Orexins actions in adolescence

食欲素在青春期的作用

• 批准号: 10571316
• 负责人: SEEMA BHATNAGAR
• 金额: $ 26.4万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10571316
• 关键词: Adolescence; Adolescent; Adrenal Glands; Adult; Animals; Behavior; Cell Density; Cells; Chronic stress; Cognitive; Complex; Corticosterone; DDX6 gene; Data; Environment; Etiology; Exhibits; Exposure to; Female; Female Adolescents; Genetic; Glucocorticoid Receptor; Glucocorticoids; Human; Hypothalamic structure; Lead; Male Adolescents; Mediating; Mental disorders; Messenger RNA; Modeling; Neurobiology; Neurons; Neurosecretory Systems; Pituitary Gland; Post-Traumatic Stress Disorders; Prevention; Rattus; Regulation; Rodent; Role; ST5 gene; Sex Differences; Site; Small Interfering RNA; Stimulus; Stress; Technology; Testing; Thalamic structure; Viral; Work; acute stress; age related; base; behavioral habituation; designer receptors exclusively activated by designer drugs; experimental study; habituation; hypocretin; improved; insight; knock-down; male; neurotransmission; prepro-orexin; promoter; receptor; receptor binding; response; restraint; stressor

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.

概括 习惯化是指对重复暴露于相同的同型压力源的反应逐渐下降。它 在从人类到啮齿动物的物种中高度保守和观察到。习惯是适应性的，因为 它允许动物过滤掉不相关的刺激并选择性地关注重要的刺激，从而促进 在复杂多变的环境中做出最佳响应。习惯重复认知的能力 应激源在多种精神疾病中受到干扰，包括创伤后应激障碍 应激障碍（PTSD）。在之前的工作中，我们发现了成年大鼠习惯性的性别差异。而男性 大鼠习惯于每天 30 分钟的限制 5 天，下丘脑 - 垂体 - 肾上腺的减少表明 与第 1 天相比，第 5 天的（HPA）活性和行为，雌性大鼠不习惯 5 天的 克制。我们发现，与成年女性相比，成年女性的食欲素表达和活性有所升高 男性会导致女性习惯性的破坏。成年女性食欲素 mRNA 的升高是 依赖于糖皮质激素受体（GR）与前食欲素原启动子的结合。然而，鲜为人知 关于青春期食欲素的功能。在初步数据中，我们表明青春期雄性和雌性大鼠 不习惯 5 天的反复束缚，男性青少年表现出更高的基础循环 糖皮质激素的使用量高于成年男性。它们还表现出比成年男性更高的食欲素表达。一起， 成年和青少年大鼠的研究结果表明，青少年大鼠中食欲素的表达和活性较高 男性和女性的糖皮质激素升高可能会促进这种情况，并导致习惯性紊乱。这 后室旁丘脑 (pPVT) 是调节习惯的重要部位，神经分布密集 食欲素和食欲素在 pPVT 中发挥作用，调节对慢性应激（如促进）的反应。这些 数据得出了一个中心假设，即青少年的食欲素表达和活性均升高 男性和女性都受到糖皮质激素的促进，并且食欲素神经传递的升高 pPVT 会破坏青春期的习惯。具体目标 1 将检验增加 GR 的假设 在青春期男性和女性中，与前食欲素原启动子的结合会提高食欲素的表达。具体的 目标 2 将检验青春期男性和女性 pPVT 中食欲素活性升高的假设 老鼠扰乱神经内分泌和行为习惯。实验将使用 DREADD 或病毒介导的 敲低食欲素受体以抑制 pPVT 中的食欲素活性。我们预计食欲素活性的抑制 pPVT 中的 pPVT 会促进雄性和雌性青春期大鼠的习惯。一起，这些实验将 提供有关青春期食欲素活性和功能的第一手信息，并提供 关于为什么在青春期没有观察到习惯化的机械见解。