ABSTRACT Down Syndrome (Ds) is the most common chromosomal cause of intellectual disability and results from triplication of chromosome 21 genes. Individuals with Ds also have cardiovascular and autonomic challenges. We have published data showing lower blood pressure and heart rate in Ts65Dn, an accepted mouse model of Ds. Additionally, we also demonstrated altered autonomic function in Ts65Dn vs. WT. Therefore, Ts65Dn is an appropriate model to investigate cardiovascular and autonomic function in Ds. Finding ways to improve cardiovascular and autonomic function would influence the lives of individuals with Ds. Exercise is a feasible and accessible intervention that results in enhanced cardiac outcomes and autonomic function in other populations. Limited reports demonstrate exercise therapy also has positive autonomic results for individuals with Ds. Additional controlled, larger cohort studies investigating the influence of chronic exercise on blood pressure, heart rate and autonomic function are important for the Ds population. This supplement proposes to conduct the initial exercise studies using a mouse model, Ts65Dn. The parent award will determine mechanisms of cardiovascular and autonomic function in Ts65Dn. Specific Aim 1 of the parent award will compare the cardiovascular profile and vascular physiology of WT and Ts65Dn mice at 3, 6 and 12 months of age. This supplemental application plans to examine the role of wheel running exercise in WT and Ts65Dn on the cardiovascular and autonomic profile in these mice at 3 and 6 months of age. The supplemental exercised mouse groups will be compared to the parent award non-exercised groups (WT and Ts65Dn) from Aim 1. We hypothesize that exercise will improve autonomic function in both WT and Ts65Dn, but will likely have a stronger influence on Ts65Dn cardiovascular outcomes. These proposed investigations address the NICHD funding priority “studies of rodent models to understand cognition, behavior, and other aspects of the phenotype across different stages of development”. Overall, this supplement plans to investigate if lifelong exercise is a safe and effective intervention for cardiovascular and autonomic function in Ts65Dn, and by clinical correlate, Ds.

NARRATIVE Down syndrome (Ds) is a developmental disability that results from triplication of chromosome 21. Persons with Ds are confronted with a variety of daily challenges including heart defects at birth and lower blood pressure and heart rate at rest and during times of activity. This work is relevant to public health it that it aims to uncover contributors of the cardiovascular phenotype observed in Ds so that future studies can be implemented with the objective of improving cardiovascular regulation in this population.