Neuroscience最新文献

Fentanyl, a potent analgesic and addictive substance, significantly impacts sleep-wakefulness (S-W). Acutely, it promotes wake, whereas chronic abuse leads to severe sleep disruptions, including insomnia, which contributes to opioid use disorders (OUD), a chronic brain disease characterized by compulsive opioid use and harmful consequences. Although the critical association between sleep disruptions and fentanyl addiction is acknowledged, the precise mechanisms through which fentanyl influences sleep remain elusive. Recent studies highlight the role of the dopaminergic system of the nucleus accumbens (NAc) in S-W regulation, but its specific involvement in mediating fentanyl’s effects on S-W remains unexplored. We hypothesized that dopamine D2 receptors mediate fentanyl-induced effects on S-W. To test this hypothesis, male C57BL/6J mice, instrumented with sleep recording electrodes and bilateral guide cannulas above the accumbal core region (NAcC), were utilized in this study. At dark onset, animals were bilaterally administered sulpiride (D2 receptors antagonist; 250 ng/side) in the NAcC followed by an intraperitoneal injection of fentanyl (1.2 mg/Kg). S-W was examined for the next 12 h. We found that systemic administration of fentanyl significantly increased wakefulness during the first 6 h of the dark which was followed by a significant increase in NREM and REM sleep during the second 6 h of the dark period. D2-receptor blockade significantly reduced this effect as evidenced by a significant reduction in fentanyl-induced wakefulness during first 6 h of dark period and sleep rebound during the second 6 h. Our findings suggest that D2 receptors in the NAcC plays a vital role in mediating the fentanyl-induced changes in S-W.

N-methyl-D-aspartate receptors (NMDARs) play a crucial role in mediating Amyloid-β (Aβ) synaptotoxicity. Our previous studies have demonstrated an opposite (neuroprotection and neurotoxicity) effect of activating astrocytic and neuronal NMDARs with higher dose (10 μM) of NMDA, an agonist of NMDARs. By contrast, activating neuronal or astrocyitc NMDARs with lower dose (1 μM) of NMDA both exerts neuroprotective effect in Aβ-induced neurotoxicity. However, the underlying mechanism of activating astrocytic NMDARs with lower dose of NMDA to protect against Aβ neurotoxicity remains unclear. Based on our previous related work, in this study, using a co-cultured cell model of primary hippocampal neurons and astrocytes, we further investigated the possible factors involved in 1 μM of NMDA activating astrocytic NMDARs to oppose Aβ-induced synaptotoxicity. Our results showed that activation of astrocytic NMDARs by 1 μM NMDA rescued Aβ-induced reduction of brain-derived neurotrophic factor (BDNF), and inhibited Aβ-induced increase of GFAP, complement 3 (C3) and activation of NF-κB. Furthermore, blockade of astrocytic GluN2A with TCN201 abrogated the ability of 1 μM NMDA to counteract the effects of Aβ decreasing BDNF, and increasing GFAP, C3 and activation of NF-κB. These findings suggest that activation of astrocytic NMDARs protect against Aβ-induced synaptotoxicity probably through elevating BDNF and suppressing GFAP and C3. Our present research provides valuable insights for elucidating the underlying mechanism of astrocytic NMDARs activation resisting the toxic effects of Aβ.

In daily life, individuals pay attention to emotional facial expressions and dynamically choose how to shift their attention, i.e. either overtly (with eye-movements) or covertly (without eye-movements). However, research on attention to emotional faces has mostly been conducted in controlled laboratory settings, in which people were instructed where to look. The current preregistered study co-registered EEG and eye-tracking to investigate differences in emotion-driven attention between instructed and uninstructed natural attention shifts in 48 adults. While a central stimulus was presented to the participant, a face appeared in the periphery, showing either a happy, neutral or an angry expression. In three counterbalanced blocks participants were instructed to either move their eyes overtly to the peripheral face, keep fixating the center and therefore covertly shift their attention, or freely look wherever they would like to look. We found that emotional content had stronger effects on the amplitude of the Early Posterior Negativity when participants shifted attention naturally, and that natural shifts of attention differed from instructed shifts in both saccade behavior and neural mechanisms. In summary, our results emphasize the importance of investigating modulation of attention using paradigms that allow participants to allocate their attention naturally.

Objective

The aim of this study was to assess the potential causal relationship between neuroticism and 12 neuroticism items with intracranial aneurysms (IAs) and aneurysmal subarachnoid hemorrhage (aSAH) using a two-sample Mendelian randomization (MR) approach.

Methods

Study data were obtained from the Genome-Wide Association Study (GWAS) pooled dataset, and we extracted summary statistics for neuroticism, 12 neuroticism items, and IAs, which were categorized into ruptured and unruptured aneurysms (IA), aSAH, and unruptured IAs (uIA). Single nucleotide polymorphisms (SNPs) were used as instrumental variables (IVs) to explore the causal relationship between exposure and outcome using five Mendelian randomization methods, with Inverse variance weighted (IVW) as the primary study method. Horizontal multiple validity tests, sensitivity analyses, and inverse MR ensured the stability of the results.

Results

The two-sample MR showed a genetically predictive association between neuroticism and IA [odds ratio (OR) = 1.16; 95 % confidence interval (95 % CI): 1.04–1.30; p = 0.009], aSAH (OR = 1.17; 95 % CI: 1.03–1.33; p = 0.013) and uIA (OR = 1.30; 95 % CI: 1.07–1.59; p = 0.009) were all genetically predictive of association. Ivw showed a positive association between 5 neuroticism items and IA risk, 5 neuroticism items and aSAH risk as well as no genetically predictive association between neuroticism items and uIA. Sensitivity analysis and inverse MR confirmed the robustness of the results.

Conclusion

Our Mendelian randomization analysis demonstrated genetic causality between neuroticism and neuroticism items with intracranial aneurysms, aneurysmal subarachnoid hemorrhage, and unruptured intracranial aneurysms, and further studies are needed to confirm these results and explore potential mechanisms of action.

Parkinson’s disease (PD) is the second-most prevalent neurodegenerative disease worldwide, which worsens with advancing age. It is a common movement disorder and is often associated with several vascular diseases with decreased stroke frequency. Circulating platelets substantially regulate vascular complications, including stroke, and share striking similarities with PD neurons. Although structural alterations in platelets are well-documented in PD, their functional parameters remain unclear. This study aimed to investigate the functional abnormalities in platelets associated with PD by evaluating key functional aspects such as adhesion, activation, secretion, aggregation, and clot retraction. To achieve this, we treated human blood platelets with 6-hydroxydopamine or 6-OHDA, that selectively destroys dopaminergic neurons, thereby creating an in vitro experimental model that closely resembles the pathogenic environment in PD, and examine its impact on platelet functions. In our study, platelet adhesion was assessed and further evaluated by a microplate reader, activation and secretion by a flow cytometer, aggregation by aggregometer, and clot retraction by Sonoclot. Phase-contrast and confocal microscopic studies further verified the results from the above experiments. Our findings showed that 6-OHDA treatment significantly inhibited thrombin (a platelet agonist)-induced functions, including adhesion, activation, aggregation, secretion, and clot retraction in human-washed platelets. In summary, this research provides pioneering evidence that 6-OHDA induces abnormal platelet functions, shedding light on the previously unexplored processes by which 6-OHDA affects platelet activity.

Ketamine is a widely used clinical drug that has several functional and clinical applications, including its use as an anaesthetic, analgesic, anti-depressive, anti-suicidal agent, among others. Among its diverse behavioral effects, it influences short-term memory and induces psychedelic effects. At the neural level across different brain areas, it modulates neural firing rates, neural tuning, brain oscillations, and modularity, while promoting hypersynchrony and random connectivity between neurons. In our recent studies we demonstrated that topical application of ketamine on the visual cortex alters neural tuning and promotes vigorous connectivity between neurons by decreasing their firing variability. Here, we begin with a brief review of the literature, followed by results from our lab, where we synthesize a dendritic model of neural tuning and network changes following ketamine application. This model has potential implications for focused modulation of cortical networks in clinical settings. Finally, we identify current gaps in research and suggest directions for future studies, particularly emphasizing the need for more animal experiments to establish a platform for effective translation and synergistic therapies combining ketamine with other protocols such as training and adaptation. In summary, investigating ketamine’s broader systemic effects, not only provides deeper insight into cognitive functions and consciousness but also paves the way to advance therapies for neuropsychiatric disorders.

Introduction

Alpha-synuclein (αSyn) is believed to play a central role in the pathogenesis of Parkinson’s disease (PD). Cerebrospinal fluid (CSF) total αSyn were significantly lower in PD patients, whereas the aggregates were higher, and this phenomenon was further exacerbated with longer disease duration. However, whether CSF αSyn can be the cause and/or a consequence in PD is not fully elucidated.

Method

We administered 2 ng or 200 ng αSyn preformed fibrils (PFFs) by intracerebroventricular injection for consecutive 7 days in C57BL/6 mice. The olfactory function was assessed by the olfactory discrimination test and buried food-seeking test. The locomotor function was assessed by the rotarod test, pole test, open field test and CatWalk gait analysis. Phosphorylated αSyn at serine 129 was detected by the immunohistochemistry staining. Iron levels was determined by Perl’s-diaminobenzidine iron staining and synchrotron-based X-ray fluorescence.

Results

The mice did not exhibit any diffuse synucleinopathy in the brain for up to 30 weeks, although αSyn PFFs induced aggregation in SH-SY5Y cells and in the substantia nigra and striatum of mice with stereotactic injection. No impairment of motor behaviors or olfactory functions were observed, although there was a temporary motor enhancement at 1 week. We then demonstrated iron levels were comparable in certain brain regions, suggesting there was no iron deposition/redistribution occurred.

Conclusion

The intraventricular injection of αSyn PFFs does not induce synucleinopathy or behavioral symptoms. These findings have implications that CSF αSyn aggregates may not necessarily contribute to the onset or progression in PD.