Grant: Foundation Grant

General anesthetics are an essential component of modern medical care. Each year, millions of patients undergo anesthesia worldwide. Despite their widespread use, general anesthetics are inherently unsafe and their molecular mechanisms are poorly understood. Such lack of knowledge has stalled the discovery of safer anesthetics and the development of treatments for their adverse effects. Our research program addresses three questions that have perplexed scientists for over a century: How do anesthetics depress brain function? What are their adverse effects? How can such adverse effects be treated? We discovered a mechanism and potential treatments for a major adverse effect: persistent postanesthetic cognitive deficits. The results are important because many patients experience long-term cognitive deficits and delirium after anesthesia and surgery. Such cognitive deficits are associated with poor long-term outcomes, increased mortality, and higher healthcare costs. The causes are unknown, and no effective treatments are available. We showed that anesthetics target both astrocytes (the most abundant support cells in the brain) and neurons. Activation of anesthetic-sensitive sensors in astrocytes may cause both the desired, acute memory-blocking effects of anesthetics and the undesired, persistent cognitive deficits. Anesthetics stimulate astrocytes to release soluble factors. These factors modify the function of neurons, which causes persistent cognitive deficits that last long after the anesthetics have been eliminated. We will determine how astrocyte-neuron crosstalk causes both the desired and undesired effects of anesthetics. We will also develop new treatments based on our patented drugs and other newly discovered compounds. Overall, this research program will advance our understanding of anesthetic mechanisms and will allow the development of new treatments to ensure that patients don't simply survive anesthesia but thrive in the postoperative period.