Impaired synaptic plasticity and decreased glutamatergic neuron excitability induced by SIRT1/BDNF downregulation in the hippocampal CA1 region are involved in postoperative cognitive dysfunction.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common complication after anesthesia/surgery, especially among elderly patients, and poses a significant threat to their postoperative quality of life and overall well-being. While it is widely accepted that elderly patients may experience POCD following anesthesia/surgery, the exact mechanism behind this phenomenon remains unclear. Several studies have indicated that the interaction between silent mating type information regulation 2 homologue 1 (SIRT1) and brain-derived neurotrophic factor (BDNF) is crucial in controlling cognitive function and is strongly linked to neurodegenerative disorders. Hence, this research aims to explore how SIRT1/BDNF impacts cognitive decline caused by anesthesia/surgery in aged mice. METHODS: Open field test (OFT) was used to determine whether anesthesia/surgery affected the motor ability of mice, while the postoperative cognitive function of 18 months old mice was evaluated with Novel object recognition test (NORT), Object location test (OLT) and Fear condition test (FC). The expressions of SIRT1 and other molecules were analyzed by western blot and immunofluorescence staining. The hippocampal synaptic plasticity was detected by Golgi staining and Long-term potentiation (LTP). The effects of SIRT1 and BDNF overexpression as well as chemogenetic activation of glutamatergic neurons in hippocampal CA1 region of 18 months old vesicular glutamate transporter 1 (VGLUT1) mice on POCD were further investigated. RESULTS: The research results revealed that older mice exhibited cognitive impairment following intramedullary fixation of tibial fracture. Additionally, a notable decrease in the expression of SIRT1/BDNF and neuronal excitability in hippocampal CA1 glutamatergic neurons was observed. By increasing levels of SIRT1/BDNF or enhancing glutamatergic neuron excitability in the CA1 region, it was possible to effectively mitigate synaptic plasticity impairment and ameliorate postoperative cognitive dysfunction. CONCLUSIONS: The decline in SIRT1/BDNF levels leading to changes in synaptic plasticity and neuronal excitability in older mice could be a significant factor contributing to cognitive impairment after anesthesia/surgery.

Repeated Ketamine Anesthesia during the Neonatal Period Impairs Hippocampal Neurogenesis and Long-Term Neurocognitive Function by Inhibiting Mfn2-Mediated Mitochondrial Fusion in Neural Stem Cells.

The mechanism of ketamine-induced neurotoxicity development remains elusive. Mitochondrial fusion/fission dynamics play a critical role in regulating neurogenesis. Therefore, this study was aimed to evaluate whether mitochondrial dynamics were involved in ketamine-induced impairment of neurogenesis in neonatal rats and long-term synaptic plasticity dysfunction. In the in vivo study, postnatal day 7 (PND-7) rats received intraperitoneal (i.p.) injection of 40 mg/kg ketamine for four consecutive times at 1 h intervals. The present findings revealed that ketamine induced mitochondrial fusion dysfunction in hippocampal neural stem cells (NSCs) by downregulating Mitofusin 2 (Mfn2) expression. In the in vitro study, ketamine treatment at 100 µM for 6 h significantly decreased the Mfn2 expression, and increased ROS generation, decreased mitochondrial membrane potential and ATP levels in cultured hippocampal NSCs. For the interventional study, lentivirus (LV) overexpressing Mfn2 (LV-Mfn2) or control LV vehicle was microinjected into the hippocampal dentate gyrus (DG) 4 days before ketamine administration. Targeted Mfn2 overexpression in the DG region could restore mitochondrial fusion in NSCs and reverse the inhibitory effect of ketamine on NSC proliferation and its faciliatory effect on neuronal differentiation. In addition, synaptic plasticity was evaluated by transmission electron microscopy, Golgi-Cox staining and long-term potentiation (LTP) recordings at 24 h after the end of the behavioral test. Preconditioning with LV-Mfn2 improved long-term cognitive dysfunction after repeated neonatal ketamine exposure by reversing the inhibitory effect of ketamine on synaptic plasticity in the hippocampal DG. The present findings demonstrated that Mfn2-mediated mitochondrial fusion dysfunction plays a critical role in the impairment of long-term neurocognitive function and synaptic plasticity caused by repeated neonatal ketamine exposure by interfering with hippocampal neurogenesis. Thus, Mfn2 might be a novel therapeutic target for the prevention of the developmental neurotoxicity of ketamine.

Neuronal excitation-inhibition imbalance in the basolateral amygdala is involved in propofol-mediated enhancement of fear memory.

Posttraumatic stress disorder (PTSD) is associated with glutamatergic neuron hyperactivation in the basolateral amygdala (BLA) brain area, while GABAergic interneurons in the BLA modulate glutamatergic neuron excitability. Studies have shown that propofol exerts its effects through potentiation of the inhibitory neurotransmitter γ-aminobutyric acid. The neuronal mechanism by which propofol anesthesia modulates fear memory is currently unknown. Here, we used optogenetics and chemogenetics to suppress glutamatergic neurons or activate GABAergic interneurons in the BLA to assess alterations in neuronal excitation-inhibition balance and investigate fear memory. The excitability of glutamatergic neurons in the BLA was significantly reduced by the suppression of glutamatergic neurons or activation of GABAergic interneurons, while propofol-mediated enhancement of fear memory was attenuated. We suggest that propofol anesthesia could reduce the excitability of GABAergic neurons through activation of GABAA receptors, subsequently increasing the excitability of glutamatergic neurons in the mice BLA; the effect of propofol on enhancing mice fear memory might be mediated by strengthening glutamatergic neuronal excitability and decreasing the excitability of GABAergic neurons in the BLA; neuronal excitation-inhibition imbalance in the BLA might be important in mediating the enhancement of fear memory induced by propofol.

The role of epigenetic modification in postoperative cognitive dysfunction.

With the ageing of the population, the health problems of elderly individuals have become particularly important. Through a large number of clinical studies and trials, it has been confirmed that elderly patients can experience postoperative cognitive dysfunction after general anesthesia/surgery. However, the mechanism of postoperative cognitive dysfunction is still unknown. In recent years, the role of epigenetics in postoperative cognitive dysfunction has been widely studied and reported. Epigenetics includes the genetic structure and biochemical changes of chromatin not involving changes in the DNA sequence. This article summarizes the epigenetic mechanism of cognitive impairment after general anesthesia/surgery and analyses the broad prospects of epigenetics as a therapeutic target for postoperative cognitive dysfunction.

GABAergic Neurons in the Nucleus Accumbens are Involved in the General Anesthesia Effect of Propofol.

The mechanism underlying the hypnosis effect of propofol is still not fully understood. In essence, the nucleus accumbens (NAc) is crucial for regulating wakefulness and may be directly engaged in the principle of general anesthesia. However, the role of NAc in the process of propofol-induced anesthesia is still unknown. We used immunofluorescence, western blotting, and patch-clamp to access the activities of NAc GABAergic neurons during propofol anesthesia, and then we utilized chemogenetic and optogenetic methods to explore the role of NAc GABAergic neurons in regulating propofol-induced general anesthesia states. Moreover, we also conducted behavioral tests to analyze anesthetic induction and emergence. We found out that c-Fos expression was considerably dropped in NAc GABAergic neurons after propofol injection. Meanwhile, patch-clamp recording of brain slices showed that firing frequency induced by step currents in NAc GABAergic neurons significantly decreased after propofol perfusion. Notably, chemically selective stimulation of NAc GABAergic neurons during propofol anesthesia lowered propofol sensitivity, prolonged the induction of propofol anesthesia, and facilitated recovery; the inhibition of NAc GABAergic neurons exerted opposite effects. Furthermore, optogenetic activation of NAc GABAergic neurons promoted emergence whereas the result of optogenetic inhibition was the opposite. Our results demonstrate that NAc GABAergic neurons modulate propofol anesthesia induction and emergence.

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.