NEUROPHYSIOLOGICAL BIOMARKERS IN PRECLINICAL ASSAYS OF SUSTAINED ATTENTION

持续注意力临床前测定中的神经生理学生物标志物

• 批准号: 10375904
• 负责人: Gregory V Carr
• 金额: $ 65.43万
• 依托单位: LIEBER INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10375904
• 关键词: Agonist; Amphetamines; Anatomy; Animal Model; Anterior; Attention; Attention deficit hyperactivity disorder; Attentional deficit; Behavior; Behavioral; Biological; Biological Assay; Biological Markers; Brain Diseases; Catecholamines; Conflict (Psychology); Coupling; Cues; Detection; Disease; Dopamine; Dopamine D1 Receptor; Dorsal; Dose; Electroencephalogram; Electrophysiology (science); Enhancers; Functional Magnetic Resonance Imaging; Human; Image; Impaired cognition; Impairment; Length; Measurement; Measures; Mental disorders; Mission; Mus; Neuromodulator; Pathway interactions; Patients; Pattern; Performance; Pharmaceutical Preparations; Pharmacology; Phase; Play; Process; Quality of life; Rattus; Reaction Time; Ritalin; Rodent; Role; Schizophrenia; Signal Transduction; Stimulus; Task Performances; Testing; Time; Translations; United States National Institutes of Health; Ventral Tegmental Area; addiction; attenuation; base; cingulate cortex; design; drug development; drug discovery; experimental study; flexibility; functional outcomes; improved; in vivo; innovation; insight; neural circuit; neurophysiology; nonhuman primate; novel therapeutics; optogenetics; performance tests; pre-clinical; psychostimulant; relating to nervous system; response; side effect; sustained attention; symptom treatment; tolcapone; tool; touchscreen; translational study

Project Summary Sustained attention, the ability to focus on an activity or stimulus over time, is impaired in many brain disorders. Continuous performance tests (CPTs) have been designed to measure sustained attention in multiple species. Similar neural circuits are engaged in both humans and model organisms during CPT performance, supporting their use in translational studies that screen for novel therapeutics. The human dorsal anterior cingulate cortex (dACC), which plays critical roles in attentional processes, shows functional and anatomical similarity to the mouse prelimbic region (PrL). These homologous regions are involved in both conflict detection and allocation of attention to cues before orientation, important components in go/no-go tasks like CPTs. Electroencephalogram (EEG) studies show that neural activity in the dACC is correlated with task engagement and performance in the CPT. The neuromodulator dopamine is hypothesized to play a critical role in regulating attention, a notion supported by the fact that dopamine D1 receptor agonists and antagonists improve and impair CPT performance, respectively. In this application we propose to optimize a mouse touchscreen-based CPT to include measurements of the effects of stimulus degradation and session length (time on task) on accuracy, reaction times, and other task parameters. In this optimized paradigm we will identify electrophysiological correlates of task performance by analyzing spectral measures of power and coupling from the EEG and PrL local field potential. We will evaluate the optimized CPT paradigm by assessing behavioral performance and EEG/LFP correlates in response to pharmacological enhancers that are documented to improve attention. Finally, we will mechanistically test the role of dopaminergic input to the dACC/PrL from the ventral tegmental area on behavioral performance and EEG/LFP correlates in the CPT.

项目摘要 持续的注意力，随着时间的推移专注于活动或刺激的能力，在许多大脑疾病中受损。 持续表现测试（CPT）被设计用于测量多个物种的持续注意力。 在CPT表现期间，人类和模式生物都参与了类似的神经回路，支持 它们在筛选新疗法的转化研究中的用途。人背侧前扣带皮层 在注意过程中起着关键作用的dACC，显示出功能和解剖学上的相似性， 小鼠前边缘区（PrL）。这些同源区域参与冲突检测和分配 注意力在定向之前的线索，在去/不去任务的重要组成部分，如CPT。 脑电图（EEG）研究表明，dACC的神经活动与任务参与相关 在CPT中的表现。神经调质多巴胺被假设在调节 注意力，这一概念得到多巴胺D1受体激动剂和拮抗剂改善和 分别损害CPT性能。在这个应用程序中，我们建议优化鼠标触摸屏为基础的 CPT包括刺激降级和会话长度（任务时间）对 准确度、反应时间和其他任务参数。在这个优化的范例中，我们将识别 通过分析功率和耦合的频谱测量， 脑电图和催乳素局部场电位我们将通过评估优化的CPT范例来评估 行为表现和EEG/LFP与药理学增强剂的反应相关， 记录以提高注意力。最后，我们将从机制上测试多巴胺能输入对神经元的作用。 CPT中来自腹侧被盖区的dACC/PrL对行为表现和EEG/LFP的相关性。