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

临床前海马区-前额叶皮质环路活动的临床前检测 治疗进展 FOA类型：PAR-19-289： 摘要：将发现科学转化为积极的临床结果的治疗失败率很高。 精神疾病证明了提高治疗的效率和严谨性的必要性 开发流水线。为此，推进体内生理和免疫功能的发现至关重要 人们已经认识到特定回路参与正常认知功能的行为测量 跨资金计划。海马区(HPC)-前额叶皮质(PFC)回路对情感性 加工以及较高的认知功能，易患一些心理健康障碍。虽然 HPC-PFC回路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，这个回路中的局部细胞相互作用如何表现为大规模的时间 协调以支持更高的认知功能仍不清楚。解决我们在以下方面的根本差距 知识将为使用基于电路的模型发现治疗靶点和 新型药效筛选工具。这项建议的长期目标，符合筹资机会 公告(PAR-19-289)，是为了加强精神病治疗的治疗开发流水线 通过优化、评估和机械测试电路的神经生理和行为测量 订婚。这项提议的主要目标是，这是实现我们目标的第一步，目的是与 啮齿类动物在人类部分配对联想学习任务(PAL)上的行为表现 剑桥神经心理测试自动化电池[CANTAB]评估和表面脑电记录 涉及HPC-PFC回路中神经协调的侵入性神经生理学测量。通过创新的 整合体内神经生理学局部场电位(LFP)记录、电路的一系列实验 操作，表面脑电和行为，我们将优化，评估和机械测试新的非侵入性 通过追求以下特定目标来实现HPC-PFC电路接触的生物标志物：1)优化行为和 无创脑电生物标志物用于推断HPC-PFC回路参与和时间协调，2) 行为和非侵入性脑电生物标志物用于确定HPC-PFC电路接合的评价 通过药物操作，以及3)机械测试HPC-PFC投射作为表面驱动因素 脑电波组织。这项拟议的研究是创新的，因为它整合了与临床相关的行为 任务，设计成类似于人类认知评估，表面脑电测量转化为 在哺乳动物身上。这将使优化、评估和测试新的和可翻译的措施成为可能 在更高的认知和全球神经组织的背景下，HPC-PFC电路的参与。这个 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开发流水线。

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.