CAREER: Interactions between Stress and Attention Circuits: Investigating Corticotropin Releasing Factor Modulation of the Basal Forebrain

我们很容易想到生活中的压力性事件如何损害认知的例子。这个项目的主要研究人员感兴趣的是压力损害持续注意力的能力，即监测罕见和不可预测事件的情况的过程。保持足够的注意力对于准确完成更复杂的认知任务至关重要。因此，压力导致的持续注意力中断可能会导致广泛的认知障碍。令人惊讶的是，压力对这类注意力的影响背后的神经生物学机制尚不清楚。该项目通过使用行为、神经解剖学和分子方法来解决这一知识差距，以测试一种特定的与应激相关的化学信号-促肾上腺皮质激素释放因子-如何调节雄性和雌性大鼠持续注意力所需的大脑回路。这项研究的结果将极大地促进我们对压力和注意力所涉及的大脑系统之间的相互作用的理解。因此，这些发现可能会为制定旨在改善应激事件中认知能力的策略奠定基础。除了科研工作，该项目还包括一项教育计划，旨在改善坦普尔大学不同本科生的学习效果，并创造公共资源，以改善大学课程的教学。在这种模式下，学生首先在课堂外学习新材料，然后利用课堂时间与同学和老师一起练习。研究已经研究了压力如何调节学习，而压力调节注意力的神经生物学机制仍未被探索。最近，该项目的主要研究人员证明，中枢注射应激相关神经肽促肾上腺皮质激素释放因子(CRF)会扰乱雄性和雌性大鼠的持续注意力。众所周知，持续的注意力是由基底前脑调节的。因此，本项目研究CRF如何从系统到分子水平调节基底前脑。目的1是验证CRF通过结合药理操作和有效验证的注意任务来直接调节基底前脑以干扰持续注意的假设。目的2是通过逆行示踪、细胞类型特异性标记和神经元激活的测量，揭示CRF影响基底前脑神经元的通路。目的3利用荧光活化细胞分选结合下一代测序技术，鉴定CRF诱导的基底前脑胆碱能神经元的分子变化。这些发现将提高我们对压力如何影响认知的基本理解。这项工作产生的丰富的测序数据是研究注意回路的研究人员的重要资源，并将公开提供给其他研究人员使用。该项目的教育计划旨在通过制定特别作业来改进翻转课堂的形式，强调认知和元认知技术，以促进对课外材料的积极参与。这些任务是通过公共媒体提供的，其有效性通过实验进行了检验。从教育计划中获得的见解将发表在教育期刊上。

It is easy to think of examples of how stressful life events can impair cognition. Of interest to the principal investigator of this project is the ability of stress to impair sustained attention, the process of monitoring situations for rare and unpredictably occurring events. Adequately sustaining attention is critical for accurately performing more complex cognitive tasks. Therefore, disruptions in sustained attention as a result of stress can lead to widespread cognitive impairments. Surprisingly, the neurobiological mechanisms that underlie the effect of stress on this type of attention are unknown. This project addresses this gap in knowledge by using behavioral, neuroanatomical, and molecular approaches to test how a specific stress-related chemical signal, corticotropin releasing factor, regulates the brain circuitry required for sustained attention in male and female rats. The results from this research will greatly advance our understanding of the interactions between the brain systems involved in stress and attention. These findings thereby may lay the groundwork for the development of strategies aimed at improving cognition during stressful events. In addition to the scientific work, this project includes an education plan designed to improve student learning outcomes for Temple University's diverse undergraduate population and create public resources for improving the teaching of college courses in the "flipped-classroom" format, in which students first learn new material outside of class and then use class time to work on exercises with classmates and the instructor.Studies have examined how stress modulates learning, the neurobiological mechanisms by which stress modulates attention remain underexplored. Recently, the principal investigator of this project demonstrated that sustained attention is disrupted by central infusions of the stress-related neuropeptide, corticotropin releasing factor (CRF) in male and female rats. Sustained attention is known to be mediated by the basal forebrain. Therefore, this project examines how CRF regulates the basal forebrain from the systems to the molecular levels. Aim 1 is to test the hypothesis that CRF directly modulates the basal forebrain to disrupt sustained attention by combining pharmacological manipulations and a well-validated attention task. Aim 2 is to uncover the circuitry by which CRF can impact basal forebrain neurons by using retrograde tracing, cell-type specific markers, and measures of neuronal activation. Aim 3 is to identify molecular changes induced by CRF in cholinergic basal forebrain neurons by using Fluorescent Activated Cell Sorting in combination with next generation sequencing. The findings will improve our fundamental understanding of how stress affects cognition. The rich sequencing data resulting from this work is an important resource for researchers studying attention circuits, and is to be made publicly available for use by other investigators. The project's education plan is designed to improve the flipped-classroom format by developing special assignments that emphasize cognitive and metacognitive techniques to promote active engagement with the out-of-class material. These assignments are made available through public media and their efficacy is examined experimentally. The insights gained from the educational plan are to be published in education journals.