Assessing the development of hippocampus-amygdala interactions during emotional l

描述(申请人提供)：越来越多的人同意，许多复杂的认知功能(特别是学习、记忆和情绪表达)需要围绕各种边缘系统结构的半独立神经回路之间的相互作用，包括海马体、杏仁核和皮质的边缘相关区域。然而，人们对这些系统的功能开发才刚刚开始了解。根据涉及的特定神经底物的不同，即使非常相似的学习、记忆和情绪处理任务似乎也有不同的个体发生谱。例如，众所周知，与离散线索形成厌恶联系的能力，如听觉或视觉经典恐惧条件反射所证明的，出现在与物理环境形成情感联系的能力之前，如语境恐惧条件反射所证明的那样。由于厌恶记忆都依赖于杏仁核，但空间和背景记忆唯一依赖于海马体，因此这些发现被解读为表明海马体发育相对缓慢。然而，我们实验室的最新数据对这一想法提出了两个挑战。首先，形成环境表征的能力(取决于海马体)比之前认为的更早出现。在将这些类型的体验与情感事件相结合并向特定环境表达恐惧的能力之前，还需要进一步的发展。此外，在杏仁核最初出现后的一段时间内，根据明确的暗示(依赖于杏仁核)表达恐惧的能力继续增强，持续时间比之前认为的要长。因此，数据表明，与之前的理解相反，大鼠的海马体依赖记忆系统早在第17天就开始发挥作用，杏仁核依赖系统继续成熟。使用情景和线索恐惧条件反射方案，当前的项目通过测试这一新的假设来检查杏仁核和海马体功能和相互作用的出现，该假说认为杏仁核-海马体相互作用发展缓慢是导致发育延迟的原因。为了验证这一假说，行为操控、即刻早期基因表达和暂时药物失活的影响将在恐惧条件反射的不同方面进行检验。总体而言，这个项目将阐明支配使用物理环境来调节发育中大鼠的厌恶情绪表达的神经结构。 公共卫生相关性：本项目调查边缘系统功能的发展。重点是创建和检查一个范例，可以用来评估包括海马体和杏仁核在内的主要边缘系统结构之间的连通性。尽管人们对它们在完整发育中的生物体中如何功能相互作用知之甚少，但在包括严重精神病、自闭症和焦虑症在内的几种发育障碍中，这些结构之间的连接性似乎发生了变化。因此，除了促进我们对典型发育的理解外，这些实验还将为进一步阐明这些疾病的机制的未来研究打开大门。因此，该项目将提供数据，有助于更好地了解边缘系统的发育，并建立更好的发育障碍动物模型。

DESCRIPTION (provided by applicant): There is growing agreement that many complex cognitive functions (especially learning, memory, and emotional expression) are best understood as requiring an interaction among semi-independent neural circuits focused around a variety of limbic system structures, including the hippocampus, amygdala and limbic-associated regions of cortex. However, the functional development of these systems is only beginning to be understood. Depending on the specific neural substrates involved, even very similar learning, memory and emotional processing tasks appear to have different ontogenetic profiles. For example, it has been well established that the ability to form aversive associations with discrete cues, as demonstrated by auditory or visual classical fear conditioning, emerges prior to the ability to form emotional associations with physical environments, as demonstrated by contextual fear conditioning. Since aversive memories all depend upon the amygdala, but spatial and contextual memories uniquely depend on the hippocampus, such findings had been interpreted as suggesting that the hippocampus was relatively slow to develop. However, recent data from our lab presents two challenges to this idea. First, the ability to form a representation of the environment (dependent upon the hippocampus) is present early than previously believed. Further development is required prior to the ability to integrate these types of experiences with emotional events and to express fear to a particular environment. Moreover, the ability to express fear to an explicit cue (dependent on the amygdala) continues to increase for some time after its initial emergence, longer than previously believed. Thus, the data show that contrary to previous understanding, the hippocampus-dependent memory system is functional as early as day 17 in rats, and the amygdala-dependent system continues to mature. Using contextual and cued fear conditioning protocols, the current project examines the emergence of amygdala and hippocampus functionality and interactions by testing the novel hypothesis that it is slow-developing amygdala- hippocampus interactions that are responsible for the developmental delay. To test this hypothesis, the effects of behavioral manipulations, immediate-early gene expression, and temporary pharmacological inactivation will be examined on various aspects fear conditioning. Overall this project will elucidate the neural structures governing the use of physical environments to regulate aversive emotional expression in developing rats. PUBLIC HEALTH RELEVANCE: This project investigates the development of limbic system function. The focus is to create and examine a paradigm that can be used to assess the connectivity between major limbic system structures including the hippocampus and amygdala. Although relatively little is known about how they functionally interact in intact developing organisms, the connectivity between these structures appears to be altered in several developmental disorders including major psychoses, autism and anxiety disorders. Thus, in addition to advancing our understanding of typical development, these experiments will open the door for future studies that further elucidate the mechanisms underlying these disorders. Therefore, this project will provide data leading to a better understanding of limbic system development and the creation of better animal models of developmental disorders.