Septohippocampal circuit deep brain stimulation for selective RDoC aspects of cognition

中隔海马环路脑深部刺激用于认知的选择性 RDoC 方面

• 批准号: 10054745
• 负责人: Darrin Jason Lee
• 金额: $ 19.63万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10054745
• 关键词: Acute; Amygdaloid structure; Animals; Anxiety; Area; Attention; Behavior; Behavioral; Biological Markers; Brain; Brain region; Chronic; Cognition; Cognitive; Cognitive deficits; Collaborations; Data; Data Analyses; Deep Brain Stimulation; Depressed mood; Development; Diffuse; Disease; Doctor of Philosophy; Electric Stimulation; Electrodes; Electrophysiology (science); Elements; Emotional; Epilepsy; Etiology; Event-Related Potentials; Exhibits; Feedback; Foundations; Frequencies; Functional disorder; Funding; Genetic; Genetic Models; Glutamates; Hippocampus (Brain); Impaired cognition; Impairment; Interneurons; K-Series Research Career Programs; Knock-out; Lead; Learning; MK801; Machine Learning; Medial; Medial Septal Nucleus; Memory; Memory impairment; Mental disorders; Mentors; Modality; Modeling; Molecular; Mus; N-Methyl-D-Aspartate Receptors; N-methyl-D-glutamate; NR1 gene; National Institute of Mental Health; Nucleus Accumbens; Outcome Measure; Pacemakers; Parvalbumins; Patients; Pattern; Pharmacology; Phase; Phenotype; Plant Roots; Play; Positioning Attribute; Prefrontal Cortex; Psychiatric therapeutic procedure; Reaction Time; Research; Research Design; Research Domain Criteria; Research Methodology; Research Personnel; Rest; Rodent Model; Role; Schizoaffective Disorders; Schizophrenia; Services; Short-Term Memory; Social Interaction; Specificity; Structure; Techniques; Testing; Thalamic Nuclei; Thalamic structure; Therapeutic; Time; Training; Traumatic Brain Injury; autism spectrum disorder; basal forebrain; behavior measurement; behavioral impairment; behavioral outcome; career; catalyst; cell type; cognitive function; effective therapy; functional restoration; genetic approach; improved; insight; knowledge base; mouse model; multidimensional data; neuroregulation; novel; novel strategies; prepulse inhibition; programs; relating to nervous system; septohippocampal; skills; targeted biomarker; treatment strategy

Project Summary The septohippocampal circuit plays a crucial role in multiple cognitive Research Domain Criteria (RDoC) domains, including memory, attention, anxiety, and sensorimotor processing. This circuit is comprised primarily of the medial septal nucleus (MSN), hippocampus and medial prefrontal cortex (mPFC). Pharmacological and genetic models targeting glutamate N-methyl-D-aspartate (NMDA) receptor hypofunction within this circuit result in memory deficits, difficulty with attention, and social interaction impairments. Therefore, we are studying the relationship between MSN-mPFC- hippocampal oscillatory activity in NMDA receptor hypofunction models to better create treatments for disrupted theta and gamma oscillations which are altered in a variety of psychiatric disorders. Recent evidence suggests that deep brain stimulation (DBS) may be one such promising treatment modality for circuit disorders. This NIMH K08 Career Development Award will provide the necessary foundation for Darrin J. Lee, MD, PhD to pursue the development of novel DBS techniques for septohippocampal circuit disorders. The project and training plan are rooted in the electrophysiological and molecular underpinnings of NMDA receptor hypofunction, while concomitantly enabling the candidate to collaborate with and learn from his mentors and consultants. This program will enable him to supplement his current skillsets in areas where he has identified gaps in his knowledge base, including relevant research methodology, study design, machine learning, and structural connectivity. The proposed research will focus on 1) characterizing neural oscillations within the septohippocampal circuit in two complementary models of NMDA receptor hypofunction (pharmacological: chronic MK-801 administration and genetic: parvalbumin interneuron-selective NR1 knockout); 2) evaluating the cognitive effects of DBS in these rodent models, and 3) evaluating the relationship between electrophysiological biomarkers and behavior using machine learning. The interpretation of data from this research will improve understanding of specific electrophysiological aspects of impaired brain function in septohippocampal circuit disorders and serve as a catalyst for a research program centered on neuromodulation for these disorders. Moreover, data collected, skills procured, and collaborations developed will enable Dr. Lee to seek R01 funding and obtain career independence. Taken together, the data collected, and training developed will ultimately facilitate development of an investigator with unique skills in service of ameliorating suffering caused by septohippocampal circuit disorders.

项目摘要 隔-海马区回路在多个认知研究领域标准(RDoC)领域中起着至关重要的作用， 包括记忆、注意力、焦虑和感觉运动处理。这条线路主要由内侧 隔核(MSN)、海马体和内侧前额叶皮质(MPFC)。靶向的药理和遗传模型 谷氨酸N-甲基-D-天冬氨酸(NMDA)受体在此回路中功能低下，导致记忆障碍、困难 注意力和社交障碍。因此，我们正在研究MSN-mPFC- NMDA受体功能减退模型中的海马区振荡活动更好地创造对Theta中断的治疗 以及在各种精神疾病中会发生改变的伽马振荡。最近的证据表明，大脑深处 刺激(DBS)可能是治疗电路障碍的一种很有前途的治疗方式。NIMH K08职业生涯 发展奖将为Darrin J.Lee，医学博士，博士提供必要的基础，以追求 隔-海马区回路障碍的DBS新技术。该项目和培训计划植根于 NMDA受体功能低下的电生理和分子基础，同时使 与他的导师和顾问合作并向他们学习的候选人。这一计划将使他能够补充他的 他在哪些领域发现了自己的知识库中的差距，包括相关的研究方法， 研究设计、机器学习和结构连接。建议的研究将集中在1)表征神经 两种互补的NMDA受体功能低下模型中隔-海马区回路内的振荡 (药理学：慢性MK-801给药和遗传学：小白蛋白中间神经元选择性NR1基因敲除)；2) 评估DBS在这些啮齿动物模型中的认知效果，以及3)评估DBS与 使用机器学习的电生理生物标志物和行为。对这项研究的数据的解释将 加深对隔-海马区脑功能受损的特定电生理方面的理解 并作为一项以神经调节为中心的研究计划的催化剂。此外，数据 收集、获取技能和发展合作关系将使Lee博士能够寻求R01资金并获得职业生涯 独立。总而言之，收集的数据和开发的培训最终将促进 具有独特技能的研究人员，服务于减轻隔-海马区回路障碍造成的痛苦。