The impact of cardio exercise on hippocampal neuronal circuits that improve cognitive function and affective behavior

Cardio exercise lowers cardiovascular mortality and risk, as well as improves cognitive performance and mental health. Depression/anxiety have been identified as independent cardiovascular disease (CVD) risk factors, and are associated with increased risk of mortality and morbidity after adverse cardiac events. The proposed studies seek to define the molecular basis of this interrelationship. Specifically, the studies focus on the mechanisms by which cardio exercise enhances cognition and reduces depressive/anxiety-like behavior in a rodent model. Increased neurogenesis in the dentate gyrus (DG) and improvements in cognitive and affective behavior occur in parallel in response to voluntary running. Previous study from our lab has demonstrated the casual relationship between neurogenesis and the affective behavioral changes through chemogentic silencing of newborn neurons. However, the number of newly generated neurons is small in comparison to the overall number of neurons in the DG, whereas the behavioral changes are large. This suggests that newly generated neurons must have different synaptic/circuit interconnections than preexisting DG neurons if they are responsible for the behavioral changes. To test this hypothesis, I will use rabies virus-mediated monosynaptic retrograde tracing to examine how running differentially affects presynaptic inputs map of newborn neurons in dorsal and ventral DG. Regarding the molecular events underlying these changes, exposure to cardio exercise decreases bone morphogenetic protein (BMP) signaling in the DG, and this decrease is required for the running-induced neurogenic effects and behavioral phenotype in mice. Inhibition of BMP signaling has also been shown to be protective against CVD in mice. I hypothesis that decreasing BMP signaling will affect the hippocampal circuit similar to that of running. I will therefore locally inhibit BMP signaling by stereotaxic DG injection of Noggin and compare with the input maps induced by voluntary running. Conversely, the role of BMP signaling in running-induced changes will be examined using BMP4 overexpression to prevent running-induced decreases in BMP signaling. The overall goal of these studies is to understand the interrelationship between cardiovascular and neurological health and specifically how cardio exercise can so profoundly alter both organ systems. Underpinning the molecular basis will ultimately facilitate the therapeutic development that could target both cardiovascular and neurological diseases.