Project Summary
The overarching goal of the present proposal is to understand how individual differences in the structure and
function of Locus Coeruleus (LC) moderate perception and memory in an older adult population. There is
substantial evidence that the LC circuit plays a central role in cognitive processes and neuronal loss in LC is
known to occur in neurodegenerative disorders such as ADRD and PD. Integrity of LC neurons is hypothesized
to mediate the preservation of cognitive abilities during normal aging as well. To date, however, there exists a
dearth of research that either characterizes differential effects of LC integrity or details relationships between LC
integrity and cognitive function in older adult humans. More generally, the link between LC activity and cognitive
processes has not been well characterized in humans. Historical reasons for this is that the LC has been difficult
to image due to its small size and thus most human research makes inferences about LC function by using pupil
dilation as a surrogate measure. To overcome existing limitations in the field, we propose a series of detailed
psychophysical and MRI-based studies in older adults aimed to characterize how LC structure and function
moderates behavior and in turn how this is mediated by activity in intermediate brain regions known to be
involved in perceptual and memory processes. We further propose computational approaches to characterize
individual differences in how LC circuit integrity relates to different patterns of cognitive performance across
tasks, and advanced neuroimaging methods to localize and image the LC, which have been pioneered by our
group. Using MRI-based methods, we will examine LC integrity using high-resolution neuromelanin-sensitive
structural imaging, tractography and functional connectivity. This approach will allow us to identify candidate
biomarkers of LC circuit integrity. We will use a series of within-subject designs where we manipulate LC activity
and examine whether relationships between LC and behavior and brain regions thought to mediate those
behaviors are consistent or not between different perceptual modalities and memory tasks. Overall this study
will provide an important and much needed understanding of how LC integrity underlies cognitive declines in
older adults. By combining advanced neuroimaging, well-controlled behavioral assessment, and computational
analysis, we expect to uncover previously inaccessible in vivo mechanisms of LC modulation and generate a
unique dataset to address fundamental mechanistic questions of how the LC integrity moderates cognition, how
this varies across older adults and the extent to which relationships between LC and cognition are generalized
or individualized to particular domains. The resulting understanding of LC circuit can help explain how
dysfunctional modulatory circuits may generate cognitive declines or be implicated in normal aging and age-
related disorders such as Alzheimer's and Alzheimer's related disorders. This, in turn, has potential to support
non-invasive methods for diagnosing pathologies associated with LC decline and developing new treatments.