The Aged Striatum: Evidence of Molecular and Structural Changes Using a Longitudinal Multimodal Approach in Mice

Bruno Lima Giacobbo; Özgün Özalay; Tomas Mediavilla; Madelene Ericsson; Jan Axelsson; Anna Rieckmann; Fahad Sultan; Daniel Marcellino

doi:10.3389/fnagi.2022.795132

The Aged Striatum: Evidence of Molecular and Structural Changes Using a Longitudinal Multimodal Approach in Mice

Front Aging Neurosci. 2022 Jan 24:14:795132. doi: 10.3389/fnagi.2022.795132. eCollection 2022.

Authors

Bruno Lima Giacobbo¹, Özgün Özalay¹, Tomas Mediavilla¹, Madelene Ericsson², Jan Axelsson³, Anna Rieckmann^{1

3}, Fahad Sultan¹, Daniel Marcellino¹

Affiliations

¹ Department of Integrative Medical Biology, Umeå University, Umeå, Sweden.
² Umeå Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
³ Department of Radiation Sciences, Umeå University, Umeå, Sweden.

Abstract

To study the aging human brain requires significant resources and time. Thus, mice models of aging can provide insight into changes in brain biological functions at a fraction of the time when compared to humans. This study aims to explore changes in dopamine D₁ and D₂ receptor availability and of gray matter density in striatum during aging in mice and to evaluate whether longitudinal imaging in mice may serve as a model for normal brain aging to complement cross-sectional research in humans. Mice underwent repeated structural magnetic resonance imaging (sMRI), and [¹¹C]Raclopride and [¹¹C]SCH23390 positron emission tomography (PET) was performed on a subset of aging mice. PET and sMRI data were analyzed by binding potential (BP _ND ), voxel- and tensor-based morphometry (VBM and TBM, respectively). Longitudinal PET revealed a significant reduction in striatal BP _ND for D₂ receptors over time, whereas no significant change was found for D₁ receptors. sMRI indicated a significant increase in modulated gray matter density (mGMD) over time in striatum, with limited clusters showing decreased mGMD. Mouse [¹¹C]Raclopride data is compatible with previous reports in human cross-sectional studies, suggesting that a natural loss of dopaminergic D₂ receptors in striatum can be assessed in mice, reflecting estimates from humans. No changes in D₁ were found, which may be attributed to altered [¹¹C]SCH23390 kinetics in anesthetized mice, suggesting that this tracer is not yet able to replicate human findings. sMRI revealed a significant increase in mGMD. Although contrary to expectations, this increase in modulated GM density may be attributed to an age-related increase in non-neuronal cells.

Keywords: PET; VBM; aging; dopamine; senescence; structural MRI.