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 隔海马回路在多个认知研究领域标准（RDoC）领域中发挥着至关重要的作用， 包括记忆、注意力、焦虑和感觉运动处理。这个回路主要由内侧 隔核（MSN）、海马和内侧前额叶皮质（mPFC）。药理学和遗传学模型靶向 谷氨酸N-甲基-D-天冬氨酸（NMDA）受体功能减退导致记忆缺陷， 注意力和社交障碍。因此，我们正在研究MSN-mPFC- 在NMDA受体功能减退模型中海马振荡活动，以更好地创建对破坏的θ 和伽马振荡，这在各种精神疾病中都会改变。最近的证据表明， 电刺激（DBS）可能是用于回路障碍的这样一种有前景的治疗方式。NIMH K 08职业生涯 发展奖将为Darrin J. Lee，MD，PhD提供必要的基础，以追求 新型DBS技术治疗隔海马回路障碍。该项目和培训计划植根于 NMDA受体功能减退的电生理和分子基础，同时使 候选人与他的导师和顾问合作并向他们学习。该计划将使他能够补充他的 在他已确定其知识基础存在差距的领域，包括相关研究方法， 研究设计、机器学习和结构连接。拟议的研究将集中在1）表征神经 在两种互补的NMDA受体功能减退模型中隔海马回路内的振荡 （药理学：MK-801长期给药和遗传学：小白蛋白神经元间选择性NR 1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。对本研究数据的解释将 提高对隔-海马回路中脑功能受损特定电生理方面的认识 该研究是一种神经失调的研究，并作为以这些失调的神经调节为中心的研究计划的催化剂。此外，数据 收集，获得技能，并发展合作将使李博士寻求R 01资金，并获得职业生涯 独立总之，收集的数据和开展的培训将最终促进 研究人员具有独特的技能，在服务中减轻痛苦所造成的隔海马电路障碍。