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bioRxiv · 10.1101/2023.09.29.560190

Attention-dependent coupling with forebrain and brainstem neuromodulatory nuclei changes across the lifespan

Cicero, N. G.·Riley, E.·Swallow, K.·De Rosa, E.·Anderson, A. K.
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Abstract

Attentional states continuously reflect the predictability and uncertainty in ones environment having important consequences for learning and memory. Beyond well known cortical contributions, rapid shifts in attention are hypothesized to also originate from deep nuclei, such as the basal forebrain (BF) and locus coeruleus (LC) neuromodulatory systems. These systems are also the first to change with aging. Here we characterized the interplay between these systems and their regulation of afferent targets - the hippocampus (HPC) and posterior cingulate cortex (PCC) - across the lifespan. To examine the role of attentional salience on task-dependent functional connectivity, we used a target-distractor go/no go task presented during functional MRI. In younger adults, BF coupling with the HPC, and LC coupling with the PCC, increased with behavioral relevance (targets vs distractors). Although the strength and presence of significant regional coupling changed in middle age, the most striking change in network connectivity was in old age, such that in older adults BF and LC coupling with their cortical afferents was largely absent and replaced by stronger interconnectivity between LC-BF nuclei. Overall rapid changes in attention related to behavioral relevance revealed distinct roles of subcortical neuromodulatory systems. The pronounced changes in functional network architecture across the lifespan suggest a decrease in these distinct roles, with deafferentation of cholinergic and noradrenergic systems associated with a shift towards mutual support during attention guided to external stimuli. Significance statementChanges in attentional control across the lifespan may originate from cortical control networks or subcortical neuromodulatory systems, which are the first sites of age-related neuropathology. In young adults, we demonstrated functional coupling of the basal forebrain with the hippocampus, and locus coeruleus with the posterior cingulate cortex varies with task relevance. This coupling changed in middle age and most strikingly in older adults. In old age, task-dependent coupling between the locus coeruleus and basal forebrain was the predominant connection remaining within the observed network. Older adults exhibit reduced subcortical-cortical connectivity, consistent with a relative neuromodulatory deafferentation, replaced by subcortical-subcortical deep nuclear connectivity. This alteration in noradrenergic and cholinergic signaling has important implications for attention and memory formation and neurocognitive aging.

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Cicero, N. G., Riley, E., Swallow, K., De Rosa, E., Anderson, A. K.. 2023-09-30. Attention-dependent coupling with forebrain and brainstem neuromodulatory nuclei changes across the lifespan. https://doi.org/10.1101/2023.09.29.560190

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