Hippocampal Neural Dynamics and Postoperative Delirium-Like Behavior in Aged Mice

Background: Post-operative delirium (POD) is a common and serious clinical condition that occurs following anesthesia/surgery. While its clinical impact is well recognized, the underlying electrophysiological mechanisms remain largely unknown, posing challenges for effective treatment. This study aims to investigate hippocampal neural dynamics before and after anesthesia/surgery in aged mice, which have a tendency of developing POD. Methods: This study included adult and aged mice with a POD model. POD-like behavior was assessed in N = 10 mice at baseline (the day before surgery), as well as at 9 hours and 24 hours post-anesthesia/surgery. A behavioral battery, including the open field test, Y-maze, buried food test, and novel object recognition, was used for assessment. In vivo chronic brain recordings were performed on awake, restrained mice using a high-density silicon probe (HSP) during the same time intervals. To further investigate hippocampal neural dynamics, in vivo two-photon calcium imaging was also conducted. Additionally, aged mice were pre-treated with indole 3-propionic acid (IPA), and its effects on POD-like behavior and neural activity were evaluated using electrophysiology and calcium imaging. Results: We first observed that aged mice exhibited significant POD-like behavior, as measured by z-scores, compared to adult mice following anesthesia/surgery. Our analysis revealed significant age-related differences in hippocampal neuronal activities. At 9 hours post-surgery, aged mice exhibited a marked increase in pyramidal cell activity and a reduction in interneuron activity compared to adult mice. These changes in neuronal dynamics were associated with the onset of POD-like symptoms in aged mice. By 24 hours post-surgery, both pyramidal cell and interneuron activity in aged mice had returned to pre-surgery levels, which coincided with an improvement in POD-like behavior. Additionally, IPA pre-treatment modulated neuronal activity in aged mice, attenuating pyramidal cell hyperactivity and partially ameliorating interneuron dysfunction, changes associated with mitigated POD-like behavior. Conclusion: Alterations in hippocampal neural activity may significantly contribute to brain dysfunction and POD-like behavior. IPA pre-treatment may modulate neural circuit imbalances in aged mice, potentially mitigating POD incidence.