The Dynamic Neuromodulome in Alzheimer's Disease and Aging

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PROJECT SUMMARY Neuromodulators such as dopamine, serotonin, acetylcholine, and norepinephrine play important roles in shaping perception, cognition, and behavior. Evidence suggests that these systems may be particularly susceptible to dysfunction in Alzheimer’s disease (AD). This dysfunction can lead to neuropsychiatric symptoms that can appear early in disease progression, before the profound decline in cellular integrity and associated deficits in memory and cognition that are hallmarks of AD. These neuromodulators vary quickly from moment to moment, but it’s not clear how these dynamics vary across aging, and when they diverge from normal aging over the progression of AD. Understanding when these changes occur relative to well-described anatomical and behavioral benchmarks of AD disease progression would reveal the “critical path” of neuromodulator pathology in AD that distinguishes it from normal aging, and could suggest potential targets for treatment or diagnosis of AD prior to the onset of memory loss and cognitive decline. The overall goals of this project are to understand how fast activity these ascending systems change during the progression of AD, and to enable the development of diagnostic tools for non-invasive assessment of disease risk. We will perform systematic measurements of neuromodulator release at multiple ages in two different Alzheimer’s disease mouse lines and control animals using a novel combination of techniques developed by our team. We will combine these in vivo functional measurements with anatomical data in the same mice that includes markers of cellular pathology, axonal integrity, and transcriptomics, as well as behavioral assays, in order to produce a multimodal atlas of disease progression bridging structure and function in the brain’s major modulatory systems. Finally, building on our previous finding that spontaneous fluctuations in pupil size are correlated with specific patterns of neuromodulator release in the brain, we will attempt to build models that allow us to infer neuromodulator levels from pupillometric measurements, and we will validate the translation relevance of these models in a unique human data set. In summary, this project will provide the clearest view to date of pathological changes in neuromodulator dynamics with AD, where they diverge from normal changes during aging, and their relationship to underlying anatomical changes throughout the brain.