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Dopamine D1-signaling modulates maintenance of functional network segregation in aging
Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).ORCID-id: 0000-0003-4139-2461
Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).ORCID-id: 0000-0002-4501-4735
Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Aging Research Center, Karolinska Institutet& Stockholm University, Stockholm, Sweden.
2023 (Engelska)Ingår i: Aging Brain, ISSN 2589-9589, Vol. 3, artikel-id 100079Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Past research has shown that as individuals age, there are decreases in within-network connectivity and increases in between-network connectivity, a pattern known as functional dedifferentiation. While the mechanisms behind reduced network segregation are not fully understood, evidence suggests that age-related differences in the dopamine (DA) system may play a key role. The DA D1-receptor (D1DR) is the most abundant and age-sensitive receptor subtype in the dopaminergic system, known to modulate synaptic activity and enhance the specificity of the neuronal signals. In this study from the DyNAMiC project (N = 180, 20-79y), we set out to investigate the interplay among age, functional connectivity, and dopamine D1DR availability. Using a novel application of multivariate Partial Least squares (PLS), we found that older age, and lower D1DR availability, were simultaneously associated with a pattern of decreased within-network and increased between-network connectivity. Individuals who expressed greater distinctiveness of large-scale networks exhibited more efficient working memory. In line with the maintenance hypotheses, we found that older individuals with greater D1DR in caudate exhibited less dedifferentiation of the connectome, and greater working memory, compared to their age-matched counterparts with less D1DR. These findings suggest that dopaminergic neurotransmission plays an important role in functional dedifferentiation in aging with consequences for working memory function at older age. 

Ort, förlag, år, upplaga, sidor
Elsevier, 2023. Vol. 3, artikel-id 100079
Nyckelord [en]
Aging, D1DR, Dedifferentiation, Dopamine, Functional connectivity, Working memory
Nationell ämneskategori
Neurovetenskaper
Forskningsämne
molekylär medicin (medicinska vetenskaper)
Identifikatorer
URN: urn:nbn:se:umu:diva-212688DOI: 10.1016/j.nbas.2023.100079OAI: oai:DiVA.org:umu-212688DiVA, id: diva2:1786304
Forskningsfinansiär
Vetenskapsrådet, 2016–01936Knut och Alice Wallenbergs StiftelseRiksbankens Jubileumsfond, P20-0515Tillgänglig från: 2023-08-08 Skapad: 2023-08-08 Senast uppdaterad: 2023-08-08Bibliografiskt granskad
Ingår i avhandling
1. The architecture of the aging brain: functional reorganization, structural changes, and the role of dopamine receptors
Öppna denna publikation i ny flik eller fönster >>The architecture of the aging brain: functional reorganization, structural changes, and the role of dopamine receptors
2023 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Aging is associated with reorganization of functional brain architecture, potentially leading tocognitive decline in older age. However, the mechanisms responsible for alterations in functionalbrain architecture remain poorly understood. Using a combination of multimodal neuroimagingtechniques and advanced statistical analyses in four independent studies, this thesis aims tocontribute to our understanding of age-related alterations in functional brain architecture andcognitive decline. Study I demonstrated age-related decline in functional brain network segregationin a longitudinal setting. Age-related changes in network segregation were associated withconcomitant losses of white matter integrity and domain-general cognitive function. Study II testedthe hypothesis that older age and lower dopamine D1-receptor (D1DR) availability concomitantly arerelated to less segregated network structure in older age. The results supported the hypothesis,revealing that greater D1DR availability in older age is associated with a more youth-like functionalarchitecture and greater working memory performance compared to age-matched counterparts withless D1DR. Study III further assessed the relationship between D1DR organization and functionalarchitecture. Using a non-linear decomposition method, we demonstrate that the spatial coexpression and distribution of D1DRs are aligned with the principal organization of brain function.Individual differences in D1DR distribution were related to the degree of functional differentiationbetween unimodal and transmodal cortices. Study IV investigated age-related differences in thefunctional organization of the hippocampus, revealing three overlapping modes of organization. Amedial-to-anterior and posterior mode largely corresponded to macroscale cortical organization ofconnectivity, aligned with local D1DR topography. Older age was associated with less distinctorganization of cortico-hippocampal connectivity, and maintenance of youth-like hippocampalorganization in older age was related to superior episodic memory function. Collectively, this thesisoffers multiple lines of evidence for age-related alterations in functional brain organization,associations with white-matter integrity and cognitive function, in addition to a novel link betweenfunctional brain architecture and the D1DR system.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå universitet, 2023. s. 104
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 2254
Nyckelord
brain architecture, functional connectivity, dopamine, aging, cognition, memory, functional magnetic resonance imaging, positron emission tomography, graph theory, Laplacian eigenmapping, gradient
Nationell ämneskategori
Neurovetenskaper
Identifikatorer
urn:nbn:se:umu:diva-212692 (URN)978-91-8070-136-5 (ISBN)978-91-8070-137-2 (ISBN)
Disputation
2023-09-01, Aula Biologica, Biologihuset, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2023-08-15 Skapad: 2023-08-08 Senast uppdaterad: 2024-07-02Bibliografiskt granskad

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Pedersen, RobinJohansson, JarkkoSalami, Alireza

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Institutionen för integrativ medicinsk biologi (IMB)Umeå centrum för funktionell hjärnavbildning (UFBI)Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM)
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