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

基本信息

批准号：
10652984
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
项目类别：
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/10652984
关键词：
Acute Amygdaloid structure Animals Anxiety Area Attention Behavior Behavioral Biological Markers 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 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 NR1 gene National Institute of Mental Health Nucleus Accumbens Outcome Measure Pacemakers Parvalbumins Patients Pattern Phase Phenotype 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 structure Therapeutic Time Training Traumatic Brain Injury antagonist autism spectrum disorder basal forebrain behavior measurement behavioral impairment behavioral outcome brain dysfunction career catalyst cell type cognitive function effective therapy functional restoration genetic approach improved insight knowledge base mouse model multidimensional data neural neuroregulation novel novel strategies pharmacologic prepulse inhibition programs septohippocampal skills targeted biomarker treatment strategy

项目摘要

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 Septohappocampal电路在多个认知研究领域标准（RDOC）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。该电路主要由内侧组成间隔核（MSN），海马和内侧前额叶皮层（MPFC）。靶向药理和遗传模型该电路内的谷氨酸N-甲基-D-天冬氨酸（NMDA）受体功能障碍导致记忆缺陷，难度注意和社会互动障碍。因此，我们正在研究MSN-MPFC- NMDA受体功能障碍模型中的海马振荡活性，以更好地创建破坏theta的治疗方法以及各种精神疾病中改变的γ振荡。最近的证据表明大脑刺激（DBS）可能是电路障碍的一种有前途的治疗方式。这个NIMH K08职业发展奖将为医学博士Darrin J. Lee提供必要的基础，以追求发展 Septohampocampal电路障碍的新型DBS技术。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，同时使能够候选人与他的导师和顾问合作并学习。该计划将使他能够补充他的当前的技能集位于他在知识库中确定差距的领域，包括相关研究方法，研究设计，机器学习和结构连通性。拟议的研究将重点是1）表征神经 NMDA受体功能障碍的两个互补模型中的Septohampocampal电路内的振荡（药理：慢性MK-801给药和遗传：白蛋白间神经元选择性NR1敲除）； 2）评估DBS在这些啮齿动物模型中的认知效应，以及3）评估使用机器学习的电生理生物标志物和行为。这项研究的数据解释将提高对septohampocampal电路中脑功能受损的特定电生理方面的理解疾病并作为以这些疾病为中心的神经调节的研究计划的催化剂。此外，数据收集，采购的技能和开发的技能将使李博士能够寻求R01资金并获得职业独立。综上所述，收集的数据以及开发的培训将最终促进具有独特技能的调查员，可改善由septohampocampal电路疾病引起的痛苦。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Frequency-specific medial septal nucleus deep brain stimulation improves spatial memory in MK-801-treated male rats.

DOI：
10.1016/j.nbd.2022.105756
发表时间：
2022-08
期刊：
NEUROBIOLOGY OF DISEASE
影响因子：
6.1
作者：
Zepeda, Nancy C.;Crown, Lindsey M.;Medvidovic, Sasha;Choi, Wooseong;Sheth, Megha;Bergosh, Matthew;Gifford, Raymond;Folz, Caroline;Lam, Phillip;Lu, Gengxi;Featherstone, Robert;Liu, Charles Y.;Siegel, Steven J.;Lee, Darrin J.
通讯作者：
Lee, Darrin J.