Intrahippocampal dynamics underlying cognitive rigidity

 描述(申请人提供)：本K01年度K01指导研究科学家发展奖旨在为Elif Engin博士提供实现下列职业目标所需的支持：1)进行高质量、多层次、多技术的研究，以加深我们对健康、S以及神经精神疾病中认知灵活性/僵化的脑回路和机制的了解；2)成为认知灵活性/僵化领域的领先专家；3)发展独立的研究事业，领导一个进行尖端研究的实验室来解决上述问题。研究复杂的现象，如认知灵活性，需要一个多层次的方法，使用与分子、电路和行为分析水平有关的技术。Engin博士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达拉斯·特雷特博士和世界知名的老鼠遗传学和行为专家乌韦·鲁道夫博士的实验室接受过培训。恩金博士还拥有组织学、药理学和光遗传学技术方面的经验。拟议项目的培训目标是：1)使用尖端的多四极管微驱动系统和复杂的分析，以及其他广泛使用的技术，如原位杂交，为Engin博士提供在自由活动的小鼠体内电生理学方面的培训；2)通过培训研究交流、领导、拨款和其他必要技能，促进Engin博士的职业发展，以成功地建立和维持一个研究实验室；3)建立一个知识库，通过负责任的研究进行培训，解决科学研究中的伦理问题；4)扩展Engin博士的专业网络，包括未来可能的合作者、导师、被辅导者5)确保通过高质量的出版物和口头陈述适当地传播科学发现。恩金博士的指导 团队由各自领域的3名专家组成。首席导师克里·雷斯勒博士将提供与恐惧学习和记忆相关的行为任务方面的技术培训，SIT杂交方面的技术培训，翻译研究方面的研究培训，以及拨款撰写、实验室管理和求职准备方面的一般培训。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，他将提供海马棘波和场电位数据分析、海马区编码和检索过程的理论基础以及职业发展方面的培训。Shantanu Jadhav博士是体内电生理学方面的专家，特别是在海马体重放/再激活领域，他将提供电生理学数据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。这项拟议的研究项目集中在海马区与认知僵化的相关性。尽管是大量神经精神疾病的认知症状，这些疾病在美国总共影响着3000多万人，但对认知僵化的神经机制还没有进行系统的研究。这项应用的总体研究目标是利用Engin和Rudolph博士开发的具有特定认知刚性表型的小鼠模型来确定认知刚性背后的海马体电路水平动力学。中心假设是，认知僵硬表型与再巩固缺陷有关，特别是在记忆不稳定阶段。在我们的第一个特定目标中，我们建议记录自由移动小鼠的局部场电位、棘波活动和放置细胞活动，这些小鼠学习使用多个四极微驱动器将奖励与迷宫上的特定位置相关联，以1)确定认知僵硬是否与海马新颖性反应的缺陷有关，通过抑制海马theta活动来衡量，2)建立认知僵硬的小鼠是否在提取/编码平衡中表现出提取偏向，如通过theta循环中CA1锥体神经元的首选尖峰阶段来衡量，以及3)确定僵硬行为是否反映在僵硬的海马对旧轨迹的重演中，通过在奖赏位置偶然性逆转后旧奖赏轨迹的重播的持久性来衡量。我们的假设是，α5DGKO小鼠的海马区新颖性反应将受到抑制，并倾向于提取，这将损害重新激活时记忆的不稳定，这一缺陷将反映在海马区对旧轨迹的刚性重播中。在我们的第二个具体目标中，我们建议使用一种药理学-遗传学-行为学相结合的方法来确定认知僵硬小鼠在重新巩固过程中的记忆失稳是否受到损害。我们相信，拟议的研究结果将产生积极的影响，因为海马体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障碍治疗策略的基础。从这项建议中获得的知识、经验和数据将直接导致研究海马体输出到下游结构和更大的大脑网络调节适应性认知灵活性，这将在3-4的R01拨款申请中提出 获奖的年头。

 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.