The Role of cAMP/PKA Signaling in Neural Circuits Underlying Memory Formation

摘要 侯选人 神经系统的一个基本功能是获取、分类和存储感觉信息，使用它来 形成对世界的预测，影响未来的行为。我对这些过程是如何发生的很感兴趣 在分子、细胞和神经元电路水平上。为了回答这些问题，我接受了以下培训 心理学、感觉生理学、学习和记忆。我的本科教育是心理学， 重点是心理生物学。在我的研究生和博士后早期培训期间，我研究了 神经系统使用电生理学和成像方法获取和处理感觉信息。 目前，我正在罗纳德·戴维斯博士的实验室研究联想学习，使用的是一种实验性的 研究嗅觉学习过程中激活的细胞信号通路的方法。细胞内 信号事件在完整的大脑中使用基因编码的光学记者进行成像，结合焦点 神经递质在大脑受限区域的应用。我计划在以下领域获得额外的培训 通过行为分析、分子生物学、活体成像和活体光刺激等方面的培训 在这项提案中。这一培训将提供坚实的科学基础，并促进启动富有成效的 两年内建成独立研究实验室。我的实验室将专注于几个广泛的研究领域 长期：i)学习修改神经元内亚细胞信号级联的方式；ii)如何 学习改变了对记忆进行编码的神经元阵列的反应特性；iii) 神经元响应性的变化改变了动物的行为--描绘了参与学习的电路， 决策和行为调整；IV)这些分子和细胞信号通路是如何 因精神疾病而改变的。如果我们能成功地回答这些问题，我们对心理的理解 健康和行为水平将显著提高。 环境 佛罗里达州斯克里普斯是开展拟议研究和培训的理想环境。戴维斯夫妇 Lab在神经遗传学和行为分析方面有着长期而出色的记录，保持着持续的 主题从果蝇的学习和记忆到人类双相情感障碍的遗传学的项目。 戴维斯博士的团队开创了在空间和时间上控制基因表达的基因技术，并且 已经建立了成年果蝇大脑的活体成像技术。斯克里普斯佛罗里达州提供最新的 最先进的设施和资源，支持许多生物和化学领域的高水平研究。 实验室之间的沟通和互助非常出色，跨传统 研究学科是一种常见的做法。最后，还有频繁的科学研讨会，职业发展 研讨会，以及对博士后研究人员的大力支持。 研究 记忆障碍是伴随许多神经精神障碍的核心缺陷。营地/库尔德工人党 信号通路对记忆获得和各种形式的突触可塑性至关重要。它看起来也是 与一些精神疾病有关，因为它与双相情感障碍、严重抑郁障碍、 和精神分裂症。因此，了解这一途径对于理解学习和记忆至关重要 以及心理健康和疾病。这项建议侧重于cAMP/PKA信号在学习中的作用， 以下具体目标：i)描述cAMP升高如何转化为PKA活动 学习；ii)研究几种候选腺苷酸环化酶在学习中的作用；iii)检查 在刺激和未刺激的神经元通路上升高cAMP以确定平行阵列 神经元编码联想记忆；IV)测试cAMP升高是否足以形成 令人厌恶的记忆。为了实现这些目标，行为分析和基因表达下调 (RNAi)将与新开发的实时成像和光刺激方法配对，利用 黑腹果蝇的遗传力。本研究将从指导阶段开始(目标I和II) 进入我职业生涯的独立阶段(目标三和目标四)。这些实验的结果将有助于揭示 CAMP/PKA信号如何在调节习得和行为的神经元阵列中发挥作用 记忆的表达。阐明神经元和电路编码和编码的基本机制 找回记忆将是我独立研究的一个主要焦点，并将扩展到理解如何 这些过程在神经精神障碍中被打乱。

Abstract Candidate A fundamental function of nervous systems is to acquire, categorize, and store sensory information, using it to form predictions about the world that influence future behavior. I am interested in how these processes occur at the molecular, cellular, and neuronal circuit levels. In pursuit of these questions, I have acquired training in psychology, sensory physiology, and learning and memory. My undergraduate education was in psychology, with an emphasis on psychobiology. During my graduate and early postdoctoral training, I studied how the nervous system acquires and processes sensory information using electrophysiology and imaging approaches. Currently, I am studying associative learning in the laboratory of Dr. Ronald Davis, using an experimental approach to study the cellular signaling pathways that are activated during olfactory learning. Intracellular signaling events are imaged in intact brains using genetically-encoded optical reporters, combined with focal application of neurotransmitters to circumscribed regions of the brain. I plan to acquire additional training in behavioral analysis, molecular biology, in vivo imaging, and in vivo photostimulation through the training laid out in this proposal. This training will provide a solid scientific foundation and facilitate launching a productive independent research laboratory within two years. My lab will focus on several broad research areas over the long term: I) the ways in which learning modifies subcellular signaling cascades within neurons; II) how learning alters the response properties across the arrays of neurons that encode memories; III) how the changes in neuronal responsivity alter animal behavior - delineating the circuits that are involved in learning, decision making, and behavioral modification; IV) how these molecular and cellular signaling pathways are altered in mental illnesses. If we can successfully answer these questions, our understanding of the mental health and behavior will be significantly advanced. Environment Scripps Florida is an ideal environment in which to carry out the proposed research and training. The Davis lab has a long and outstanding track record in neurogenetics and behavioral analysis, maintaining ongoing projects on topics ranging from Drosophila learning and memory to the genetics of bipolar disorder in humans. Dr. Davis' group has pioneered genetic techniques to control gene expression spatially and temporally, and has established techniques for in vivo imaging of the adult Drosophila brain. Scripps Florida provides state-of- the-art facilities and resources, supporting high-caliber research across many areas of biology and chemistry. Communication and mutual assistance between labs is outstanding, and collaboration across traditional research disciplines is common practice. Finally, there are frequent scientific seminars, career development workshops, and strong support for postdoctoral researchers. Research Memory impairment is a core deficit accompanying many neuropsychiatric disorders. The cAMP/PKA signaling pathway is critical for memory acquisition and various forms of synaptic plasticity. It also appears to be involved in some mental illnesses, as it has been implicated in bipolar disorder, major depressive disorder, and schizophrenia. Therefore, understanding this pathway is critical for understanding learning and memory as well as mental health and illness. This proposal focuses on the role of cAMP/PKA signaling in learning, with the following specific aims: I) characterize how cAMP elevation translates into PKA activity during associative learning; II) investigate the roles of several candidate adenylyl cyclases in learning; III) examine the effects of elevating cAMP on stimulated and unstimulated neuronal pathways to determine how parallel arrays of neurons encode associative memories; IV) test whether cAMP elevation is sufficient for the formation of aversive memories. To accomplish these aims, behavioral analysis and knock-down of gene expression (RNAi) will be paired with newly-developed live imaging and photostimulation methods, taking advantage of the genetic power of Drosophila melanogaster. This research will extend from the mentored phase (aims I and II) into the independent phase of my career (aims III and IV). The results of these experiments will help reveal how cAMP/PKA signaling functions across arrays of neurons that mediate the acquisition and behavioral expression of memory. Elucidating the fundamental mechanisms with which neurons and circuits encode and retrieve memories will be a major focus of my independent research, and will be extended to understand how these processes are disrupted in neuropsychiatric disorders.