Intrahippocampal dynamics underlying cognitive rigidity

认知僵化背后的海马内动态

• 批准号: 9109298
• 负责人: ELIF ENGIN
• 金额: $ 17.63万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9109298
• 关键词: Address; Affect; Affective; Anxiety; Anxiety Disorders; Applications Grants; Area; Autistic Disorder; Award; Behavior; Behavioral; Behavioral Genetics; Brain; Characteristics; Cognitive; Collection; Communication Research; Complex; Computer Simulation; Data; Detection; Electrophysiology (science); Equilibrium; Ethical Issues; Extinction (Psychology); Failure; Foundations; Freezing; Fright; Future; Goals; Grant; Health; Hippocampus (Brain); Impairment; In Situ Hybridization; Investigation; Knock-out; Knowledge; Laboratories; Laboratory Research; Lead; Leadership; Learning; Link; Location; Measures; Mediating; Memory; Mental Depression; Mental disorders; Mentored Research Scientist Development Award; Mentors; Modeling; Molecular; Mood Disorders; Mus; Neurobehavioral Manifestations; Occupations; Oral; Outcome; Outcome Study; Output; Pattern; Phase; Phenotype; Play; Post-Traumatic Stress Disorders; Preparation; Process; Publications; Pyramidal Cells; Research; Research Project Grants; Research Technics; Research Training; Retrieval; Rewards; Rodent; Role; Schizophrenia; Spike Potential; Structure; Symptoms; System; Techniques; Testing; Therapeutic; Thinking; Training; Translational Research; Update; Work; Writing; autism spectrum disorder; base; behavioral pharmacology; brain circuitry; career; career development; career networking; cognitive rigidity; conditioned fear; dentate gyrus; entorhinal cortex; experience; flexibility; hippocampal pyramidal neuron; improved; in vivo; knowledge base; memory consolidation; memory retrieval; mouse model; neuromechanism; neurophysiology; neuropsychiatric disorder; optogenetics; public health relevance; receptor; relating to nervous system; response; responsible research conduct; skills; therapeutic development

 DESCRIPTION (provided by applicant): This K01 Mentored Research Scientist Development Award aims to provide Dr. Elif Engin with the support required to reach the following career goals: 1) to conduct high-quality, multi-level, multi-technique research to improve our understanding of the brain circuitry and mechanisms of cognitive flexibility / rigidity in health, s well as in neuro-psychiatric disease, 2) to become a leading expert in the area of cognitive flexibility / rigidity; 3) to develop an independent research career, leading a laboratory that doe cutting edge research to address the above questions. The study of complex phenomena such as cognitive flexibility requires a multi-level approach using techniques pertaining to molecular, circuit and behavioral levels of analysis. Dr. Engin has a strong background in molecular and behavioral techniques, having received training in the laboratories of Dr. Dallas Treit, a pioneer in the field of rodent behavioral pharmacology, and Dr. Uwe Rudolph, a world renowned expert in mouse genetics and behavior. Dr. Engin also has experience in histological, pharmacological and optogenetic techniques. The training objectives of the proposed project are to 1) Provide Dr. Engin with training in in vivo electrophysiology in freely moving mice, using cutting-edge multi-tetrode microdrive systems and sophisticated analyses, as well as in other widely-used techniques, such as in situ hybridization, 2) Facilitate Dr. Engin's career development through training in research communication, leadership, grant-writing and other necessary skills to successfully establish and maintain a research laboratory, 3) Establish a knowledge base to address ethical issues in scientific research through training in responsible conduct of research, 4) Extend Dr. Engin's professional network to include possible future collaborators, mentors, mentees, experts in related scientific areas, and 5) Assure the appropriate dissemination of the scientific findings through high quality publications and oral presentations. Dr. Engin's mentoring team is comprised of 3 experts in their respective areas. The primary mentor, Dr. Kerry Ressler, will provide technical training in behavioral tasks related to fear learning and memory, and in sit hybridization, research training in translational research, as well as general training in grant-writing, laboratory management, and the preparation for a job search. Dr. Michael Hasselmo is an expert in hippocampal neurophysiology and computational modeling of neural systems, and will provide training in the analysis of hippocampal spike and field potential data, the theoretica underpinnings of hippocampal encoding and retrieval processes, as well as in career development. Dr. Shantanu Jadhav is an expert in in vivo electrophysiology, especially in the field of hippocampal replay / reactivation, and will provide technical training in the collection ad analysis of electrophysiology data. All three mentors will be involved in responsible conduct of research training. The proposed research project concentrates on the hippocampal correlates of cognitive rigidity. Despite being a cognitive symptom in a large number of neuro-psychiatric diseases, which together affect more than 30 million people in the US, a systematic study of the neural mechanisms of cognitive rigidity has not been undertaken. The overall research objective of this application is to determine the hippocampal circuit level dynamics underlying cognitive rigidity by utilizing a mouse model developed by Drs. Engin and Rudolph, which has a specific cognitive rigidity phenotype. The central hypothesis is that the cognitive rigidity phenotype is associated with a deficiency in reconsolidation, specifically in the memory destabilization phase. In our first specific aim, we propose to record local field potentials, spike activity and place cel activity in freely moving mice learning to associate rewards with specific locations on a maze using multi-tetrode micro drives to 1) Determine whether cognitive rigidity is associated with deficiencies in the hippocampal novelty response, as measured by the suppression of the hippocampal theta activity, 2) Establish if cognitively rigid mice show retrieval bias in the retrieval/encoding balance, as measured by the preferred spiking phase of the CA1 pyramidal neurons within the theta cycle, and 3) Determine whether rigid behavior is reflected in rigid hippocampal replay of old trajectories, as measured by the persistence of the replay of old reward trajectories following a reversal of the reward-location contingency. Our hypothesis is that the α5DGKO mice will have a dampened hippocampal novelty response and a bias towards retrieval, which would impair memory destabilization upon reactivation, and that this deficiency would be reflected in rigid hippocampal replay of old trajectories. In our second specific aim, we propose to use a combined pharmacological-genetic-behavioral approach to determine whether memory destabilization during reconsolidation is impaired in cognitively rigid mice. We believe the outcomes of the proposed studies will have a positive impact because the hippocampus-mediated processes constitute the foundation for the systematic study of the brain mechanisms of cognitive flexibility and the development of therapeutic strategies for neuro-psychiatric disorders. The knowledge, experience and data gained from this proposal will lead directly to the study of hippocampal outputs to downstream structures and the larger brain network mediating adaptive cognitive flexibility, which will be proposed in an R01 grant application in 3-4 years of the award.

 描述（由申请人提供）：本次K01指导研究科学家发展奖旨在为Elif Engin博士提供实现以下职业目标所需的支持：1）进行高质量、多层次、多技术的研究，以提高我们对健康以及神经精神疾病中认知灵活性/刚性的大脑回路和机制的理解，2) 成为认知灵活性/刚性领域的领先专家3)；发展独立的研究生涯，领导一个进行前沿研究来解决上述问题的实验室，对认知灵活性等复杂现象的研究需要采用与分子、电路和行为水平分析相关的技术的多层次方法。 Engin在分子和行为技术方面拥有深厚的背景，曾在啮齿动物行为药理学领域的先驱Dallas Treit博士和世界著名的小鼠遗传学和行为学专家Uwe Rudolph博士的实验室接受过培训。恩金也有经验。拟议项目的培训目标是 1) 使用尖端的多四极微驱动系统和复杂的分析，为 Engin 博士提供自由活动小鼠的体内电生理学培训。其他广泛使用的技术，如原位杂交，2) 通过研究沟通、领导力、资助写作和其他成功建立和维持研究实验室所需的技能培训，促进 Engin 博士的职业发展，3)建立知识库，通过负责任的研究行为培训来解决科学研究中的伦理问题，4) 扩展 Engin 博士的专业网络，以包括未来可能的合作者、导师、受训者、相关科学领域的专家，以及 5) 确保适当的传播通过高质量的出版物和 Engin 博士的指导来了解科学发现。 团队由3名各自领域的专家组成，首席行为导师Kerry Ressler博士将提供与恐惧学习和记忆相关的任务的技术培训、原位杂交、转化研究的研究培训以及一般培训。 Michael Hasselmo 博士是海马神经生理学和神经系统计算建模方面的专家，他将提供海马尖峰和场电位数据分析方面的培训。 Shantanu Jadhav 博士是体内电生理学专家，特别是海马重放/重新激活领域的专家，并将提供电生理学收集和分析方面的技术培训。所有三位导师都将参与负责任的研究培训，该研究项目的重点是认知僵化的海马体相关性。大量神经精神疾病共同影响了美国超过 3000 万人，但尚未对认知僵化的神经机制进行系统研究，该应用的总体研究目标是确定海马回路水平动态。利用 Engin 和 Rudolph 博士开发的小鼠模型来研究潜在的认知僵化，该模型具有特定的认知僵化表型。中心假设是认知僵化表型与再巩固缺陷有关，特别是记忆不稳定。在我们的第一个具体目标中，我们建议记录自由移动小鼠的局部场电位、尖峰活动和位置细胞活动，学习使用多四极微驱动器将奖励与迷宫上的特定位置相关联，以 1) 确定认知僵化是否是。与海马新奇反应缺陷相关，通过抑制海马 theta 活动来测量，2) 确定认知僵化的小鼠是否在检索/编码平衡中表现出检索偏差，如通过 theta 周期内 CA1 锥体神经元的首选尖峰阶段来测量，以及 3) 确定刚性行为是否反映在旧轨迹的刚性海马重放中，如通过逆转后旧奖励轨迹重放的持久性来测量我们的假设是，α5DGKO 小鼠的海马新奇反应会减弱，并且会偏向检索，这会损害记忆不稳定。重新激活后，这种缺陷将反映在旧轨迹的刚性海马重放中。在我们的第二个具体目标中，我们建议使用药理学-遗传-行为相结合的方法来确定认知刚性小鼠在重新巩固过程中的记忆不稳定是否受到损害。我们相信所提出的研究结果将产生积极影响，因为海马介导的过程构成了系统研究认知灵活性的大脑机制和开发神经精神治疗策略的基础从该提案中获得的知识、经验和数据将直接用于对海马输出到下游结构和介导适应性认知灵活性的更大大脑网络的研究，这将在 3-4 的 R01 拨款申请中提出。 获奖年数。