Neural mechanisms of stress effects across hippocampal encoding and prediction

项目摘要 压力事件或急性压力源是日常生活中不可避免的一部分，可以加速精神疾病的发作。 健康失调急性压力促进心理发展的一种强大机制是 健康问题是通过改变海马体的结构和功能，海马体是一个重要的大脑结构， 学习然而，这种关系是复杂的：急性应激既可以增强也可以损害海马体的学习， 使得治疗的靶向机制不清楚。对啮齿动物的研究表明，这些矛盾的 研究结果可以部分解释不同的压力作用在不同的途径和亚区域内， 海马体。这些机制是否延伸到人类尚不清楚。缓解急性压力的措施 学习有助于精神病理学和设计有针对性的干预措施，迫切需要 了解压力改变人类海马学习的机制。探索性的R21 该提案利用认知神经科学的最新进展开发创新的功能性神经成像 和针对不同海马通路的行为方案，以便将动物的应激结果 建立模型，并揭示压力对人类不同类型学习产生偏见的机制。我们将测试 新的假设，情节编码，其中涉及三突触通路（显示受损， 啮齿动物模型中的应激：内嗅皮层、齿状回、角氨[CA] 3和CA 1）将被 急性应激，而统计学习，其中涉及单突触通路（显示幸免或 应激增强：内嗅皮层，CA 1）将被急性应激增强。这项工作标志着第一个 研究压力对统计学习的影响，统计学习是一种普遍存在的学习过程，最近与心理学有关。 疾病和治疗结果。初步数据表明，一个单一的行为范式可以提供指数， 情节编码和统计学习的研究，绘制了不同的海马相关物。在目标1.1中，我们将优化 在目标1.2中，我们将确定一个行为模式的后果， 急性应激诱导学习和延迟检索这些情节和统计表示。在aim中 2、将功能性神经成像（fMRI）与海马子场分割相结合， 单变量，多变量和连接分析，以量化压力调节的神经机制 这些不同的学习过程。这些目标的成功实现为翻译奠定了基础 从啮齿动物到人类的应激行为的神经生物学机制，提供关键信息，以揭示 新的干预目标，减轻压力导致的负面心理健康结果的风险。

PROJECT SUMMARY Stressful events, or acute stressors, are an inescapable part of daily life and can precipitate the onset of mental health disorders. One powerful mechanism by which acute stress contributes to the development of mental health problems is through altering the structure and function of the hippocampus, a crucial brain structure for learning. However, this relationship is complex: acute stress can both enhance and impair hippocampal learning, making target mechanisms for treatment unclear. Research in rodents has shown that these contradictory findings can be partly explained by distinct stress actions on different pathways and subregions within the hippocampus. Whether these mechanisms extend to humans is unknown. To mitigate acute stress actions on learning that contribute to psychopathology and design targeted interventions, there is a pressing need to understand the mechanisms by which stress alters hippocampal learning in humans. This exploratory R21 proposal leverages recent advances in cognitive neuroscience to develop innovative functional neuroimaging and behavioral protocols targeting distinct hippocampal pathways in order to translate stress findings from animal models and uncover the mechanisms by which stress biases different types of learning in humans. We will test the novel hypothesis that episodic encoding, which involves the trisynaptic pathway (shown to be impaired by stress in rodent models: entorhinal cortex, dentate gyrus, cornu ammonis [CA] 3, and CA 1) will be impaired by acute stress, whereas statistical learning, which involves the monosynaptic pathway (shown to be spared or enhanced by stress: entorhinal cortex, CA1) will be enhanced by acute stress. This work marks the first investigation of stress effects on statistical learning, a ubiquitous learning process recently implicated in mental illness and treatment outcomes. Preliminary data indicate that a single behavioral paradigm can provide indices of episodic encoding and statistical learning that map distinct hippocampal correlates. In Aim 1.1, we will optimize this behavioral paradigm for detecting stress effects, and in Aim 1.2 we will determine the consequences of an acute stress induction for learning and delayed retrieval of these episodic and statistical representations. In Aim 2, we will use functional neuroimaging (fMRI) together with hippocampal subfield segmentation and sophisticated univariate, multivariate, and connectivity analyses, to quantify the neural mechanisms by which stress modulates these distinct learning processes. Successful completion of these aims lays the foundation for translating neurobiological mechanisms of stress actions from rodents to humans, providing critical information to reveal novel targets for interventions that mitigate the risk of negative mental health outcomes resulting from stress.