Millions of individuals in the US undergo surgery every year for medically necessary conditions and are at risk for developing long-lasting memory impairments, also referred to as postoperative cognitive dysfunction (POCD). Although risk factors, including age, have been identified, the mechanisms underlying surgical effects on cognitive outcomes are unknown. Thus, there is an urgent need to characterize the neural mechanisms that lead to memory dysfunction after surgery and to develop therapeutic strategies against this potentially devastating complication. Using a clinically-relevant model of orthopedic surgery in mice we linked surgical procedures to the development of inflammation in brain regions that are responsible for memory retention and recall. Further, our preliminary data suggest that pharmacological activation of a cholinergic anti-inflammatory reflex can mitigate POCD in mice. The objective of this incubator award is to determine the efficacy of electrical vagus nerve stimulation (VNS) to activate the cholinergic anti-inflammatory reflex as a treatment for POCD. Our hypothesis is that activation of cholinergic neurons with VNS will reduce neuroinflammation, prevent surgery-associated reductions in neurogenesis, and mitigate surgery induced memory deficits in our mouse model of POCD. This project will have both fundamental and translational impact. From a basic science perspective, it will clarify the fundamental relationship between inflammation, neurogenesis and cholinergic function in a clinically relevant model of peripheral surgical trauma. From a translational perspective, this work will offer a novel therapeutic approach to treat POCD without directly disrupting the innate immune response to trauma.