Biology subjects

De Rosa, E.

Publications and source records attributed to De Rosa, E..

7 recordsLinked to original sources

bioRxiv2026

Pupil size and pupil change correlate with distinct cortical neurochemical systems across the adult lifespan

Pupillometry is often used as a proxy for locus coeruleus (LC) activity, but whether this relationship changes across the lifespan is unknown, and important to establish due to the known change in LC biology with age. We collected simultaneous pupillometry and multi-echo fMRI in 89 adults aged 19-78 during a visual oddball task. Oddball-evoked pupillary responses were robust in all age groups but strongest in middle age. Oddball-evoked LC BOLD responses were relatively weak and did not predict individual pupillary responses, so we characterized pupil-BOLD coupling across the whole brain. Pupil size and its first derivative correlated with BOLD on distinct timescales (2.25 s and 5.00 s) and in distinct spatial patterns. Against 19 PET maps, derivative coupling correlated uniquely with norepinephrine transporter (NET) density, and size-unique coupling with -opioid (MOR) and cannabinoid CB1 density. Only pupil derivative-specific relationships with BOLD activity (both extent of coupling and association with NET) weakened with age, though both remained significant; other pupil-BOLD relationships did not differ with age. Pupil size and pupil change therefore carry different information about cortical activity throughout the lifespan.

neuroscience↗

bioRxiv2025

Vagal nerve stimulation alters task-evoked pupillary responses in older adults but not younger adults in a single-blind sham-controlled crossover trial

IntroductionThe locus coeruleus (LC) undergoes age-related changes and is involved in Alzheimers disease pathogenesis. Vagal nerve stimulation (VNS) may modulate LC activity and could be used therapeutically, but age-related differences in VNS responses remain unexplored. MethodsWe used a single-blind, sham-controlled, crossover design in 41 participants (21 younger, 20 older adults). Participants completed a visual oddball task with pupillometry during transcutaneous auricular VNS (verum: cymba concha; sham: earlobe) with [~]30-minute washout between conditions. ResultsOlder adults showed smaller baseline pupil diameter but larger normalized task-evoked responses than younger adults a priori. VNS produced age-specific effects: older adults demonstrated increased tonic pupil size throughout stimulation and reduced oddball-evoked responses, with stronger effects with more current. Younger adults showed no consistent VNS effects. DiscussionVNS affects LC-related physiological measures differently across age groups, with older adults showing more robust responses. These age-specific effects may reflect different baseline LC activity states.

neuroscience↗

bioRxiv2024

Attentional priority and limbic activity favor gains over losses

Prospect theory has suggested that decisions reflect a bias toward avoidance of loss compared to equivalent gains. In our study we examine whether a similar bias is found in decisions regarding whether a loss associated stimulus or a gain associated stimulus is given priority in perception. We find that for most people, gains are given priority over loss in the decision of which of the two stimuli occurs first. We also ask whether gains are reflected in greater activity in limbic systems related to emotion. In an fMRI study, we find that most people show greater emotional response to gains, not losses. We consider how these findings might be related to risk aversion in studies of decision making.

neuroscience↗

bioRxiv2023

Locus coeruleus neuromelanin accumulation and dissipation across the lifespan

The pigment neuromelanin, produced in the locus coeruleus (LC) as a byproduct of catecholamine synthesis, gives the "blue spot" its name, and both identifies LC neurons and is thought to play an important yet complex role in normal and pathological aging. Using neuromelanin-sensitive T1-weighted turbo spin echo MRI scans we characterized volume and neuromelanin signal intensity in the LC of 96 participants between the ages of 19 and 86. Although LC volume did not change significantly throughout the lifespan, LC neuromelanin signal intensity increased from early adulthood, peaked around age 60 and precipitously declined thereafter. Neuromelanin intensity was greater in the caudal relative to rostral extent and in women relative to men. With regard to function, rostral LC neuromelanin intensity was associated with fluid cognition in older adults (60+) only in those above the 50th percentile of cognitive ability for age. The gradual accumulation of LC neuromelanin across the lifespan, its sudden dissipation in later life, and relation to preserved cognitive function, is consistent with its complex role in normal and pathological aging.

neuroscience↗

bioRxiv2023

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

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.

neuroscience↗

bioRxiv2019

Phosphoprotein-based Biomarkers as Predictors for Cancer Therapy

Disparities in cancer patient responses have prompted widespread searches to identify differences in sensitive vs. non-sensitive populations and form the basis of personalized medicine. This customized approach is dependent upon the development of pathway-specific therapeutics in conjunction with biomarkers that predict patient responses. Here, we show that Cdk5 drives growth in subgroups of human patients with multiple types of neuroendocrine neoplasms. Phosphoproteomics and high throughput screening identified novel phosphorylation sites downstream of Cdk5. These phosphorylation events serve as biomarkers of Cdk5 activity and effectively pinpoint Cdk5-driven tumors. Toward achieving targeted therapy, we demonstrate that mouse models of neuroendocrine cancer are responsive to selective Cdk5 inhibitors and biomimetic nanoparticles are effective vehicles for enhanced tumor targeting and reduction of drug toxicity. Finally, we show that biomarkers of Cdk5-dependent tumors effectively predict response to anti-Cdk5 therapy in patient-derived xenografts. Thus, a phosphoprotein-based diagnostic assay combined with Cdk5-targeted therapy is a rational treatment approach for neuroendocrine malignancies.

cancer biology↗

bioRxiv2017

Functional segregation of the human basal forebrain using resting state neuroimaging

The basal forebrain (BF) is poised to play an important neuromodulatory role in brain re-gions important to cognition due to its broad projections and complex neurochemistry. While significant in vivo work has been done to elaborate BF function in nonhuman rodents and primates, comparatively limited work has examined the in vivo function of the human BF. In the current study we used multi-echo resting state functional magnetic resonance imaging (rs-fMRI) from 100 young adults (18-34 years) to assess the potential segregation of human BF nuclei as well as their associated projections. Bottom-up clustering of voxel-wise functional connectivity maps yielded adjacent functional clusters within the BF that closely aligned with the distinct, hypothesized nuclei important to cognition: the nucleus basalis of Meynert (NBM) and the me-dial septum/diagonal band of Broca (MS/DB). Examining their separate functional connections, the NBM and MS/DB revealed distinct projection patterns, suggesting a conservation of nuclei-specific functional connectivity with homologous regions known to be anatomically innervated by the BF. Specifically, the NBM demonstrated coupling with a widespread cortical network as well as the amygdala, whereas the MS/DB revealed coupling with a more circumscribed net-work, including the orbitofrontal cortex and hippocampal complex. Collectively, these in vivo rs-fMRI data demonstrate that the human BF nuclei support functional networks distinct as-pects of resting-state functional networks, suggesting the human BF may be a neuromodulatory hub important for orchestrating network dynamics.\n\nHighlightsO_LIThe basal forebrain NBM and the MS/DB support two distinct functional networks\nC_LIO_LIFunctional networks closely overlap with known anatomical basal forebrain\nC_LIO_LIBasal forebrain networks are distinct from known resting-state functional networks\nC_LI

neuroscience↗