The locus coeruleus on stress: Bridging the translational gap

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AbstractBackgroundLoss of locus coeruleus (LC) neurons is one of the earliest and most pronounced features of Alzheimer's disease (AD). Stress is one of the most powerful activators of LC activity, and a risk factor for the development of AD. However, the small size of the LC, and its location deep in the brainstem, make systematic investigations of this nucleus extremely challenging. Here, we develop translational tools that can link animal and human research to study how stress impacts the LC, and how this might contribute to the risk of developing AD.MethodsFirst, to study how the LC drives functional changes across brain networks, we developed a new chemo‐connectomic approach that combines DREADD/chemogenetic manipulation of the LC with resting‐state fMRI analyses (rs‐fMRI) in mice. Second, we employ pupillometry – a clinically widespread and readily available tool – together with optogenetic LC stimulation to assess the impact of various, physiologically relevant LC stimulation paradigms on pupil diameter. Third, we leverage novel genetic tools to perform multi‐omic molecular screens in the mouse LC, to analyze sex differences and stress‐induced molecular changes.ResultsChemo‐connectomics shows that strong LC activation triggers a rapid network reset and potently activates saliency networks, thus revealing striking similarities between LC activation in the mouse and stress‐related rs‐fMRI data in humans. Pupillometry shows that optogenetic LC stimulation faithfully triggers pupil dilation, a response that scales with stimulation intensity and frequency. Molecular screening reveals – for the first time – the impact of acute stress on the transcriptional and translational landscape of the locus coeruleus, while sex differences appear to be subtle.ConclusionIn combination, these approaches allow us to dissect LC function from molecules to circuits to brain‐wide networks. While pupillometry provides a simple and clinically available window into LC function, chemo‐connectomics holds the potential to identify noradrenaline‐based network signatures that can identify high‐risk populations (or specific subgroups) of AD patients using rs‐fMRI. Finally, the ability to perform high‐throughput molecular screens in mice allows us to explore stress‐induced changes in LC function, and link these changes to neurodegenerative disease processes.