Septohippocampal circuit deep brain stimulation for selective RDoC aspects of cognition

项目概要 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。该电路主要由内侧组成 间隔核（MSN）、海马和内侧前额皮质（mPFC）。药理学和遗传模型靶向 该回路内的谷氨酸 N-甲基-D-天冬氨酸 (NMDA) 受体功能低下会导致记忆缺陷、困难 注意力和社交互动障碍。因此，我们正在研究MSN-mPFC-之间的关系 NMDA 受体功能减退模型中的海马振荡活动，以更好地创建针对破坏的 theta 的治疗方法 和伽玛振荡，这些振荡在各种精神疾病中都会改变。最近的证据表明，深部大脑 刺激（DBS）可能是一种很有前景的回路疾病治疗方式。 NIMH K08 职业生涯 发展奖将为 Darrin J. Lee 医学博士、哲学博士追求发展提供必要的基础 用于治疗间隔海马回路疾病的新型 DBS 技术。该项目和培训计划植根于 NMDA 受体功能减退的电生理学和分子基础，同时使 候选人与他的导师和顾问合作并向他们学习。这个计划将使他能够补充他的 他发现其知识库中存在差距的领域的当前技能，包括相关的研究方法， 研究设计、机器学习和结构连接。拟议的研究将重点关注 1）表征神经网络 NMDA 受体功能减退的两种互补模型中隔海马回路内的振荡 （药理学：长期 MK-801 给药和遗传：小白蛋白中间神经元选择性 NR1 敲除）； 2） 评估 DBS 在这些啮齿动物模型中的认知效果，以及 3) 评估之间的关系 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 提高对隔海马回路脑功能受损的特定电生理学方面的理解 疾病，并作为以这些疾病的神经调节为中心的研究计划的催化剂。此外，数据 收集、获得的技能和发展的合作将使李博士能够寻求 R01 资金并获得职业生涯 独立性。总而言之，收集的数据和开发的培训将最终促进开发 具有独特技能的研究人员，致力于改善中隔海马回路疾病引起的痛苦。

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.