PLASTICITY IN THE STRESS AXIS

这项建议的重点是研究边缘-下丘脑- 垂体-肾上腺(LHPA)轴随发育的变化 事件、遗传易感性和对重复压力的暴露，以及如何 这些因素导致了个体压力的差异。 在整个生命中，包括在衰老过程中的反应能力。 压力暴露的确切时间和方式可能会导致 对内分泌、分子、神经元和 动物的行为功能。理解“可塑性” LHPA轴在帮助我们描述系统如何 保持对压力的最佳反应，以及它如何结合过去 将经验融入应对过程。因此，我们将探讨这些问题 通过3组相互关联的研究：1)在一系列发展中 研究，我们将检查应激的神经元基础 大鼠的低反应期及其相关机制 随着动物的出现而进入应激反应。我们 应观察早期应激的4种模式的后果(母体 不同时间的剥夺，以及产仔大小的变化) SHRP的持续时间，以及成年生活中的压力反应， 专注于将大脑回路的变化与大脑中的 内分泌以及学习、记忆和对新奇事物的反应；2) 在专注于衰老的研究中，我们将检查一些决定因素 老年动物应激反应的个体差异 为了理解为什么有些动物受损，而其他动物则没有 他们会变老。我们将研究遗传易感性对 通过对比两个品系的大鼠，费舍尔和刘易斯， 它们具有不同的应力响应曲线。我们会 还要研究在开发过程中发生的事件如何影响 老龄化过程，通过研究发展模式的后果 随着动物年龄的增长，包括对应激反应的影响，大脑 反应性、学习和记忆；3)以年轻人为重点的研究 成年动物，我们将研究神经机制。 对反复的压力源敏感和习惯性。特别是，我们 应侧重于特定大脑结构的作用(例如 视交叉上核和前额叶皮质)参与 这种可塑性。最后，我们将开始调查 NMDA受体在这些可塑性过程中的潜在作用。这 综合研究应该能让我们更好地了解 应力轴在动物的整个生命过程中是如何改变的，以及 这如何导致个体在压力反应上的差异 以及如何应对。

The focus of this proposal is to study how the limbic-hypothalamo- pituitary-adrenal (LHPA) axis changes as a function of developmental events, genetic predisposition and exposure to repeated stress, and how these factors contribute to individual differences in stress responsiveness throughout life, including during the aging process. Exactly when and how the stress exposure takes place may lead to different consequences on the endocrine, molecular, neuronal and behavioral functioning of the animal. Understanding the "plasticity" of the LHPA axis is important in helping us describe how the system maintains optimal responsiveness to stress, and how it incorporates past experience into the coping process. Thus we shall explore these issues via 3 interrelated sets of studies: 1) In a series of developmental studies, we shall examine the neuronal bases of the stress hyporesponsive period (SHRP) in the rat and the mechanisms associated with the animal's emergence from it into stress responsiveness. We shall look at the consequences of 4 models of early stress (maternal deprivation with various timing, and changes in litter size) on the duration of the SHRP, and on stress responsiveness in adult life, focusing on relating changes in the brain circuits to alterations in endocrine profiles and in learning, memory and response to novelty; 2) In studies focused on aging, we shall examine some of the determinants of individual differences in stress responsiveness in aged animals in order to understand why some animals are impaired and others are not as they age. We shall study the effect of genetic predisposition on the aging process by contrasting two strains of rats, Fisher and Lewis, which are known to have different stress response profiles. We shall also study how events taking place during development may impact on the aging process, by studying the consequences of the developmental models as the animals age, including effects on stress responsiveness, brain responsiveness and learning and memory; 3) In studies focused on young adult animals, we shall investigate the neuronal mechanisms of sensitization and habituation to repeated stressors. In particular, we shall focus on the role of specific brain structures (e.g., the suprachiasmatic nucleus, and the prefrontal cortex) in contributing to this type of plasticity. Finally, we shall begin to investigate the potential role of NMDA receptors in these plastic processes. This combination of studies should provide us with a better understanding of how the stress axis is modified throughout the life of the animal, and how this contributes to individual differences in stress responsiveness and coping.