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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要在许多脑部疾病中，持续注意力（即长时间专注于某项活动或刺激的能力）会受到损害。持续表现测试（CPT）旨在衡量多个物种的持续注意力。在 CPT 表现期间，人类和模型生物体都参与类似的神经回路，支持它们在筛选新疗法的转化研究中的应用。人类背侧前扣带皮层（dACC）在注意力过程中发挥着关键作用，显示出与小鼠前边缘区（PrL）。这些同源区域参与冲突检测和分配在定向之前注意线索，这是进行/不进行任务（如 CPT）的重要组成部分。脑电图 (EEG) 研究表明 dACC 中的神经活动与任务投入相关以及 CPT 中的表现。假设神经调节剂多巴胺在调节中发挥关键作用多巴胺 D1 受体激动剂和拮抗剂可改善和改善这一事实，这一观点得到了支持。分别损害 CPT 性能。在此应用中，我们建议优化基于鼠标触摸屏的 CPT 包括测量刺激退化和会话长度（任务时间）对准确性、反应时间和其他任务参数。在这个优化范例中，我们将确定通过分析功率和耦合的频谱测量来确定任务表现的电生理学相关性来自 EEG 和 PrL 局部场电位。我们将通过评估优化的 CPT 范式行为表现和 EEG/LFP 与药理增强剂的反应相关记录下来以提高注意力。最后，我们将机械地测试多巴胺能输入对腹侧被盖区的 dACC/PrL 与 CPT 中的行为表现和 EEG/LFP 相关。