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Learning causal relationships relies on understanding how often one event precedes another. To investigate how dopamine neuron activity and neurotransmitter release change when a retrospective relationship is degraded for a specific pair of events, we used outcome-selective Pavlovian contingency degradation in rats. Conditioned responding was attenuated for the cue-reward contingency that was degraded, as was dopamine neuron activity in the midbrain and dopamine release in the ventral striatum in response to the cue and subsequent reward. Contingency degradation also abolished the trial-by-trial history dependence of the dopamine responses at the time of trial outcome. This profile of changes in cue- and reward-evoked responding is not easily explained by a standard reinforcement learning model. An alternative model based on learning causal relationships was better able to capture dopamine responses during contingency degradation, as well as conditioned behavior following optogenetic manipulations of dopamine during noncontingent rewards. Our results suggest that mesostriatal dopamine encodes the contingencies between meaningful events during learning.

Sodium-based batteries have attracted significant attention due to their abundant resources and low cost. Sodium-metal batteries exhibit higher energy density. However, the performance of sodium metal anodes is constrained by the inevitable corrosion of organic electrolytes and uncontrolled growth of Na dendrites. Here, a NaF solid electrolyte interphase (SEI) is fabricated on the surface of sodium metal using a facile and straightforward gas–solid reaction between evaporated organic acid salt and sodium metal, to alleviate the reactivity of the sodium metal surface and prevent corrosion induced by organic electrolytes. DFT calculation verifies that the NaF artificial SEI reduces the de-solvation energy of Na+ and has a strong binding force with FEC to rapidly provide sources of Na+ and accelerate the reactions of the formation of the NaF-rich SEI layer. As a result, the side reactions from EC and DEC are limited, and the surficial Na2CO3 is dramatically decreased. It is verified that the synergistic effect of the NaF artificial SEI and FEC significantly improved the cycle life of the Na metal anode. By employing an electrolyte with FEC, symmetrical cells utilizing NaF@Na anodes demonstrate a remarkable cycling duration of 1500 h at a current density of 0.5 mA cm−2 and a capacity limit of 0.5 mA h cm−2. Furthermore, full cells incorporating NVP cathodes and NaF@Na anodes exhibit stable cycling performance for up to 4000 cycles at a rate of 20C. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Currently, the conclusions of studies on subthalamic nucleus (STN) deep brain stimulation (DBS) for improving Parkinson's disease (PD) with depression are inconsistent, and the reasons for improvement or deterioration remain unclear.The aim was to investigate the prognosis of PD with depression after bilateral STN‐DBS and the factors related to the improvement in depression. The local and network effects of DBS on depression in PD (DPD) were further explored based on the volume of tissue activation (VTA). The study analyzed 80 primary PD patients who had undergone bilateral STN‐DBS, comprising 47 patients with improved depression and 33 patients without improvement. Two groups of clinical profiles and stimulation parameters were compared, and the network models for improving depression were constructed.The improvement in depression was closely associated with improvement in anxiety (odd rate [OR] = 1.067, P = 0.006) and the standardized space left y‐coordinate (OR = 0.253, P = 0.005). The VTA overlapping with the left motor STN subregion is most significantly associated with improvement in depression (RSpearman = 0.53, P < 0.001; RPearson = 0.43, P < 0.001). The y‐coordinates in the improvement group were closer to the optimal stimulation site for improving motor symptoms. Finally, both the structural and functional network models indicate a positive correlation between depression improvement and the connectivity of the sensorimotor cortex.The amelioration of DPD is primarily attributed to the stimulation of bilateral motor STN, particularly on the left. However, this stimulatory effect manifests as an indirect influence. [ABSTRACT FROM AUTHOR]

Addiction is thought to be a maladaptive form of learning and memory caused by drug-evoked aberrant synaptic plasticity. We previously showed that alcohol facilitates synaptic plasticity in the dorsomedial striatum (DMS), a brain region that drives goal-directed behaviors. The majority of DMS cells are medium spiny neurons (MSNs) that express dopamine D1 receptors (D1Rs) or D2 receptors (D2Rs), which drive "Go" or "No-Go" behaviors, respectively. Here, we report that alcohol induces cell type-specific synaptic and structural plasticity in the DMS. Using mice that express a fluorescence marker to visualize D1R or D2R MSNs, we show that repeated cycles of systemic administration of alcohol or alcohol consumption induces a long-lasting increase in AMPAR activity specifically in DMS D1R but not in D2R MSNs. Importantly, we report that alcohol consumption increases the complexity of dendritic branching and the density of mature mushroom-shaped spines selectively in DMS D1R MSNs. Finally, we found that blockade of D1R but not D2R activity in the DMS attenuates alcohol consumption. Together, these data suggest that alcohol intake produces profound functional and structural plasticity events in a subpopulation of neurons in the DMS that control reinforcement-related learning.Significance statementAlcohol addiction is considered maladaptive learning and memory processes. Here we unraveled a long-lasting cellular mechanism that may contribute to the memory of alcohol-seeking behaviors. Specifically, we found that alcohol consumption produces a long-lasting enhancement of channel activity and persistent alterations of neuronal morphology in a part of the brain (DMS) that controls alcohol-drinking behaviors. Furthermore, we show that these alterations occur only in a subpopulation of neurons that positively control reward and reinforcement of drugs of abuse. Finally, we report that blocking the activity of this neuronal population reduces alcohol intake. As such synaptic and structural changes are the cellular hallmarks of learning and memory, and these neuroadaptations may drive the development of pathological heavy alcohol consumption.

Background: In advanced Parkinson's disease (PD), axial symptoms are common and can be debilitating. Although deep brain stimulation (DBS) significantly improves motor symptoms, conventional high-frequency stimulation (HFS) has limited effectiveness in improving axial symptoms. In this study, we investigated the effects on multiple axial symptoms after DBS surgery with three different frequency programming paradigms comprising HFS, low-frequency stimulation (LFS), and variable-frequency stimulation (VFS). Methods: This study involved PD patients who had significant preoperative axial symptoms and underwent bilateral subthalamic nucleus (STN) DBS. Axial symptoms, motor symptoms, medications, and quality of life were evaluated preoperatively (baseline). One month after surgery, HFS was applied. At 6 months post-surgery, HFS assessments were performed, and HFS was switched to LFS. A further month later, we conducted LFS assessments and switched LFS to VFS. At 8 months after surgery, VFS assessments were performed. Results: Of the 21 PD patients initially enrolled, 16 patients were ultimately included in this study. Regarding HFS, all axial symptoms except for the Berg Balance Scale (p < 0.0001) did not improve compared with the baseline (all p > 0.05). As for LFS and VFS, all axial symptoms improved significantly compared with both the baseline and HFS (all p < 0.05). Moreover, motor symptoms and medications were significantly better than the baseline (all p < 0.05) after using LFS and VFS. Additionally, the quality of life of the PD patients after receiving LFS and VFS was significantly better than at the baseline and with HFS (all p < 0.0001). Conclusion: Our findings indicate that HFS is ineffective at improving the majority of axial symptoms in advanced PD. However, both the LFS and VFS programming paradigms exhibit significant improvements in various axial symptoms. [ABSTRACT FROM AUTHOR]

Diabetic foot ulcers (DFUs) are one of the most common and challenging complications of diabetes, yet our understanding of their pathogenesis remains limited. We collected gene expression data of DFU patients from public databases. Bioinformatics tools were applied for systematic analysis, including the identification of differentially expressed genes (DEGs), weighted gene co‐expression network analysis (WGCNA) and enrichment analysis. We further used single‐cell RNA sequencing to identify the distribution of different cell populations in DFU. Finally, key results were validated using reverse transcription‐quantitative polymerase chain reaction (RT‐qPCR) and flow cytometry. We identified 217 DEGs between ulcerated and healthy skin, and 37 DEGs between healing ulcers and ulcers. WGCNA revealed that the cyan module had the highest positive correlation with healthy skin and negative correlation with ulcers. The black module had the highest negative correlation with healthy skin and positive correlation with ulcers. Enrichment analysis showed that the genes in the cyan module were mainly associated with complement and coagulation cascades, while the genes in the black module were mainly associated with the IL‐17 signalling pathway. In addition, CD8 T cells were significantly lower in ulcers than in healthy and healing ulcers. By comparing marker genes of CD8 T cells, we identified key genes in the cyan and black modules and validated their expression using RT‐qPCR. The proportion of CD8 T cells was increased in healing ulcers. Flow cytometry detected increased levels of CD8 T, B and natural killer cells in healing ulcers. CD8 T cells and related key genes play an important role in the healing process of DFU. The results of this study provide a new perspective for understanding the pathogenesis and treatment of DFU. [ABSTRACT FROM AUTHOR]

Exposure to addictive substances impairs flexible decision making. Cognitive flexibility is mediated by striatal cholinergic interneurons (CINs). However, how chronic alcohol drinking alters cognitive flexibility through CINs remains unclear. Here, we report that chronic alcohol consumption and withdrawal impaired reversal of instrumental learning. Chronic alcohol consumption and withdrawal also caused a long-lasting (21 days) reduction of excitatory thalamic inputs onto CINs and reduced pause responses of CINs in the dorsomedial striatum (DMS). CINs are known to inhibit glutamatergic transmission in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) but facilitate this transmission in D2-MSNs, which may contribute to flexible behavior. We discovered that chronic alcohol drinking impaired CIN-mediated inhibition in D1-MSNs and facilitation in D2-MSNs. Importantly, in vivo optogenetic induction of long-term potentiation of thalamostriatal transmission in DMS CINs rescued alcohol-induced reversal learning deficits. These results demonstrate that chronic alcohol drinking reduces thalamic excitation of DMS CINs, compromising their regulation of glutamatergic transmission in MSNs, which may contribute to alcohol-induced impairment of cognitive flexibility. These findings provide a neural mechanism underlying inflexible drinking in alcohol use disorder., Introduction Alcohol use disorder is a chronic brain disorder characterized by an inability to stop drinking despite the resultant adverse consequences (1, 2). This inability is associated with impaired flexibility [...]