NEUROPHYSIOLOGICAL BIOMARKERS IN PRECLINICAL ASSAYS OF SUSTAINED ATTENTION

项目摘要 持续注意力是指随着时间的推移将注意力集中在一项活动或刺激上的能力，在许多大脑疾病中都会受到损害。 持续表现测试(CPT)被设计用来测量多个物种的持续注意力。 在CPT执行过程中，人类和模型生物体中都有类似的神经回路，支持 它们在筛选新疗法的转化性研究中的应用。人背前扣带回皮质 (DACC)在注意过程中起关键作用，在功能和解剖学上与 小鼠前区(PRL)。这些同源区域参与冲突检测和分配 注意定位前的线索，这是像CPTS这样进行/不进行任务的重要组成部分。 脑电研究表明，dACC中的神经活动与任务投入有关 以及在CPT中的表现。神经调节剂多巴胺被认为在调节 注意，多巴胺D1受体激动剂和拮抗剂改善和 分别影响CPT性能。在此应用程序中，我们建议优化基于触摸屏的鼠标 CPT包括对刺激退化和会话时间(任务时间)的影响的测量 准确性、反应时间和其他任务参数。在这个优化的范例中，我们将确定 通过分析功率和耦合的频谱测量与任务绩效的电生理关联 从EEG和PRL局部场势。我们将通过评估优化的CPT范式来评估 行为表现与EEG/LFP对药物增强剂的反应相关 记录下来可以提高人们的注意力。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对行为表现的影响与CPT的EEG/LFP相关。

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.