Preclinical Assays of Hippocampal-Prefrontal Cortical Circuit Engagement for Application in Therapeutic Development

海马-前额皮质环路参与的临床前测定在治疗开发中的应用

• 批准号: 10676273
• 负责人: SARA N BURKE
• 金额: $ 62.41万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676273
• 关键词: Address; Affect; Affective; Animal Model; Animals; Anxiety; Behavior; Behavior assessment; Behavioral; Biological Assay; Biological Markers; Bipolar Disorder; Brain; Clinical; Clinical Trials; Cognition; Communication; Coupling; Data; Development; Elderly; Electroencephalography; Evaluation; Failure; Foundations; Funding; Funding Opportunities; Goals; Health; Heart Diseases; Hippocampus; Human; Impaired cognition; Impairment; Individual; Knowledge; Link; Malignant Neoplasms; Mammals; Measures; Mental disorders; Mission; Modeling; National Institute of Mental Health; Neurobiology; Neurons; Neuropsychological Tests; Neuropsychology; Neurotransmitters; Outcome; Paired-Associate Learning; Parietal; Performance; Personal Satisfaction; Pharmacologic Substance; Pharmacological Treatment; Phase; Physiological; Prefrontal Cortex; Psychiatric therapeutic procedure; Psychiatry; Public Health; Research; Rodent; Schizophrenia; Science; Screening procedure; Series; Severities; Severity of illness; Surface; System; Task Performances; Technology; Temporal Lobe; Testing; Therapeutic; Translating; Traumatic Brain Injury; Validation; analog; autism spectrum disorder; behavior measurement; behavioral outcome; cholinergic; clinically relevant; cognitive function; cognitive process; cognitive testing; comparative; density; design; designer receptors exclusively activated by designer drugs; diagnostic tool; drug discovery; drug efficacy; drug testing; emotion regulation; experimental study; high throughput screening; improved; in vivo; innovation; mental development; neural; neurophysiology; novel; novel diagnostics; novel therapeutics; pharmacologic; pre-clinical; predictive marker; screening; therapeutic development; therapeutic target; therapy development; touchscreen; treatment optimization

TITLE: Preclinical Assays of Hippocampal-Prefrontal Cortical Circuit Engagement for Application in Therapeutic Development FOA type: PAR-19-289: Abstract: The high failure rate of translating discovery science to positive clinical outcomes in the treatment of psychiatric diseases demonstrates the necessity of improving the efficiency and rigor of the therapeutic development pipeline. To this end, the critical importance of advancing the discovery of in vivo physiological and behavioral measures of the engagement of specific circuits for normal cognitive function has been acknowledged across funding initiatives. The hippocampus (HPC)-prefrontal cortical (PFC) circuit is critical for affective processing as well as higher cognitive functions and vulnerable in a number of mental health disorders. Although disrupted functional connectivity in the HPC-PFC circuit is a common feature of anxiety, bipolar disorder, schizophrenia, and autism, how local cellular interactions within this circuit manifest as large-scale temporal coordination to support higher cognitive functions remains unknown. Addressing this fundamental gap in our knowledge will establish a foundation for using circuit-based models for therapeutic target discovery and screening tools of novel drug efficacy. The long-term goal of this proposal, in line with the Funding Opportunity Announcement (PAR-19-289), is to enhance the therapeutic development pipeline for mental illness treatment by optimizing, evaluating, and mechanistically testing neurophysiological and behavioral measures of circuit engagement. The primary objective of this proposal, which is the first step towards achieving our goal, is to relate behavioral performance on the rodent analog on the Paired Associates Learning task (PAL), part of human Cambridge Neuropsychological Test Automated Batteries [CANTAB] assessment, and surface EEG recordings to invasive neurophysiological measures of neural coordination in the HPC-PFC circuit. Through an innovative series of experiments that integrate in vivo neurophysiological local field potential (LFP) recordings, circuit manipulation, surface EEG, and behavior, we will optimize, evaluate and mechanistically test novel noninvasive biomarkers of HPC-PFC circuit engagement by pursuing the following specific aims: 1) Optimize behavioral and non-invasive EEG biomarkers for inferring HPC-PFC circuit engagement and temporal coordination, 2) Evaluation of behavioral and non-invasive EEG biomarkers for determining HPC-PFC circuit engagement through pharmacological manipulation, and 3) Mechanistically test HPC-PFC projections as a driver of surface EEG organization. The proposed research is innovative because it integrates a clinically relevant behavioral task, designed to be analogous to human cognitive assessments, with surface EEG measures that translate across mammals. This will enable the optimization, evaluation, and testing of novel and translatable measures of HPC-PFC circuit engagement in the context of higher cognition and global neural organization. The significance of this contribution will be to provide novel diagnostic tools that can be used to enhance the therapeutic development pipeline for treating mental illness.

标题：海马-前额皮质回路接合的临床前试验，用于 治疗开发 FOA类型：PAR-19-289： 翻译后摘要：在治疗中，将发现科学转化为积极的临床结果的失败率很高， 精神疾病表明，有必要提高效率和严谨的治疗 发展管道。为此，推进体内生理学和生物学的发现是至关重要的。 对于正常认知功能的特定回路的参与的行为测量已经被认可 跨融资倡议。海马（HPC）-前额叶皮层（PFC）回路是情感调节的关键环节 处理以及更高的认知功能和易受一些心理健康障碍。虽然 HPC-PFC回路中的功能连接中断是焦虑，双相情感障碍， 精神分裂症和自闭症，这个回路内的局部细胞相互作用如何表现为大规模的时间 支持更高认知功能的协调仍然是未知的。解决我们国家的这一根本差距 知识将为使用基于电路的模型进行治疗靶点发现奠定基础， 新药疗效筛选工具。本提案的长期目标符合融资机会 公告（PAR-19-289），旨在加强精神疾病治疗的治疗开发管道 通过优化、评估和机械测试回路的神经生理和行为测量， 订婚这一建议的主要目的是实现我们目标的第一步， 在配对联想学习任务（PAL）上啮齿动物模拟物的行为表现，人类的一部分 剑桥神经心理测试自动电池[CANTAB]评估和表面EEG记录 HPC-PFC电路中神经协调的侵入性神经生理学测量。通过创新的 一系列实验，整合在体内神经生理局部场电位（LFP）记录，电路 操作，表面脑电图和行为，我们将优化，评估和机械测试新的非侵入性 HPC-PFC电路参与的生物标志物，通过追求以下具体目标：1）优化行为和 用于推断HPC-PFC电路接合和时间协调的非侵入性EEG生物标志物，2） 用于确定HPC-PFC电路接合的行为和非侵入性EEG生物标志物的评价 通过药理学操作，和3）机械测试HPC-PFC投影作为表面的驱动器 EEG组织。这项研究是创新的，因为它整合了临床相关的行为 任务，旨在类似于人类认知评估，表面EEG测量， 在哺乳动物中。这将使新的和可翻译的措施的优化，评估和测试成为可能 HPC-PFC电路参与的背景下，更高的认知和全球神经组织。的 这一贡献的意义将是提供新的诊断工具，可用于增强 治疗精神疾病的治疗发展管道。