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事件如何损害认知的例子。该项目的主要研究者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发生情况的过程。持续保持注意力对于准确执行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导致广泛的认知障碍。令人惊讶的是，压力对这种类型的注意力的影响的神经生物学机制是未知的。该项目通过使用行为，神经解剖学和分子方法来测试特定的压力相关化学信号，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脑回路，从而解决了这一知识差距。这项研究的结果将大大促进我们对压力和注意力相关的大脑系统之间相互作用的理解。因此，这些发现可能为制定旨在改善应激事件中认知的策略奠定基础。除了科学工作外，该项目还包括一项教育计划，旨在改善坦普尔大学多样化本科生的学习成果，并为改善“翻转课堂”形式的大学课程教学创造公共资源，学生首先在课外学习新材料，然后利用课堂时间与同学和老师一起做练习。虽然压力调节学习，但压力调节注意力的神经生物学机制仍然没有得到充分的研究。最近，该项目的主要研究者证明，持续的注意力被破坏的压力相关的神经肽，促肾上腺皮质激素释放因子（CRF）在雄性和雌性大鼠的中央输注。持续的注意力是由基底前脑介导的。 因此，本研究从系统到分子水平探讨CRF对基底前脑的调节作用。目的1是测试的假设，CRF直接调制基底前脑，破坏持续的注意力相结合的药理学操作和一个验证良好的注意力任务。目的2是通过逆行追踪、细胞类型特异性标记物和神经元激活的测量来揭示CRF影响基底前脑神经元的回路。目的3：利用荧光激活细胞分选技术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力回路的研究人员的重要资源，并将公开供其他研究人员使用。该项目的教育计划旨在通过开发强调认知和元认知技术的特殊作业来改善翻转课堂的形式，以促进积极参与课外材料。这些任务通过公共媒体提供，并通过实验检验其有效性。 从教育计划中获得的见解将在教育期刊上发表。

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.