Role of the circRNA_34414/miR-6960a-5p/SIRT3 axis in postoperative delirium via CA1 Vglut1+ neurons in older mice.

AIMS: Postoperative delirium (POD) is a common neurological complication in elderly patients after anesthesia/surgery. The main purpose of this study is to explore the effect of circRNA-targeted miRNA regulating SIRT3 on mitochondrial function through ceRNA mechanism under the surgical model of tibial fracture and to further explore the potential mechanism of postoperative delirium mediated by circRNA, so as to provide new ideas for clinical diagnosis and prevention of POD. METHODS: The surgical model of tibial fracture under sevoflurane anesthesia caused acute delirium-like behavior in elderly mice. We observed that the decrease of SIRT3 and mitochondrial dysfunction was related to POD, and miRNA and circRNA (circRNA_34414) related to SIRT3 were further studied. Through luciferase and RAP, we observed that circRNA_34414, as a miRNA sponge, was involved in the regulation of SIRT3 expression. RESULTS: Postoperative delirium in elderly mice showed decreased expression of hippocampal circRNA_34414, increased expression of miR-6960-5p, decreased expression of SIRT3, and impaired mitochondrial membrane potential. Overexpression of circRNA_34414, or knockdown of miR-6960-5p, or overexpression of SIRT3 in hippocampal CA1 glutamatergic neurons significantly upregulated hippocampal SIRT3 expression, increased mitochondrial membrane potential levels, and significantly ameliorated postoperative delirium in aged mice; CircRNA_34414 ameliorates postoperative delirium in mice, possibly by targeting miR-6960-5p to upregulate SIRT3. CONCLUSIONS: CircRNA_34414 is involved in the improvement of postoperative delirium induced by anesthesia/surgery by upregulating SIRT3 via sponging miR-6960-5p.

The Effect of SIRT3/Ac-SOD2 Mediated Oxidative Stress and HCN1 Channel Activity on Anesthesia/Surgery Induced Anxiety-Like Behavior in Mice.

Anxiety disorders are the most common psychiatric diseases, and perioperative factors often increase the incidence of anxiety. However, the mechanism and treatment for perioperative anxiety, especially anesthesia/surgery-induced postoperative anxiety, are largely unknown. Sirtuin 3 (SIRT3) which located in the mitochondria is the NAD-dependent deacetylase protein. SIRT3 mediated oxidative stress is associated with several neuropsychiatric diseases. In addition, hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channel is also reported involved in anxiety symptoms. The purpose was to assess the role of SIRT3 on postoperative anxiety like behavior in C57/BL6 mice. We found that SIRT3 level reduced and HCN1 expression level increased in mice medial prefrontal cortex (mPFC) as well as anxiety like behavior postoperatively. In interventional research, SIRT3 adeno-associated virus vector or control vector was injected into the mPFC brain region. Enzyme-linked immunosorbent assay, immunofluorescence staining, and western blotting were employed to detect oxidative stress reactions and HCN1 channel activity. SIRT3 overexpression attenuated postoperative anxiety in mice. Superoxide dismutase 2 (SOD2) acetylation levels, SOD2 oxidative stress activity, mitochondrial membrane potential levels, and HCN1 channels were also inhibited by SIRT3 overexpression. Furthermore, the HCN1 channel inhibitor ZD7288 significantly protected against anesthesia/surgery-induced anxiety, but without SIRT3/ac-SOD2 expression or oxidative stress changes. Our results suggest that SIRT3 may achieve antianxiety effects through regulation of SOD2 acetylation-mediated oxidative stress and HCN1 channels in the mPFC, further strengthening the therapeutic potential of targeting SIRT3 for anesthesia/surgery-induced anxiety-like behavior.

Hippocampal SIRT1-Mediated Synaptic Plasticity and Glutamatergic Neuronal Excitability Are Involved in Prolonged Cognitive Dysfunction of Neonatal Rats Exposed to Propofol.

Neonates who receive repeated or prolonged general anesthesia before the age of 4 are at a significantly higher risk of developing cognitive dysfunction later in life. In this study, we investigated the effects of repeated neonatal propofol exposure on hippocampal synaptic plasticity, neuronal excitability, and cognitive function. Adeno-associated SIRT1 virus with CaMKIIɑ promotor and a viral vector carrying the photosensitive gene ChR2 with the CaMKIIɑ promotor, as well as their control vectors, were stereotaxically injected into the hippocampal CA1 region of postnatal day 5 (PND-5) rats. PND-7 rats were given intraperitoneal injection of 60 mg/kg propofol or fat emulsion for three consecutive days. Western blotting, Golgi staining, and double immunofluorescence staining were used to evaluate the SIRT1 expression, synaptic plasticity, and the excitability of neurons in the hippocampal CA1 region. The Morris water maze (MWM) test was conducted on PND-30 to assess the learning and memory abilities of rats. Repeated neonatal propofol exposure reduced SIRT1 expression, suppressed synaptic plasticity, decreased glutamatergic neuron excitability in the hippocampus, and damaged learning and memory abilities. Overexpression of SIRT1 attenuated propofol-induced cognitive dysfunction, excitation-inhibition imbalance, and synaptic plasticity damage. After optogenetic stimulation of glutamatergic neurons in the hippocampal CA1 region, the learning and memory abilities of rats exposed to propofol were improved on PND-30. Our findings demonstrate that SIRT1 plays an important role in cognitive dysfunction induced by repeated neonatal propofol exposure by suppressing synaptic plasticity and neuronal excitability.