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

cAMP/PKA 信号传导在记忆形成神经回路中的作用

• 批准号: 8769165
• 负责人: Seth M Tomchik
• 金额: $ 24.9万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-22 至 2015-12-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8769165
• 关键词: Adenylate Cyclase; Adult; Affect; Animal Behavior; Area; Behavior; Behavior Therapy; Behavioral; Behavioral Assay; Biological; Biological Assay; Biology; Bipolar Disorder; Brain; Brain region; Caliber; Chemistry; Collaborations; Communication; Conditioned Stimulus; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Decision Making; Discipline; Disease; Dopamine; Drosophila genus; Drosophila melanogaster; Educational workshop; Electrophysiology (science); Ensure; Environment; Event; Florida; Foundations; Functional Imaging; Future; Gene Expression; Genetic; Genetic Techniques; Goals; Health behavior; Human; Image; In Vitro; Kinetics; Knowledge; Laboratories; Laboratory Research; Lead; Learning; Life; Light; Major Depressive Disorder; Mediating; Memory; Memory Disorders; Memory impairment; Mental Depression; Mental Health; Mental disorders; Mentors; Methods; Molecular; Molecular Biology; Nervous System Physiology; Nervous system structure; Neurobiology; Neurons; Neurosciences Research; Neurotransmitters; Octopamine; Olfactory Learning; Optical reporter; Pathway interactions; Performance; Phase; Process; Production; Property; Psychology; Publishing; Punishment; RNA Interference; Reporter; Research; Research Personnel; Research Training; Resources; Rewards; Role; Rutabaga; Schizophrenia; Sensory; Sensory Physiology; Sensory Process; Signal Pathway; Signal Transduction; Solid; Stimulus; Synaptic plasticity; Techniques; Testing; Training; Translating; abstracting; adenylyl cyclase 1; base; career; career development; classical conditioning; experience; in vivo; in vivo imaging; insight; interest; knock-down; memory acquisition; memory encoding; mutant; neural circuit; neurogenetics; neuronal circuitry; neuropsychiatry; optical imaging; post-doctoral training; psychobiology; reinforcer; research study; response; undergraduate education

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.

摘要 候选 神经系统的一个基本功能是获取、分类和储存感觉信息，并利用它来 形成对世界的预测，从而影响未来的行为。我感兴趣的是这些过程是如何发生的 在分子、细胞和神经回路水平上。为了回答这些问题，我接受了以下训练： 心理学、感觉生理学、学习和记忆。我本科学的是心理学， 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， 方法来研究在嗅觉学习过程中激活的细胞信号通路。细胞内 使用基因编码的光学报告分子，结合聚焦显微镜， 将神经传递素应用于大脑的特定区域。我计划接受更多的培训， 行为分析、分子生物学、体内成像和体内光刺激通过培训奠定了 在这个提案中。这项培训将提供坚实的科学基础，并促进开展富有成效的 两年内建立独立研究实验室。我的实验室将集中在几个广泛的研究领域， 长期：I）学习改变神经元内亚细胞信号级联的方式; II）如何 学习改变了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改变了动物的行为-描绘了参与学习的回路， 决策和行为改变; IV）这些分子和细胞信号通路是如何 精神疾病的改变。如果我们能成功地回答这些问题， 健康和行为将得到显著改善。 环境 斯克里普斯佛罗里达是一个理想的环境，在其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， 从果蝇的学习和记忆到人类双相情感障碍的遗传学。 博士戴维斯的研究小组开创了基因技术来控制基因表达的空间和时间， 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了州- 最先进的设施和资源，支持生物和化学许多领域的高素质研究。 实验室之间的沟通和互助非常出色， 研究学科是普遍的做法。最后，还有频繁的科学研讨会，职业发展 研讨会，并大力支持博士后研究人员。 研究 记忆障碍是伴随许多神经精神疾病的核心缺陷。cAMP/PKA 信号通路对于记忆获得和各种形式的突触可塑性至关重要。同时他的议程似乎 与一些精神疾病有关，因为它与双相情感障碍，重度抑郁症， 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。该提案的重点是cAMP/PKA信号在学习中的作用， 以下具体目标：I）表征在关联性过程中cAMP升高如何转化为PKA活性， 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 升高刺激和未刺激的神经元通路上的cAMP，以确定 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的敲低 （RNAi）将与新开发的实时成像和光刺激方法配对，利用 黑腹果蝇的遗传能力这项研究将从指导阶段（目标一和二） 进入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信号如何在介导获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的基本机制， 恢复记忆将是我独立研究的一个主要重点，并将扩展到了解如何 这些过程在神经精神障碍中被破坏。

项目成果

Cyclic AMP-dependent plasticity underlies rapid changes in odor coding associated with reward learning.

环 AMP 依赖性可塑性是与奖励学习相关的气味编码快速变化的基础。

• DOI: 10.1073/pnas.1709037115
• 发表时间: 2018
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Louis,Thierry;Stahl,Aaron;Boto,Tamara;Tomchik,SethM
• 通讯作者: Tomchik,SethM

Dopaminergic modulation of cAMP drives nonlinear plasticity across the Drosophila mushroom body lobes.

• DOI: 10.1016/j.cub.2014.03.021
• 发表时间: 2014-04-14
• 期刊: CURRENT BIOLOGY
• 影响因子: 9.2
• 作者: Boto, Tamara;Louis, Thierry;Jindachomthong, Kantiya;Jalink, Kees;Tomchik, Seth M.
• 通讯作者: Tomchik, Seth M.

Neurofibromin Loss of Function Drives Excessive Grooming in Drosophila.

• DOI: 10.1534/g3.115.026484
• 发表时间: 2016-04-07
• 期刊: G3 (Bethesda, Md.)
• 作者: King LB;Koch M;Murphy KR;Velazquez Y;Ja WW;Tomchik SM
• 通讯作者: Tomchik SM