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

神经系统的一个基本功能是获取、分类和存储感觉信息，用它来预测影响未来行为的世界。我感兴趣的是这些过程是如何在分子、细胞和神经元回路水平上发生的。为了研究这些问题，我接受了心理学、感觉生理学、学习和记忆方面的训练。我的本科教育是心理学，重点是心理生物学。在我的研究生和早期博士后培训期间，我研究了神经系统如何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，使用实验方法研究嗅觉学习过程中激活的细胞信号通路。使用遗传编码的光学报告分子，结合神经递质在大脑限定区域的局部应用，在完整大脑中对细胞内信号传导事件进行成像。我计划通过本提案中列出的培训获得行为分析、分子生物学、体内成像和体内光刺激方面的额外培训。这一培训将提供坚实的科学基础，并有助于在两年内启动一个富有成效的独立研究实验室。从长远来看，我的实验室将专注于几个广泛的研究领域：I）学习改变神经元内亚细胞信号级联的方式; II）学习如何改变编码记忆的神经元阵列的反应特性; III）神经元反应性的变化如何改变动物行为-描绘参与学习，决策和行为改变的电路; IV）这些分子和细胞信号通路在精神疾病中是如何改变的。如果我们能够成功地回答这些问题，我们对心理健康和行为的理解将大大提高。环境斯克里普斯佛罗里达是一个理想的环境中进行拟议的研究和培训。戴维斯实验室在神经遗传学和行为分析方面有着长期而出色的记录，保持着从果蝇学习和记忆到人类双相情感障碍遗传学等主题的持续项目。戴维斯博士的团队开创了控制基因表达空间和时间的遗传技术，并建立了成年果蝇大脑的体内成像技术。斯克里普斯佛罗里达提供最先进的设施和资源，支持生物学和化学许多领域的高素质研究。实验室之间的交流和互助非常出色，传统研究学科之间的合作是常见的做法。最后，有频繁的科学研讨会，职业发展研讨会，并为博士后研究人员提供强有力的支持。研究记忆障碍是伴随许多神经精神疾病的核心缺陷。cAMP/PKA信号通路对记忆获得和各种形式的突触可塑性至关重要。它似乎也涉及一些精神疾病，因为它与双相情感障碍，重度抑郁症和精神分裂症有关。因此，了解这一途径对于理解学习和记忆以及心理健康和疾病至关重要。本研究的主要目的是：（1）研究cAMP/PKA信号通路在学习中的作用;（2）研究几种腺苷酸环化酶在学习中的作用;（3）研究cAMP升高对受刺激和未受刺激的神经元通路的影响，以确定平行排列的神经元如何编码联想记忆; IV）测试cAMP升高是否足以形成厌恶性记忆。为了实现这些目标，行为分析和基因表达敲低（RNAi）将与新开发的实时成像和光刺激方法相结合，利用果蝇的遗传能力。这项研究将从指导阶段（目标I和II）延伸到我职业生涯的独立阶段（目标III和IV）。这些实验的结果将有助于揭示cAMP/PKA信号如何在介导记忆获得和行为表达的神经元阵列中发挥作用。阐明神经元和回路编码和检索记忆的基本机制将是我独立研究的主要重点，并将扩展到了解这些过程如何在神经精神疾病中被破坏。

DESCRIPTION (provided by applicant): 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.