Genetic Control of Phrenic Motor Neuron Development and Maintenance

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Project Summary/Abstract Respiratory dysfunction is both a risk factor and a common symptom in Alzheimer’s disease (AD), but the molecular mechanisms that underlie this pathology are not well understood. AD patients exhibit phosphorylated tau accumulation in the brainstem and cervical spinal cord, which contain neurons critical for breathing, at preclinical stages but the impact of these changes on respiratory circuit function is not clear. It is also not known how respiratory dysfunction contributes to the progression of AD pathology. In this supplement, we will examine changes in respiratory circuit connectivity and function with aging and in the PS19 AD mouse model, in order to begin to understand the link between respiratory dysfunction and AD progression. Our data will reveal both novel risk factors and potential future therapeutic targets for AD. In Aim 1 we will define changes in respiratory neuron connectivity and function with aging and in the PS19 AD mouse model. In Aim 2 we will determine transcriptomic and epigenetic changes in respiratory neuron populations over time in control and PS19 mice to elucidate age-related risk factors and AD-induced changes. We will utilize a combinatorial approach established in our lab as part of the parent award for interrogating respiratory circuits. We have developed an integrative methodology combining genetic models, single-cell RNA- sequencing, ATAC-sequencing, expansion microscopy, retrograde viral tracing, and behavioral assays, such as plethysmography, to address these questions in vivo. Our approach has the potential to reveal novel therapeutic targets by investigating a vital, yet understudied, circuit implicated in AD progression.