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.
Memory dysfunction is a common complication in patients after major surgery and may last for several months, even years, after an operation. We do not yet know why this decline in memory function occurs, and currently there is no effective medical treatment to prevent this complication. This project will identify cellular processes that may cause memory deficits after surgery. We will focus particularly on interactions between the nervous and immune systems. Overall, this work is expected to have a major impact on global health by reducing the negative effects of surgery on memory and cognitive ability.
| Huffman, William J; Subramaniyan, Saraswathi; Rodriguiz, Ramona M et al. (2018) Modulation of neuroinflammation and memory dysfunction using percutaneous vagus nerve stimulation in mice. Brain Stimul : |
