Age-dependent Transcriptional and Circuit Alterations in the brain Underlie Post-Anesthesia Neurobehavioral Dysfunction

With rising life expectancy, more elderly individuals are undergoing surgery, highlighting the need to understand postoperative neurological complications. Studies have linked general anesthesia (GA) to olfactory dysfunction (OD) and cognitive decline following operation (OP), though mechanisms remain unclear. Using aged C57BL/6 mice subjected to laparotomy and 2-hour isoflurane exposure, we assessed behavioral and molecular outcomes through functional tests and bulk RNA sequencing (RNAseq). We observed persistent OD in the weeks following GA/OP, along with reduced limb strength and motor coordination, indicative of increased frailty. While no immediate cognitive deficits were apparent, aged mice exhibited delayed cognitive impairments, including diminished learning and memory in Y-maze and novel object recognition tasks, as well as increased apathy in nest-building behavior. RNAseq of the olfactory bulb (OB) at 1-day post-GA/OP revealed upregulation of ubiquitin-dependent proteins and catabolic processes in the aged mice compared to sham group. In contrast, transcriptomic analysis of the hippocampus (HI) at 5 weeks after GA/OP showed more extensive molecular pathway changes, correlating with the delayed impairment of cognitive functions. Compared to young adult mice, aged GA/OP mice demonstrated upregulated expression of genes associated with innate immunity and reduced neurogenesis in the OB, along with increased gliogenesis and reduced RNA splicing activity in the HI. Additionally, in vivo electrophysiology recordings from the OB mitral cell layer revealed alterations in neuronal excitability and circuit disruptions after GA/OP. Taken together, our findings provided functional, molecular, and circuit-level insights into the age-dependent persistent olfactory impairment and delayed cognitive dysfunctions following general anesthesia and surgery.