The roles of anesthetics and neuroimmune interactions in postoperative cognitive dysfunction

Project Summary General anesthetics are routinely administered during surgical procedures to induce a reversible state of unconsciousness, amnesia, analgesia, and immobility. However, it has become evident that anesthetics can have detrimental effects on neurophysiological processes, including alterations in attention, sleep, and memory, particularly in vulnerable populations such as neonates and older adults. Despite this knowledge, the precise mechanisms underlying these undesired effects of anesthetics remain elusive. Our research aims to delve into these mechanisms at the neural circuit, cellular, and molecular levels. Recent findings from our laboratory have revealed the emergence of hyperactive neurons in the prefrontal cortex (PFC) following anesthesia as an early functional indicator of subsequent neurocognitive changes. Building upon these findings, we will further determine the involvement of local inhibitory circuits and deeper brain centers, such as the hippocampus, which send long-range projections to the PFC. Using a combination of in vivo calcium imaging, virus-based circuit tracing, and chemogenetics, we will elucidate the functional relevance of these circuits to the detrimental effects induced by anesthetics and develop strategies to protect cognitive function after anesthesia. In addition, our preliminary data suggest that astrocytes, the most abundant glial cells expressing GABAA receptors, respond to GABAergic anesthetics and subsequently activate the unfolded protein response. We will test the hypothesis that sustained activation of the unfolded protein response in astrocytes leads to reduced release of soluble factors crucial for synaptogenesis, resulting in synapse loss and long-term memory decline. Additionally, we will investigate whether restoring astrocytic function through a novel gene delivery strategy capable of permeating the blood-brain barrier would alleviate neurocognitive deficits induced by anesthesia. Collectively, the proposed research will contribute to a mechanistic understanding of the detrimental effects of anesthetics on the brain. This knowledge is critical for optimizing anesthesia practices and mitigating potential adverse effects. By unraveling the intricate interplay between anesthetics, neuro-immune-glial interactions, and brain plasticity, our research holds promise for advancing perioperative care and promoting brain health.