Delta opioid peptide [d-Ala2, d-Leu5] enkephalin confers neuroprotection by activating delta opioid receptor-AMPK-autophagy axis against global ischemia.
Δ 阿片肽 [d-Ala2，d-Leu5] 脑啡肽通过激活 δ 阿片受体-AMPK-自噬轴对抗全脑缺血赋予神经保护作用。
- 作者列表："Lai Z","Gu L","Yu L","Chen H","Yu Z","Zhang C","Xu X","Zhang M","Zhang M","Ma M","Zhao Z","Zhang J
Background:Ischemic stroke poses a severe risk to human health worldwide, and currently, clinical therapies for the disease are limited. Delta opioid receptor (DOR)-mediated neuroprotective effects against ischemia have attracted increasing attention in recent years. Our previous studies revealed that DOR activation by [d-Ala2, d-Leu5] enkephalin (DADLE), a selective DOR agonist, can promote hippocampal neuronal survival on day 3 after ischemia. However, the specific molecular and cellular mechanisms underlying the DOR-induced improvements in ischemic neuronal survival remain unclear. Results:We first detected the cytoprotective effects of DADLE in an oxygen-glucose deprivation/reperfusion (OGD/R) model and observed increased viability of OGD/R SH-SY5Y neuronal cells. We also evaluated changes in the DOR level following ischemia/reperfusion (I/R) injury and DADLE treatment and found that DADLE increased DOR levels after ischemia in vivo and vitro. The effects of DOR activation on postischemic autophagy were then investigated, and the results of the animal experiment showed that DOR activation by DADLE enhanced autophagy after ischemia, as indicated by elevated LC3 II/I levels and reduced P62 levels. Furthermore, the DOR-mediated protective effects on ischemic CA1 neurons were abolished by the autophagy inhibitor 3-methyladenine (3-MA). Moreover, the results of the cell experiments revealed that DOR activation not only augmented autophagy after OGD/R injury but also alleviated autophagic flux dysfunction. The molecular pathway underlying DOR-mediated autophagy under ischemic conditions was subsequently studied, and the in vivo and vitro data showed that DOR activation elevated autophagy postischemia by triggering the AMPK/mTOR/ULK1 signaling pathway, while the addition of the AMPK inhibitor compound C eliminated the protective effects of DOR against I/R injury. Conclusion:DADLE-evoked DOR activation enhanced neuronal autophagy through activating the AMPK/mTOR/ULK1 signaling pathway to improve neuronal survival and exert neuroprotective effects against ischemia.
背景: 缺血性卒中在世界范围内对人类健康构成严重威胁，目前临床治疗方法有限。Δ 阿片受体 (DOR) 介导的抗缺血神经保护作用近年来日益受到关注。我们以前的研究揭示了选择性 DOR 激动剂 [d-Ala2，d-Leu5] 脑啡肽 (DADLE) 激活 DOR 可以促进缺血后第 3 天海马神经元的存活。然而，DOR 诱导的缺血性神经元存活改善的具体分子和细胞机制仍不清楚。 结果: 我们首先在氧糖剥夺/再灌注 (OGD/R) 模型中检测到 DADLE 的细胞保护作用，并观察到 OGD/R SH-SY5Y 神经元细胞的活力增加。我们还评估了缺血/再灌注 (I/R) 损伤和 DADLE 治疗后 DOR 水平的变化，发现 DADLE 在体内和体外缺血后增加了 DOR 水平。随后考察了 DOR 激活对缺血后自噬的影响，动物实验结果表明，DADLE 激活 DOR 增强了缺血后自噬,如 LC3 II/I 水平升高和 P62 水平降低所示。此外，自噬抑制剂 3-甲基腺嘌呤 (3-MA) 消除了 DOR 介导的对缺血 CA1 神经元的保护作用。此外，细胞实验结果表明，DOR 激活不仅增强了 OGD/R 损伤后的自噬，而且减轻了自噬通量功能障碍。随后研究了缺血条件下 DOR 介导的自噬的分子通路，体内和体外数据显示 DOR 激活通过触发 AMPK/mTOR/ULK1 信号通路升高自噬缺血后,而 AMPK 抑制剂化合物 C 的加入消除了 DOR 对 I/R 损伤的保护作用。 结论: DADLE 诱发的 DOR 激活通过激活 AMPK/mTOR/ULK1 信号通路增强神经元自噬，改善神经元存活，发挥抗缺血的神经保护作用。
METHODS::In recent years, transcranial electrical stimulation (tES) has been used to improve cognitive and perceptual abilities and to boost learning. In the visual domain, transcranial random noise stimulation (tRNS), a type of tES in which electric current is randomly alternating in between two electrodes at high frequency, has shown potential in inducing long lasting perceptual improvements when coupled with tasks such as contrast detection. However, its cortical mechanisms and online effects have not been fully understood yet, and it is still unclear whether these long-term improvements are due to early-stage perceptual enhancements of contrast sensitivity or later stage mechanisms such as learning consolidation. Here we tested tRNS effects on multiple spatial frequencies and orientation, showing that tRNS enhances detection of a low contrast Gabor, but only for oblique orientation and high spatial frequency (12 cycles per degree of visual angle). No improvement was observed for low contrast and vertical stimuli. These results indicate that tRNS can enhance contrast sensitivity already after one training session, however this early onset is dependent on characteristics of the stimulus such as spatial frequency and orientation. In particular, the shallow depth of tRNS is likely to affect superficial layers of the visual cortex where neurons have higher preferred spatial frequencies than cells in further layers, while the lack of effect on vertical stimuli might reflect the optimization of the visual system to see cardinally oriented low contrast stimuli, leaving little room for short-term improvement. Taken together, these results suggest that online tRNS effects on visual perception are the result of a complex interaction between stimulus intensity and cortical anatomy, consistent with previous literature on brain stimulation.
METHODS:OBJECTIVE:There is growing interest in treating diseases by electrical stimulation and block of peripheral autonomic nerves, but a paucity of studies on excitation and block of small diameter autonomic axons. We conducted in vivo quantification of the strength-duration properties, activity-dependent slowing (ADS), and responses to kilohertz frequency (KHF) signals for the rat vagus nerve (VN). APPROACH:We conducted acute in vivo experiments in urethane-anesthetised rats. We placed two cuff electrodes on the left cervical VN and one cuff electrode on the anterior subdiaphragmatic VN. The rostral cervical cuff was used to deliver pulses to quantify recruitment and ADS. The caudal cervical cuff was used to deliver KHF signals. The subdiaphragmatic cuff was used to record compound action potentials (CAPs). MAIN RESULTS:We quantified the input-output recruitment and strength-duration curves. Fits to the data using standard strength-duration equations were qualitatively similar, but the resulting chronaxie and rheobase estimates varied substantially. We measured larger thresholds for the slowest fibres (0.5 to 1 m/s), especially at shorter pulse widths. Using a novel cross-correlation CAP-based analysis, we measured ADS of ~2.3% after 3 min of 2 Hz stimulation, which is comparable to ADS reported for sympathetic efferents in somatic nerves, but much smaller than ADS in cutaneous nociceptors. We found greater ADS with higher stimulation frequency and non-monotonic changes in CV in select cases. We found monotonically increasing block thresholds across frequencies from 10 to 80 kHz for both fast and slow fibres. Further, following 25 s of KHF signal, neural conduction could require tens of seconds to recover. SIGNIFICANCE:The quantification of mammalian autonomic nerve responses to conventional and KHF signals provides essential information for development of peripheral nerve stimulation therapies and for understanding their mechanisms of action.
METHODS:BACKGROUND:Early accounts of forced thought were reported at the onset of a focal seizure, and characterized as vague, repetitive, and involuntary intellectual auras distinct from perceptual or psychic hallucinations or illusions. Here, we examine the neural underpinnings involved in conceptual thought by presenting a series of 3 patients with epilepsy reporting intrusive thoughts during electrical stimulation of the left lateral prefrontal cortex (PFC) during invasive surgical evaluation. We illustrate the widespread networks involved through two independent brain imaging modalities: resting state functional magnetic resonance imaging (fMRI) (rs-fMRI) and task-based meta-analytic connectivity modeling (MACM). METHODS:We report the clinical and stimulation characteristics of three patients with left hemispheric language dominance who demonstrate forced thought with functional mapping. To examine the brain networks underlying this phenomenon, we used the regions of interest (ROI) centered at the active electrode pairs. We modeled functional networks using two approaches: (1) rs-fMRI functional connectivity analysis, representing 81 healthy controls and (2) meta-analytic connectivity modeling (MACM), representing 8260 healthy subjects. We also determined the overlapping regions between these three subjects' rs-fMRI and MACM networks through a conjunction analysis. RESULTS:We identified that left PFC was associated with a large-scale functional network including frontal, temporal, and parietal regions, a network that has been associated with multiple cognitive functions including semantics, speech, attention, working memory, and explicit memory. CONCLUSIONS:We illustrate the neural networks involved in conceptual thought through a unique patient population and argue that PFC supports this function through activation of a widespread network.