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.