Aims: Delayed neurocognitive recovery (dNCR) is a common postoperative complication in geriatric surgical patients for which there is no efficacious therapy. Cholecystokinin octapeptide (CCK‐8), an immunomodulatory peptide, regulates memory and learning. Here, we explored the effects and mechanism of action of CCK‐8 on dNCR.Methods: We applied laparotomy to establish a model of dNCR in aged mice. Morris water maze and fear conditioning tests were used to evaluate cognition. Immunofluorescence was used to detect the density of CCK‐8, A1 reactive astrocytes, glutamatergic synapses, and activation of microglia in the hippocampus. Quantitative PCR was performed to determine mRNA levels of synapse‐associated factors. A1 reactive astrocytes, activated microglia, and glutamatergic synapse‐associated protein levels in the hippocampus were assessed by western blotting.Results: Administration of CCK‐8 suppressed the activation of microglia, the induction of A1 reactive astrocytes, and the expression of tumor necrosis factor alpha, complement 1q, and interleukin 1 alpha in the hippocampus. Furthermore, it promoted glutamatergic synaptogenesis and neurocognitive recovery in aged dNCR model mice.Conclusion: Our findings indicated that CCK‐8 alleviated cognitive impairment and promoted glutamatergic synaptogenesis by inhibiting the induction of A1 reactive astrocytes and the activation of microglia. CCK‐8 is, therefore, a potential therapeutic target for dNCR.

Postoperative neurocognitive impairment is an urgent problem with global aging accelerating. The prevention and treatment of postoperative neurocognitive impairment have been widely investigated but lack effective strategies. Low-intensity pulsed ultrasound (LIPUS), a non-invasive tool, has shown an effect on neuroprotection, but whether it could attenuate the postoperative neurocognitive impairment and the underlying mechanisms remains unknown. An experimental setup for LIPUS stimulation of the hippocampus was well established. A laparotomy model in aged mice was applied, and a Morris water maze was used to assess cognitive function. RT-qPCR and western blotting were used to detect levels of Piezo1, synapse-associated proteins in the hippocampus, respectively. Immunofluorescent staining was also used to determine the neural activation and Piezo1 expression. The results showed that LIPUS increased synapse-related proteins of the hippocampus and attenuated cognitive impairment in aged mice. Meanwhile, LIPUS suppressed the overexpression of Piezo1 in the hippocampus. We further found that LIPUS promoted Calpain1 activity and increased extracellular regulated protein kinases (Erk) phosphorylation. Our results suggested that LIPUS could improve cognitive impairment and increase hippocampal synaptogenesis through the Piezo1-mediated Calpain1/ Erk pathway. LIPUS could be used as an effective physical intervention to alleviate postoperative cognitive dysfunction in the aged population.

Background: The selection of the maintenance of general anesthesia may affect the development of postoperative delirium (POD), notably for Parkinson’s disease (PD) patients, due to their lower cognitive reserve. The present study was designed to compare the potential impact of propofol vs. sevoflurane based general anesthesia maintenance methods on the development of POD in PD patients following deep brain stimulation (DBS) surgery. Methods: A total of 125 PD patients who were scheduled to undergo DBS surgery were randomly divided into the propofol (n = 63) and the sevoflurane groups (n = 62). The patients in the two groups randomly received propofol- or sevoflurane-based general anesthesia. The Confusion Assessment Method (CAM) was employed by an investigator who was blinded to the anesthesia regimen and was administered twice per day from postoperative day 1 until discharge. Results: The incidence of POD was 22.22% (14/63) with propofol anesthesia and 20.97% (13/62) with sevoflurane anesthesia (p = 0.865). In addition, no difference was noted in the duration and severity of delirium between the propofol and sevoflurane groups. Conclusions: In the present study, propofol- and sevoflurane-based general anesthesia exhibited comparable results with regard to the POD incidence in PD patients undergoing deep brain stimulation surgery.

Sepsis-associated encephalopathy (SAE) is characterised by cognitive impairment and is a common complication in patients with sepsis. Microglia are involved in various cognitive impairment-related diseases through phagocytic synapses. Cholecystokinin (CCK), an abundant neuropeptide in the brain, is closely related to cognitive function. However, the role of CCK in SAE and the relationship between CCK and microglial phagocytosis of synapses are unknown. Lipopolysaccharide (LPS) was used to construct SAE models in 3-month-old male mice and BV2 microglial cells. To investigate the effects of CCK on cognitive impairment in SAE model mice, we used exogenous CCK injection into the dorsal hippocampal CA1 region or the chemogenetic activation of CCK-positive neurons to promote endogenous CCK release. Morris water maze and fear conditioning test were used to assess cognitive function in mice. RNA sequencing was performed to explore the potential signalling pathways involved in CCK-induced neuroprotection. Western blot and immunofluorescence were used to assess the effects of CCK on microglial phagocytosis of synapses, neurotoxic astrocytes, and excitatory synapses. Whole-cell recording was used to determine excitatory synaptic transmission. LPS successfully established in vivo and in vitro models of SAE. Both exogenous CCK injection and activation of CCK-positive neurons in hippocampal CA1 region attenuated cognitive impairment in SAE mice. Mechanistically, CCK significantly alleviated excitatory synaptic plasticity damage via inhibiting complement 1q (C1q)-mediated microglial phagocytosis of synapses and neurotoxic astrocyte polarisation. Moreover, in vitro SAE model of BV2 cells demonstrated that CCK exerts neuroprotective effects through microglial CCK2-type receptor. CCK may alleviate cognitive impairment by inhibiting microglia C1q-mediated phagocytosis of excitatory synapses, suggesting that both CCK drugs and specific activation of CCK-positive neurons are potential treatments for SAE.

Delayed neurocognitive recovery (dNCR) is a common complication that occurs post-surgery, especially in elderly individuals. The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex plays an essential role in various membrane fusion events, such as synaptic vesicle exocytosis and autophagosome–lysosome fusion. Although SNARE complex dysfunction has been observed in several neurodegenerative disorders, the causal link between SNARE-mediated membrane fusion and dNCR remains unclear. We previously demonstrated that surgical stimuli caused cognitive impairment in aged rats by inducing α-synuclein accumulation, inhibiting autophagy, and disrupting neurotransmitter release in hippocampal synaptosomes. Here, we evaluated the effects of propofol anesthesia plus surgery on learning and memory and investigated levels of SNARE proteins and chaperones in hippocampal synaptosomes. Aged rats that received propofol anesthesia and surgery exhibited learning and memory impairments in a Morris water maze test and decreased levels of synaptosome-associated protein 25, synaptobrevin/vesicle-associated membrane protein 2, and syntaxin 1. Levels of SNARE chaperones, including mammalian uncoordinated-18, complexins 1 and 2, cysteine string protein-α, and N-ethylmaleimide-sensitive factor, were all significantly decreased following anesthesia with surgical stress. However, the synaptic vesicle marker synaptophysin was unaffected. The autophagy-enhancer rapamycin attenuated structural and functional disturbances of the SNARE complex and ameliorated disrupted neurotransmitter release. Our results indicate that perturbations of SNARE proteins in hippocampal synaptosomes may underlie the occurrence of dNCR. Moreover, the protective effect of rapamycin may partially occur through recovery of SNARE structural and functional abnormalities. Our findings provide insight into the molecular mechanisms underlying dNCR.

Alcohol addiction is regarded as a series of dynamic changes to neural circuitries. A comparison of the global network during different stages of alcohol addiction could provide an efficient way to understand the neurobiological basis of addiction. Two animal models (P-rats screened from an alcohol preference family, and NP-rats screened from an alcohol non-preference family) were trained for alcohol preference with a two-bottle free choice method for 4 weeks. To examine the changes in the neural response to alcohol during the development of alcohol preference and acute stimulation, different trials were studied with resting-state fMRI methods during different periods of alcohol preference. The correlation coefficients of 28 regions in the whole brain were calculated, and the results were compared for alcohol preference related to the genetic background/training association. The variety of coherence patterns was highly related to the state and development of alcohol preference. We observed significant special brain connectivity changes during alcohol preference in P-rats. The comparison between the P- and NP-rats highlighted the role of genetic background in alcohol preference. The results of this study support the alterations of the neural network connection during the formation of alcohol preference and confirm that alcohol preference is highly related to the genetic background. This study could provide an effective approach for understanding the neurobiological basis of alcohol addiction.