Intrahippocampal dynamics underlying cognitive rigidity

认知僵化背后的海马内动态

• 批准号: 9462227
• 负责人: ELIF ENGIN
• 金额: $ 17.17万
• 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/9462227
• 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; Genetic; Goals; Grant; Health; Hippocampus (Brain); Histologic; Impairment; In Situ Hybridization; Investigation; Knock-out; Knowledge; Laboratories; Laboratory Research; Lead; Leadership; Learning; Link; Location; Measures; Mediating; Memory; Memory impairment; Mental Depression; Mentored Research Scientist Development Award; Mentors; Modeling; Molecular; Mood Disorders; Mus; Neurobehavioral Manifestations; Occupations; Oral; Outcome; Outcome Study; Output; Pathologic; Pattern; Pharmacology; 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; Structure; Symptoms; System; Techniques; Testing; Therapeutic; Thinking; Training; Translational Research; Update; 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; neural model; neuromechanism; neurophysiology; neuropsychiatric disorder; optogenetics; public health relevance; receptor; 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）：K 01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，以提高我们对健康和神经精神疾病中认知灵活性/刚性的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，领导一个实验室进行尖端研究，以解决上述问题。对认知灵活性等复杂现象的研究需要使用与分子、电路和行为水平分析有关的技术的多层次方法。Engin博士在分子和行为技术方面有很强的背景，曾在啮齿动物行为药理学领域的先驱达拉斯Treit博士和世界知名的小鼠遗传学和行为专家Uwe Rudolph博士的实验室接受过培训。Engin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）为Engin博士提供自由移动小鼠体内电生理学培训，使用尖端的多四极微驱动系统和复杂的分析，以及其他广泛使用的技术，例如原位杂交，2）通过研究沟通、领导力、资助写作和其他必要的技能，以成功地建立和维持一个研究实验室，3）建立一个知识库，以解决科学研究中的道德问题，通过培训负责任的研究行为，4）扩大博士。5）确保通过高质量的出版物和口头报告适当传播科学成果。Engin博士的指导 团队由各自领域的3名专家组成。Kerry Ressler博士将提供与恐惧学习和记忆相关的行为任务的技术培训，以及原位杂交，转化研究的研究培训，以及赠款写作，实验室管理和求职准备的一般培训。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方面的培训，海马编码和检索过程的理论基础，以及职业发展。Shantanu Jadhav博士是体内电生理学方面的专家，特别是在海马重放/重新激活领域，并将提供电生理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。拟议的研究项目集中在认知僵化的海马相关。尽管在大量的神经精神疾病中认知症状，这些疾病在美国总共影响超过3000万人，但尚未对认知僵化的神经机制进行系统研究。本申请的总体研究目标是通过利用Engin和Rudolph博士开发的具有特定认知僵化表型的小鼠模型来确定认知僵化背后的海马回路水平动力学。核心假设是认知僵化表型与再巩固缺陷相关，特别是在记忆不稳定阶段。在我们的第一个具体目标中，我们提出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，这些小鼠使用多四极微驱动器学习将奖励与迷宫上的特定位置相关联，以1）确定认知刚性是否与海马新奇反应的缺陷相关，如通过海马θ活动的抑制所测量的，2）确定认知刚性小鼠是否在检索/编码平衡中显示检索偏差，如通过θ周期内CA 1锥体神经元的优选尖峰相位所测量的，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，如通过在奖励位置偶然性反转之后旧奖励轨迹的重放的持续性所测量的。我们的假设是，α5DGKO小鼠的海马新奇反应减弱，并偏向于提取，这将损害重新激活后的记忆不稳定性，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，我们建议使用一种结合药理学-遗传学-行为学的方法来确定在认知僵化的小鼠中，记忆再巩固过程中的不稳定是否受损。我们相信，拟议的研究结果将产生积极的影响，因为大脑皮层介导的过程构成了认知灵活性的大脑机制的系统研究和神经精神疾病的治疗策略的发展的基础。从该提案中获得的知识、经验和数据将直接导致海马输出到下游结构的研究，以及介导适应性认知灵活性的更大的大脑网络，这将在3-4的R 01资助申请中提出。 获奖的年份