Image-guided phenotyping of ovariectomized mice: altered functional connectivity, cognition, myelination, and dopaminergic functionality

A large proportion of the population suffers from endocrine disruption, e.g., menopausal women, which might result in accelerated aging and a higher risk for developing cognitive disorders. Therefore, it is crucial to fully understand the impact of such disruptions on the brain to identify potential...

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Bibliographic Details
Published in:Neurobiology of aging 2019-02, Vol.74, p.77-89
Main Authors: Anckaerts, Cynthia, van Gastel, Jaana, Leysen, Valerie, Hinz, Rukun, Azmi, Abdelkrim, Simoens, Pascal, Shah, Disha, Kara, Firat, Langbeen, An, Bols, Peter, Laloux, Charlotte, Prevot, Vincent, Verhoye, Marleen, Maudsley, Stuart, Van der Linden, Annemie
Format: Article
Language:English
Subjects:
Aging
Behavior
Cognition
Dopamine
Functional connectivity
Mass spectrometry
Myelination
Ovariectomy
Quantitative proteomics
Resting-state fMRI
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Summary:A large proportion of the population suffers from endocrine disruption, e.g., menopausal women, which might result in accelerated aging and a higher risk for developing cognitive disorders. Therefore, it is crucial to fully understand the impact of such disruptions on the brain to identify potential therapeutic strategies. Here, we show using resting-state functional magnetic resonance imaging that ovariectomy and consequent hypothalamus-pituitary-gonadal disruption result in the selective dysconnectivity of 2 discrete brain regions in mice. This effect coincided with cognitive deficits and an underlying pathological molecular phenotype involving an imbalance of neurodevelopmental/neurodegenerative signaling. Furthermore, this quantitative mass spectrometry proteomics-based analysis of molecular signaling patterns further identified a strong involvement of altered dopaminergic functionality (e.g., DAT and predicted upstream regulators DRD3, NR4A2), reproductive signaling (e.g., Srd5a2), rotatin expression (rttn), cellular aging (e.g., Rxfp3, Git2), myelination, and axogenesis (e.g., Nefl, Mag). With this, we have provided an improved understanding of the impact of hypothalamus-pituitary-gonadal dysfunction and highlighted the potential of using a highly translational magnetic resonance imaging technique for monitoring these effects on the brain. •Resting-state fMRI detects aberrant long-range functional connectivity after ovariectomy•Decreased anterior-posterior connectivity coincident with cognitive deficits•Phenotype driven by an underlying pathological molecular signaling pattern•Abnormal neurodegenerative/neurodevelopmental and dopaminergic signaling
ISSN:0197-4580
1558-1497
DOI:10.1016/j.neurobiolaging.2018.10.012