Losing specificity: the role of the locus coeruleus in age-related distractibility

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PROJECT SUMMARY A growing body of research has highlighted the importance of frontal regions, at both the functional and structural levels, in age-related declines in attentional and cognitive processing. However, the underlying neurobiological pathophysiological changes in the brain that contribute to these declines are still largely unclear. The objective of this proposal is to investigate neural mechanisms of age-related attentional distractibility, focusing on the neural circuit initiated from the locus coeruleus (LC). In the current proposal, we will test the hypothesis that the neural dysconnectivity of LC with the salience network (SN) drives failures of ignoring distractors in older adults. To this end, we will examine humans’ and animals’ brains simultaneously through 1) an integrative approach combining human brain imaging and animal-based neural circuit manipulation and 2) equivalent research designs, including compatible attention task paradigms, analogous neural network analyses, and rescue strategies between human and animal. Using our novel unidirectional circuit-specific gene manipulation approach in vitro and in vivo, we will directly impair and rescue the LC-SN circuit in animals and examine how the circuit manipulation changes attention performance in the presence of distractors in the animal model. For human older adults, we will examine how LC-SN connectivity is associated with selective attention performance, and how improved LC-SN connectivity through a cognitive training program may lead to improved attentional performance. To increase fidelity in LC signal estimation, we will utilize two advanced imaging approaches at both the structural and functional level, namely neuromelanin-weighted structural MRI and physio-noise correction. Finally, we will include a measure of family history of Alzheimer’s disease (first degree relative) as variable of potential interest for exploratory analyses. The proposed project will provide an essential springboard to future work to identify and protect against age-related declines in attention, including among individuals at-risk for Alzheimer’s disease.