NEUROPHYSIOLOGICAL BIOMARKERS IN PRECLINICAL ASSAYS OF SUSTAINED ATTENTION

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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.