Lifespan Neuromodulation of Cognition (LINE)

Research Scientists
Martin Dahl (Project Leader)

Agnieszka Kulesza (COMP2PSYCH)
Tiantian Li (MPSCog, since 10/2024)
Ulman Lindenberger
Alexia Marriott (Fulbright scholar, since 09/2025)
Zoya Mooraj (COMP2PSYCH)
Shieun (Angela) Seo (MPSCog, since 04/2026)

MRI-Indexed Locus Coeruleus Integrity Is Linked to Neural Pathology and Cognition
Locus Coeruleus-Related Insula Activation Supports Implicit Learning
Outlook

Neuromodulators such as dopamine and noradrenaline are synthesized in small subcortical nuclei and released throughout the brain by widespread projections. Their release shapes the efficacy of synaptic transmission in its target regions and thus has a profound influence on cognitive processes, such as attention and memory. Furthermore, neuromodulatory nuclei are susceptible to degeneration in the course of normal and pathological aging, thereby contributing to age-related cognitive decline in later adulthood and old age. LINE uses a multimodal approach to investigate structural and functional age differences and age changes in neuromodulation and their associations with normal and pathological forms of cognitive aging. Conceptually, the project aims at a comprehensive understanding of the role of neuromodulation in cognitive aging (Dahl, Kulesza, et al., 2023; Dahl, Mather, & Werkle-Bergner, 2022; Mooraj et al., 2025). During the reporting period, LINE's work focused on two interrelated themes and initiated two large-scale data collection efforts.

MRI-Indexed Locus Coeruleus Integrity is Linked to Neural Pathology and Cognition

Established theories of human cognitive aging emphasize dopaminergic decline in the substantia nigra–ventral tegmental area (VTA) as a key contributor to memory loss. However, recent viral-tracing evidence synthesized by the LINE group (Dahl, Kulesza, et al., 2023) shows that the noradrenergic locus coeruleus sends denser projections to the hippocampus than the VTA, and is able to co-release both noradrenaline and dopamine, given their biosynthetic dependencies. In line with this evidence, a series of optogenetic studies in rodents confirms a crucial dopaminergic role of the locus coeruleus for hippocampal memory processes, highlighting the locus coeruleus as a major neuromodulator of long-term memory (Figure 1). These considerations have prompted us to directly compare the roles of the locus coeruleus and substantia nigra–ventral tegmental area in human cognitive aging.

*Figure 1.* *Dopamine and noradrenaline modulate hippocampal memory processes.* a) Projections of the dopaminergic substantia nigra–ventral tegmental area (SN–VTA; orange) and catecholaminergic locus coeruleus (LC; blue) to the hippocampus (dark grey). b) Locus coeruleus–hippocampus projections are denser than those of the substantia nigra–ventral tegmental area and provide hippocampal noradrenaline and potentially a majority of its dopamine. Noradrenaline may have a stronger modulatory impact in the dentate gyrus (green), whereas dopamine may affect processing in CA1 more (red), implying differential roles of the catecholamines in pattern separation and novelty processing. Different effects in the different subfields of the hippocampus are schematically represented by the coloring of the pie charts. For CA3, more data are required. c) Different hippocampal subregions are associated with different memory processes. The dentate gyrus (green) is implicated in a process called pattern separation, that aids the mnemonic discrimination of similar memories by reducing the degree of representational similarity among overlapping experiences. By contrast, mainly the Cornu Ammonis 3 (purple) region is involved in retrieving a complete memory representation from partial cues, a process called pattern completion. Asterisks (*) indicate pathways and processes that show pronounced age-related changes. CA, Cornu Ammonis; DG, dentate gyrus. Figure 1 was in part created with BioRender.

Image: Neuroscience and Biobehavioral Reviews
Dahl et al. (2023)

*Figure 1.* *Dopamine and noradrenaline modulate hippocampal memory processes.* a) Projections of the dopaminergic substantia nigra–ventral tegmental area (SN–VTA; orange) and catecholaminergic locus coeruleus (LC; blue) to the hippocampus (dark grey). b) Locus coeruleus–hippocampus projections are denser than those of the substantia nigra–ventral tegmental area and provide hippocampal noradrenaline and potentially a majority of its dopamine. Noradrenaline may have a stronger modulatory impact in the dentate gyrus (green), whereas dopamine may affect processing in CA1 more (red), implying differential roles of the catecholamines in pattern separation and novelty processing. Different effects in the different subfields of the hippocampus are schematically represented by the coloring of the pie charts. For CA3, more data are required. c) Different hippocampal subregions are associated with different memory processes. The dentate gyrus (green) is implicated in a process called pattern separation, that aids the mnemonic discrimination of similar memories by reducing the degree of representational similarity among overlapping experiences. By contrast, mainly the Cornu Ammonis 3 (purple) region is involved in retrieving a complete memory representation from partial cues, a process called pattern completion. Asterisks (*) indicate pathways and processes that show pronounced age-related changes. CA, Cornu Ammonis; DG, dentate gyrus. Figure 1 was in part created with BioRender.

Image: Neuroscience and Biobehavioral Reviews
Dahl et al. (2023)

Building on our earlier work assessing locus coeruleus integrity in the Berlin Aging Study II (cf. Dahl et al., 2019) and in collaboration with Mara Mather (University of Southern California), LINE has used multiple MRI modalities—proton density-, magnetization transfer-, and T₁-weighted imaging (PDw, MTw, T1w)—to assess locus coeruleus and substantia nigra–VTA integrity in 69 younger and 251 older adults. The high intracellular water and low macromolecular content of these nuclei make them appear as bright clusters on dedicated MRI scans (Figure 2), enabling noninvasive measurement of their structural integrity (Dahl, Bachman, et al., 2023; Dahl & Mather, 2023).

Using latent-variable modeling, we integrated multimodal MRI data (PDw, MTw, T₁w) into latent factors for locus coeruleus and substantia nigra–VTA integrity to separate common variance from modality-specific measurement error. Next, to probe the behavioral implications of individual differences in locus coeruleus and substantia nigra–ventral tegmental area integrity, we made use of a comprehensive cognitive test battery and a previously established factor structure, yielding latent measures of episodic memory, working memory, and fluid intelligence. We observed that the two neuromodulatory systems, though positively coupled, differentially relate to late-life cognition. Locus coeruleus integrity was positively linked to episodic memory performance, while the substantia nigra–VTA was associated with better working memory performance (Figure 2). Importantly, these brain–behavior relations remained significant when controlling for the integrity of the other neuromodulatory system and volumes in the medial temporal lobe, a key node in the memory network, indicating unique associations.

Finally, making use of the longitudinal nature of the data set, we estimated changes in neuromodulatory nuclei over a delay of about 2 years and found that older age was linked to declines in the locus coeruleus and substantia nigra–VTA, suggesting late-life neurodegeneration. Importantly, individual changes in the locus coeruleus (time point 1–time point 2) predicted episodic memory performance at a subsequent measurement wave (time point 3). Taken together, convergent evidence from rodent research (Dahl, Kulesza, et al., 2023) and human cognitive aging (Dahl, Bachman, et al., 2023) underscores a prominent role of the locus coeruleus for late-life episodic memory, potentially through co-release of dopamine.

Research dissecting the brains of people who died at different ages indicates that the first signs of Alzheimer-related pathology, abnormally phosphorylated tau (pTau), begin to accumulate early in life in the locus coeruleus. To investigate whether late-life declines in MRI-indexed locus coeruleus integrity and memory could be driven by pathological processes (Dahl, Mather, Werkle-Bergner, et al., 2022), we secured third-party funding from the BrightFocus foundation. Specifically, in a collaboration with Charité – Universitätsmedizin Berlin (Ilja Demuth), Universität zu Lübeck (Lars Bertram), and University of Gothenburg (Henrik Zetterberg), we are currently quantifying blood-based biomarkers for Alzheimer's disease using the NULISAseq CNS Disease Panel. We evaluate individual changes in Alzheimer's biomarkers, such as brain-derived pTau217, over a period of about 10 years and link these to changes in neuromodulatory nuclei and cognition to arrive at a more mechanistic understanding of preclinical disease development (Dissertation Agnieszka Kulesza).

Key References

Dahl, M. J., Bachman, S. L., Dutt, S., Düzel, S., Bodammer, N. C., Lindenberger, U., Kühn, S., Werkle-Bergner, M., & Mather, M. (2023). The integrity of dopaminergic and noradrenergic brain regions is associated with different aspects of late-life memory performance. Nature Aging, 3(9), 1128–1143. https://doi.org/10.1038/s43587-023-00469-z

MPG.PuRe

DOI

publisher-version

supplementary-material

Dahl, M. J., Kulesza, A., Werkle-Bergner, M., & Mather, M. (2023). Declining locus coeruleus-dopaminergic and noradrenergic modulation of long-term memory in aging and Alzheimer’s disease. Neuroscience & Biobehavioral Reviews, 153, Article 105358. https://doi.org/10.1016/j.neubiorev.2023.105358

[These authors contributed equally (shared senior authorship): Markus Werkle-Bergner, Mara Mather.].

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DOI

post-print

Dahl, M. J., Mather, M., Düzel, S., Bodammer, N. C., Lindenberger, U., Kühn, S., & Werkle-Bergner, M. (2019). Rostral locus coeruleus integrity is associated with better memory performance in older adults. Nature Human Behaviour, 3, 1203–1214. https://doi.org/10.1038/s41562-019-0715-2

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DOI

publisher-version

Locus Coeruleus-Related Insula Activation Supports Implicit Learning

Advances in structural MRI techniques allow the characterization of individual differences in the integrity of neuromodulatory nuclei. At the same time, animal research indicates that salient stimuli elicit a burst of activity in neuromodulatory centers, facilitating their processing and subsequent behavioral adaptation. Recent studies across various species have revealed an association between luminance-independent changes in pupil dilation and neuromodulatory activity, particularly of the locus coeruleus. This suggests that pupil dilation may serve as a moment-to-moment proxy of noradrenergic activity.

To investigate noradrenergic influences on cortical network dynamics and cognition, the LINE team adapted a paradigm shown to reliably increase locus coeruleus spiking in primates (Dahl et al., 2025). Specifically, we combined concurrent pupillometry–fMRI, and PET-derived noradrenergic transporter maps—with repeated behavioral assessments to investigate noradrenergic contributions to implicit learning across 39 younger and 38 older adults.

In on-going analyses, we found that salient expectation-violating stimuli (i) elicited pupil dilation, indicating enhanced neuromodulation, (ii) activated the action-mode network, and (iii) deactivated the default-mode network. Analyses of, pupil-linked BOLD responses further suggested a functional coupling between the locus coeruleus and the action-mode network, supported by spatial overlap of activation patterns with PET-derived noradrenergic transporter maps. Additional locus coeruleus MRI-guided functional connectivity analyses demonstrated that locus coeruleus activity is coupled to anterior insula activation, suggesting a noradrenergic role in shifting cortical dynamics toward action-oriented processing.

Behavioral evidence shows that participants implicitly learned the statistical task structure over time, as evidenced by reaction time adjustments based on stimulus probabilities. Critically, greater locus coeruleus integrity, higher task-related anterior insula activation, and more pronounced pupil dilation were associated with enhanced implicit learning, underscoring the behavioral relevance of noradrenergic neuromodulation. Notably, noradrenergic responses and their link to learning were also observed in the older age group, suggesting a robust noradrenergic role in supporting adaptive behavior throughout adulthood and old age.

Together, these analyses provide novel insights into the neuromodulatory mechanisms underlying learning and cognitive flexibility, emphasizing the pivotal role of locus coeruleus–action-mode network interactions in behavioral adaptation (see also Kosciessa et al., 2024).

Outlook

Our current work extends these lines of research by using non-invasive stimulation approaches to experimentally modulate neuromodulatory activity. Specifically, we apply brief bursts of transcutaneous vagus nerve stimulation while concurrently recording brainstem fMRI, pupillometry, and peripheral physiological responses (Dissertations Agnieszka Kulesza & Tiantian Li). In collaboration with Matt Nassar (Brown University), the same participants also complete a latent state transition task in a separate session to evaluate noradrenergic contributions to how we adapt to environmental transitions (Dissertation Tiantian Li), continuing our work on locus coeruleus–cortical interactions. Finally, in collaboration with the Center for Environmental Neuroscience, we evaluate within-person fluctuations in quantitative MRI estimates of locus coeruleus microstructure, leveraging the unique Day2Day Environment dataset (Dissertation Tiantian Li). Together, these endeavors advance our mission to elucidate how neuromodulatory systems shape cognition and its changes across the lifespan.