能的第一批信息，并提供 关于为什么在青春期没有观察到习惯性的机械性见解。

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.