The effects of noradrenergic activity on age-related distractibility

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Post mortem and neuroimaging data suggest an intact locus coeruleus helps to maintain cognitive performance in older adults. However, the basic mechanisms of this relationship are still unknown. The locus coeruleus is the source of most of the brain's noradrenaline but it is not yet clear how age-related decline in the locus coeruleus affects noradrenergic activity, and in turn, how these changes in noradrenergic activity modulate cognitive behavior. For instance, it is unknown whether age-related deficiencies in neuromodulation and processing result from decreased or increased locus coeruleus activity. Our long-term objectives are to determine the role of noradrenergic activity in modulating cognitive impairments and to identify means of preserving stable autonomic function to prevent or delay the progression of neurodegenerative diseases. The specific research goals of this proposal are to identify the mechanisms by which noradrenergic activity modulates distractibility by salient but irrelevant distractors in older and young adults. Both specific aims will utilize resting state recordings and an oculomotor search task that measures attentional inhibition of eye movements to determine whether tonic noradrenergic discharge directly modulates inhibitory mechanisms of attentional control. In Aim 1, we will investigate whether elevating tonic noradrenergic activity in older and young adults using threat of unpredictable shock induces arousal by pupillometric and electrophysiological measures. Furthermore, we will examine whether these changes will influence attentional control by modulating the magnitude of attentional inhibition of eye movements and phasic noradrenergic responses. We predict that older adults' distractibility will be less modulated by threat of shock than that of younger adults given our hypothesis that older adults already sustain higher levels of tonic noradrenergic release and hyperactivity. In Aim 2, we will investigate whether reducing tonic noradrenergic activity following slow-paced breathing and meditative practices improves attentional focus in older adults and young adults with high basal sympathetic activity. The goal of this aim is to determine the functional benefits of managing noradrenergic activity for attentional control as well as for measures of general arousal and phasic noradrenergic discharge. We predict that the benefits of the intervention in Aim 2 will be greater in older adults than that in young adults. The overall findings from this proposal will address a critical gap in knowledge connecting the mechanisms of neuromodulation on age-related declines to behavior, with theoretical implications in neuroprotection and preservation during aging. In addition, the training goals and objectives builds on the applicant's research expertise in psychophysiological research and fMRI with research expertise in the field of aging, training in EEG methodologies and analyses tools that are used in the field, and the professional development necessary to transition into an independent academic investigator. The research and mentorship team comprised of Drs. Mara Mather, Rael Cahn, and Markus Werkle-Bergner are the ideal fit to train the applicant in accomplishing his research and training goals throughout this fellowship.