Microglia are involved in regulating histamine-dependent and non-dependent itch transmissions with distinguished signal pathways.

Although itch and pain have many similarities, they are completely different in perceptual experience and behavioral response. In recent years, we have a deep understanding of the neural pathways of itch sensation transmission. However, there are few reports on the role of non-neuronal cells in itch. Microglia are known to play a key role in chronic neuropathic pain and acute inflammatory pain. It is still unknown whether microglia are also involved in regulating the transmission of itch sensation. In the present study, we used several kinds of transgenic mice to specifically deplete CX3CR1+ microglia and peripheral macrophages together (whole depletion), or selectively deplete microglia alone (central depletion). We observed that the acute itch responses to histamine, compound 48/80 and chloroquine were all significantly reduced in mice with either whole or central depletion. Spinal c-fos mRNA assay and further studies revealed that histamine and compound 48/80, but not chloroquine elicited primary itch signal transmission from DRG to spinal Npr1- and somatostatin-positive neurons relied on microglial CX3CL1-CX3CR1 pathway. Our results suggested that microglia were involved in multiple types of acute chemical itch transmission, while the underlying mechanisms for histamine-dependent and non-dependent itch transmission were different that the former required the CX3CL1-CX3CR1 signal pathway.

Transcranial Direct Current Stimulation Improves Some Neurophysiological Parameters but not Clinical Outcomes after Severe Traumatic Brain Injury.

BACKGROUND: Disorders of consciousness (DOC) are one of the clinical hallmarks of severe traumatic brain injury (TBI). DOC impair patient life quality and increase the burden on their families and society. METHODS: A double-blind, randomized, controlled clinical trial was conducted to determine the efficacy of routine rehabilitation combined with transcranial direct current stimulation (tDCS) in DOC patients after TBI. A total of 78 DOC patients were randomly divided after TBI into two groups: participants in the treatment group received routine rehabilitation combined with an active tDCS protocol. In contrast, participants in the control group received routine rehabilitation combined with a sham tDCS protocol. An anode was placed over the left dorsolateral prefrontal cortex and a cathode was placed over the right supraorbital area. The stimulation intensity was 2 mA. Both tDCS protocols lasted for eight consecutive weeks (20 minutes per day, six days per week). Patients were followed up for a further eight weeks. Glasgow Outcome Scale (GOS), Glasgow Coma Scale (GCS), brainstem auditory evoked potentials, somatosensory evoked potentials and electroencephalogram were measured at weeks zero, two, four, six, eight and sixteen from the start of tDCS. RESULTS: Neither the GOS nor GCS scores differed significantly between the two groups, while brainstem auditory evoked potentials, somatosensory evoked potentials and electroencephalogram scores did. CONCLUSIONS: This study found that tDCS improves some neurophysiological parameters but not clinical outcomes of DOC patients after TBI. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1800014808 (The version is V.1.0). Registered on February 7, 2018. http://www.chictr.org.cn/showproj.aspx?proj=25003.

The Evaluation Indexes Suitable for Nonhuman Primates can be Extracted from Clinical Consciousness Disorder Assessment Scales: A Hypothesis.

BACKGROUND: Currently, case studies or clinical trials in different patient populations remain the main resource underlying the understanding of disorder of consciousness (DoC). This provides a low efficacy for the derivation of data and the implementation of associated controlled experimental designs. Preclinical models provide precise controls, reduced variability, rich data output and limited ethical complexity. Nonhuman primates are suitable model animals for disorders of consciousness due to their brain structure being very similar to that of humans. Behavioral tests remain the primary standard for assessing the consciousness status of humans. However, there is currently no behavioral assessment scale available for evaluation of the state of consciousness disorder in nonhuman primates. This presents a significant challenge for the establishment of different models of consciousness disorder. Therefore, there is considerable motivation to focus on the development of a proper tool for assessment of the state of consciousness associated with nonhuman primate models that are based on clinically common consciousness assessment scales. METHODS: It is assumed that the Delphi and level analysis methods based on clinical consciousness disorder assessment scales may provide an effective way to select and include assessment indexes for levels of consciousness in nonhuman primates. RESULTS: 8 first-level indicators with 41 second-level indexes were selected preliminary as a pool of evaluation entries of state of consciousness of nonhuman primates. CONCLUSIONS: It may be practicable to extract appropriate indicators for non-human primates from the clinical consciousness disorder assessment scales. Besides, a combination of Delphi method, behavioral analysis, electroencephalography, neuroimaging (such as positron emission tomography-computed tomography) and functional magnetic resonance imaging is necessary to test the reliability and validity of the novel scale reported here.

Alleviation of Anxiety/Depressive-Like Behaviors and Improvement of Cognitive Functions by Lactobacillus plantarum WLPL04 in Chronically Stressed Mice.

BACKGROUND: Intestinal microorganisms play an important role in regulating the neurodevelopment and the brain functions of the host through the gut-brain axis. Lactobacillus, one of the most representative intestinal probiotics, produces important effects on human physiological functions. Our previous studies reveal that the Lactobacillus plantarum WLPL04 has a series of beneficial actions, such as antiadhesion of pathogens, protection from the harmful effect of sodium dodecyl sulfate, and anti-inflammatory stress on Caco2 cells. However, its effects on brain functions remain unknown. The present study aims to evaluate the potential effect of L. plantarum WLPL04 on anxiety/depressive-like behaviors in chronically restrained mice. METHODS: Newly weaned mice were exposed to chronic restraint stress for four weeks and raised daily with or without L. plantarum WLPL04 water supplement. Animals were behaviorally assessed for anxiety/depression and cognitive functions. The 16S rRNA sequencing was performed to analyze the intestinal microbiota structure. The levels of the medial prefrontal cortical (mPFC) brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) and serum 5-hydroxytryptamine (5-HT) were examined using Western blot and enzyme-linked immunosorbent assay. RESULTS: The chronic stress-induced anxiety/depressive-like behaviors and cognitive deficits were significantly alleviated by the L. plantarum WLPL04 treatment. The 16S rRNA sequencing analysis showed that the chronic stress reduced the diversity and the richness of intestinal microbiota, which were rescued by the L. plantarum WLPL04 treatment. The levels of BDNF and TrkB in the mPFC and the concentration of 5-HT in the serum remained unchanged in chronically restrained mice treated with the L. plantarum WLPL04. CONCLUSIONS: The L. plantarum WLPL04 can rescue anxiety/depressive-like behaviors and cognitive dysfunctions, reverse the abnormal change in intestinal microbiota, and alleviate the reduced levels of 5-HT, BDNF, and TrkB induced by chronic stress in mice, providing an experimental basis for the therapeutic application of L. plantarum on anxiety/depression.

Neonatal Maternal Separation Impairs Prefrontal Cortical Myelination and Cognitive Functions in Rats Through Activation of Wnt Signaling.

Adverse early-life experience such as depriving the relationship between parents and children induces permanent phenotypic changes, and impairs the cognitive functions associated with the prefrontal cortex (PFC). However, the underlying mechanism remains unclear. In this work, we used rat neonatal maternal separation (NMS) model to illuminate whether and how NMS in early life affects cognitive functions, and what the underlying cellular and molecular mechanism is. We showed that rat pups separated from their dam 3 h daily during the first 3 postnatal weeks alters medial prefrontal cortex (mPFC) myelination and impairs mPFC-dependent behaviors. Myelination appears necessary for mPFC-dependent behaviors, as blockade of oligodendrocytes (OLs) differentiation or lysolecithin-induced demyelination, impairs mPFC functions. We further demonstrate that histone deacetylases 1/2 (HDAC1/2) are drastically reduced in NMS rats. Inhibition of HDAC1/2 promotes Wnt activation, which negatively regulates OLs development. Conversely, selective inhibition of Wnt signaling by XAV939 partly rescue myelination arrestment and behavior deficiency caused by NMS. These findings indicate that NMS impairs mPFC cognitive functions, at least in part, through modulation of oligodendrogenesis and myelination. Understanding the mechanism of NMS on mPFC-dependent behaviors is critical for developing pharmacological and psychological interventions for child neglect and abuse.

Neurons in dorsal premotor cortex represent the switching of intended hand path in a delayed reaching task.

Dorsal premotor cortex (PMd) is considered to play a crucial role in motor preparation, yet how the variation of neuronal activity affects the generation of different circumstances dependent movements remains unclear. Here we trained two monkeys to perform a delayed reaching task instructed by two sets of cues, one for indicating the target locations and another for indicating a conditionally presented virtual obstacle in the reaching path, which required the monkey to make a bypassing instead of straight reaching. We recorded the activity of PMd neurons and investigated how they responded to the switching of intended hand path induced by obstacle bypassing. Comparing the neuronal activity between hand bypassing trials and straight reaching trials, we found 30% of the total 687 set-related neurons showed different overall discharging level, and another 24% showed different onset time during the delay period. We also found 16% of the neurons were modulated only by target location and 14% were modulated by both target location and path switching. Our results demonstrate PMd neurons not only represent the planning of reaching to different target locations, as many previous studies have shown, but also represent the switching of intended reaching path induced by hand bypassing, suggesting how PMd neurons coordinate for such circumstances dependent motor planning.

Neuronal representation of stand and squat in the primary motor cortex of monkeys.

BACKGROUND: Determining neuronal topographical information in the cerebral cortex is of fundamental importance for developing neuroprosthetics. Significant progress has been achieved in decoding hand voluntary movement with cortical neuronal activity in nonhuman primates. However, there are few successful reports in scientific literature for decoding lower limb voluntary movement with the cortical neuronal firing. We once reported an experimental system, which consists of a specially designed chair, a visually guided stand and squat task training paradigm and an acute neuron recording setup. With this system, we can record high quality cortical neuron activity to investigate the correlation between these neuronal signals and stand/squat movement. METHODS/RESULTS: In this research, we train two monkeys to perform the visually guided stand and squat task, and record neuronal activity in the vast areas targeted to M1 hind-limb region, at a distance of 1 mm. We find that 76.9% of recorded neurons (1230 out of 1598 neurons) showing task-firing modulation, including 294 (18.4%) during the pre-response window; 310 (19.4%) for standing up; 104 (6.5%) for the holding stand phase; and 205 (12.8%) during the sitting down. The distributions of different type neurons have a high degree of overlap. They are mainly ranged from +7.0 to 13 mm in the Posterior-Anterior dimension, and from +0.5 to 4.0 mm in Dosal-lateral dimension, very close to the midline, and just anterior of the central sulcus. CONCLUSIONS/SIGNIFICANCE: The present study examines the neuronal activity related to lower limb voluntary movements in M1 and find topographical information of various neurons tuned to different stages of the stand and squat task. This work may contribute to understanding the fundamental principles of neural control of lower limb movements. Especially, the topographical information suggests us where to implant the chronic microelectrode arrays to harvest the most quantity and highest quality neurons related to lower limb movements, which may accelerate to develop cortically controlled lower limb neuroprosthetics for spinal cord injury subjects.

A Soft Robot Tactile Finger Using Oxidation-Reduction Graphene-Polyurethane Conductive Sponge.

Currently, intelligent robotics is supplanting traditional industrial applications. It extends to business, service and care industries, and other fields. Stable robot grasping is a necessary prerequisite for all kinds of complex application scenarios. Herein, we propose a method for preparing an elastic porous material with adjustable conductivity, hardness, and elastic modulus. Based on this, we design a soft robot tactile fingertip that is gentle, highly sensitive, and has an adjustable range. It has excellent sensitivity (~1.089 kpa-1), fast response time (~35 ms), and measures minimum pressures up to 0.02 N and stability over 500 cycles. The baseline capacitance of a sensor of the same size can be increased by a factor of 5-6, and graphene adheres better to polyurethane sponge and has good shock absorption. In addition, we demonstrated the application of the tactile fingertip to a two-finger manipulator to achieve stable grasping. In this paper, we demonstrate the great potential of the soft robot tactile finger in the field of adaptive grasping for intelligent robots.

Chronic but not acute nicotine treatment ameliorates acute inflammation-induced working memory impairment by increasing CRTC1 and HCN2 in adult male mice.

BACKGROUND: Systemic inflammation in which lipopolysaccharide (LPS) is released into circulation can cause cognitive dysfunction and we have previously shown that LPS impaired working memory (WM) which refers to the ability to guide incoming behavior by retrieving recently acquired information. However, the mechanism is not very clear, and currently, there is no approved strategy to improve inflammation-induced WM deficit. Notably, epidemiological studies have demonstrated a lower occurrence rate of inflammatory-related diseases in smoking patients, suggesting that inflammation-induced WM impairment may be improved by nicotine treatment. Here, our object is to investigate the effect and potential mechanisms of acute and chronic nicotine treatment on LPS-produced WM deficiency. METHODS: Delayed alternation T-maze task (DAT) was applied for evaluating WM which includes both the short-term information storage and the ability to correct errors in adult male mice. Immunofluorescence staining and immunoblotting were used for assessing the levels and distribution of CREB-regulated transcription coactivator 1 (CRTC1) and hyperpolarization-activated cation channels 2 (HCN2) in the medial prefrontal cortex (mPFC) and hippocampus. Quantitative PCR and ELISA were employed for analyzing the mRNA and protein levels of TNF-α and IL-1ß. RESULTS: Our results revealed that administration of LPS (i.p.) at a dose of 0.5 mg/kg significantly produced WM impairment in the DAT task accompanied by an increase in IL-1ß and TNF-α expression in the mPFC. Moreover, intra-mPFC infusion of IL-1Ra, an IL-1 antagonist, markedly alleviated LPS-induced WM deficiency. More important, chronic (2 weeks) but not acute nicotine (0.2 mg/kg, subcutaneous) treatment significantly alleviated LPS-induced WM deficiency by upregulating CRTC1 and HCN2. Of note, intra-mPFC infusion of HCN blocker ZD7288 produced significant WM deficiency. CONCLUSIONS: In summary, in this study, we show that chronic nicotine treatment ameliorates acute inflammation-induced working memory deficiency by increasing CRTC1 and HCN2 in adult male mice.

Fasting-induced RNF152 resensitizes gallbladder cancer cells to gemcitabine by inhibiting mTORC1-mediated glycolysis.

Abnormal mTORC1 activation by the lysosomal Ragulator complex has been implicated in cancer and glycolytic metabolism associated with drug resistance. Fasting upregulates RNF152 and mediates the metabolic status of cells. We report that RNF152 regulates mTORC1 signaling by targeting a Ragulator subunit, p18, and attenuates gemcitabine resistance in gallbladder cancer (GBC). We detected levels of RNF152 and p18 in tissues and undertook mechanistic studies using activators, inhibitors, and lentivirus transfections. RNF152 levels were significantly lower in GBC than in adjacent non-cancer tissues. Fasting impairs glycolysis, induces gemcitabine sensitivity, and upregulates RNF152 expression. RNF152 overexpression increases the sensitivity of GBC cells to gemcitabine, whereas silencing RNF152 has the opposite effect. Fasting-induced RNF152 ubiquitinates p18, resulting in proteasomal degradation. RNF152 deficiency increases the lysosomal localization of p18 and increases mTORC1 activity, to promote glycolysis and decrease gemcitabine sensitivity. RNF152 suppresses mTORC1 activity to inhibit glycolysis and enhance gemcitabine sensitivity in GBC.

CRTC1 is a potential target to delay aging-induced cognitive deficit by protecting the integrity of the blood-brain barrier via inhibiting inflammation.

Aging can cause attenuation in the functioning of multiple organs, and blood-brain barrier (BBB) breakdown could promote the occurrence of disorders of the central nervous system during aging. Since inflammation is considered to be an important factor underlying BBB injury during aging, vascular endothelial cell senescence serves as a critical pathological basis for the destruction of BBB integrity. In the current review, we have first introduced the concepts related to aging-induced cognitive deficit and BBB integrity damage. Thereafter, we reviewed the potential relationship between disruption of BBB integrity and cognition deficit and the role of inflammation, vascular endothelial cell senescence, and BBB injury. We have also briefly introduced the function of CREB-regulated transcription co-activator 1 (CRTC1) in cognition and aging-induced CRTC1 changes as well as the critical roles of CRTC1/cyclooxygenase-2 (COX-2) in regulating inflammation, endothelial cell senescence, and BBB injury. Finally, the underlying mechanisms have been summarized and we propose that CRTC1 could be a promising target to delay aging-induced cognitive deficit by protecting the integrity of BBB through promoting inhibition of inflammation-mediated endothelial cell senescence.

Laminar Distribution of Cannabinoid Receptor 1 in the Prefrontal Cortex of Nonhuman Primates.

Cannabis is an annual herb of the genus Cannabis, with a history of medical use going back thousands of years. However, its abuse causes many side-effects, including confusion of consciousness, alienation, and mental disorders such as schizophrenia and depression. Research conducted on rodents suggests that there are two types of cannabinoid receptors-cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R). CB1R is found mostly in the central nervous system, particularly in the prefrontal cortex (PFC), and alterations in its expression in the PFC have been strongly linked to mental disorders. Within the layers of the PFC, Brodmann area 46 is associated with the processing of complex cognitive information. However, it remains unclear whether CB1R is expressed in the PFC 46 area of non-human primate. In this work, we applied western blotting along with immunofluorescent histochemical staining to investigate the distribution pattern of CB1R in the PFC of nonhuman primate, Our findings reveal that CB1R is highly expressed in the monkey PFC, especially in area 46. Furthermore, CB1R exhibits a layered distribution pattern within area 46 of the PFC, with the inner granular layer displaying the highest expression levels. Additionally, CB1R+PV+ cells are widely distributed in lay II-VI of area 46, with layer IV showing notable prevalence. In conclusion, CB1R is distributed in the PV interneurons in area 46 of the prefrontal cortex, particularly in layer IV, suggesting that cannabis may modulate PFC activities via regulating interneuron in the PFC. And cannabis-induced side effects may be caused by abnormal expression of CB1R.

Behavioral assessment scale of consciousness for nonhuman primates: A Delphi study.

OBJECTIVE: Nonhuman primates (NHPs) are suitable for being model animals in the study of consciousness and loss of consciousness (LoC) with a similar brain structure and function to humans. However, there is no effective consciousness assessment scale for them. This study aimed to develop a behavioral assessment scale of consciousness for NHPs. METHODS: We constructed an initial indicator framework based on the clinical consciousness disorder assessment scales and the physiological characteristics, consciousness, and arousal behavior of NHPs. A two-round online Delphi method was conducted by a multidisciplinary expert panel to construct a behavioral assessment scale of consciousness for NHPs. The indicators and descriptions were revised according to the experts' feedback and then sent out for repeated consultations along with a summary of the results of the previous round of consultations. The accepted competencies of indicators were established with mean scores in two scoring criteria (importance and feasibility) ≥4.0, agreement rate with a rating of importance or essential ≥70.0%, and a coefficient of variation ≤0.25, as well as discussions of the research group. RESULTS: Consensus was achieved after the second round of consultations, which was completed by 28 experts who specialized in rehabilitation, neuroscience, psychology, neurosurgery, and neurology. A new behavioral assessment scale of consciousness for NHPs, including 37 items organized hierarchically within seven dimensions including visual function, auditory function, motor function, orofacial movements, arousal, brainstem reflexes, and respiration, was developed in this study. CONCLUSIONS: This study has successfully developed a behavioral assessment scale for measuring the conscious state of NHPs or NHP models with LoC. This tool is expected to facilitate future research into the underlying mechanisms of consciousness by providing a detailed and comprehensive means of measurement.

Prefrontal Dopaminergic Regulation of Cue-Guided Risky Decision-Making Performance in Rats.

Risky decision-making is the decision made by individuals when they know the probability of each outcome. In order to survive in unpredictable environments, it is necessary for individuals to assess the probability of events occurring to an make appropriate decisions. There are few studies on the neural basis of risky decision-making behavior guided by external cues, which is related to the relative paucity of animal behavioral paradigms. Previous studies have shown that the prefrontal cortex (PFC) plays a key role in risk-based decision-making. The PFC receives projections from the dopamine (DA) system from the ventral tegmental area of the midbrain. The mesocorticolimbic DA system regulates the judgments of reward and value in decision-making. However, the specific receptor mechanism for prefrontal DA regulation of cue-guided risky decision-making behavior remains unclear. Here we established a cue-guided risky decision-making behavioral paradigm (RDM task) to detect the behavior of rats making decisions between a small certain reward and a large uncertain reward in a self-paced manner. The D1 receptor antagonist SCH-23390 (5 mM) or agonist SKF-82958 (5 mM), and the D2 receptor antagonist thioridazine hydrochloride (5 mM) or agonist MLS-1547 (5 mM) was injected into the mPFC, respectively, to investigate how the behavior in the RDM task was changed. The results showed that: (1) rats were able to master the operation of the cue-guided RDM task in a self-paced way; (2) a majority of rats were inclined to choose risk rather than a safe option when the reward expectations were equal; and (3) risk selection was reduced upon inhibition of D1 receptors or stimulation of D2 receptors, but increased upon stimulation of D1 receptors or inhibition of D2 receptors, suggesting that the RDM performance is regulated by D1 and D2 receptors in the mPFC. The present results suggest that DA receptors in the mPFC of rats are involved in regulating cue-guided RDM behavior, with differential involvement of D1 and D2 receptors in the regulation.

Muscimol-induced inactivation of the ventral prefrontal cortex impairs counting performance in rhesus monkeys.

Numbers are one of the three basic concepts of human abstract thinking. When human beings count, they often point to things, one by one, and read numbers in a positive integer column. The prefrontal cortex plays a wide range of roles in executive functions, including active maintenance and achievement of goals, adaptive coding and exertion of general intelligence, and completion of time complexity events. Nonhuman animals do not use number names, such as "one, two, three," or numerals, such as "1, 2, 3" to "count" in the same way as humans do. Our previous study established an animal model of counting in monkeys. Here, we used this model to determine whether the prefrontal cortex participates in counting in monkeys. Two 5-year-old female rhesus monkeys (macaques), weighing 5.0 kg and 5.5 kg, were selected to train in a counting task, counting from 1 to 5. When their counting task performance stabilized, we performed surgery on the prefrontal cortex to implant drug delivery tubes. After allowing the monkeys' physical condition and counting performance to recover, we injected either muscimol or normal saline into their dorsal and ventral prefrontal cortex. Thereafter, we observed their counting task performance and analyzed the error types and reaction time during the counting task. The monkeys' performance in the counting task decreased significantly after muscimol injection into the ventral prefrontal cortex; however, it was not affected after saline injection into the ventral prefrontal cortex, or after muscimol or saline injection into the dorsal prefrontal cortex. The ventral prefrontal cortex of the monkey is necessary for counting performance.

Behavior of Rats in a Self-Paced Risky Decision-Making Task Based on Definite Probability.

Risky decision-making (RDM) is when individuals make choices based on the definite cognition for the probabilities of the options. Risk is embodied in the certainty of reward, and the smaller the probability is, the greater the risk will be. As simulated in human behavior paradigms, RDM scenarios in real life are often guided by external cues that inform the likelihood of receiving certain rewards. There are few studies on the neural basis of RDM behavior guided by external cues, which is related to the relative paucity of the animal behavioral paradigms. Here, we established a cue-guided RDM task to detect the behavior of rats making a decision between a small certain reward and a large uncertain reward in a naturalistic manner. The reward of the risk option could be adjusted to observe the change of choice. Our results showed that: (1) rats were able to master the operation of the cue-guided RDM task; (2) many rats were inclined to choose risk rather than the safe option when the reward expectations were equal; (3) rats were able to adjust the decision strategy in time upon a change in risk, suggesting that they have the ability to perceive risk indicated by the external cues.

Effects of transcranial direct current stimulation on patients with post-stroke fatigue: a study protocol for a double-blind randomized controlled trial.

INTRODUCTION: Post-stroke fatigue (PSF) is an abnormal, persistent, and unexplained physical and psychological tiredness in patients after stroke. It is a common symptom of stroke patients with poor quality of life and bleak prognosis, and the incidence rate is up to 39% to 72%. It has been widely reported that medicine treatments achieved a lot of progress, there still needs to develop more powerful new strategies to more powerful effect. The transcranial direct-current stimulation (tDCS) shows great potential for the treatment of PSF. This study proposes to apply a double-blind randomized controlled clinical trial to explore the effect and safety of tDCS combined with routine rehabilitation for PSF. METHODS AND ANALYSIS: One hundred patients with PSF will be randomly divided into two groups. One of the groups will receive conventional rehabilitation therapy and active tDCS, whereas another group will receive conventional rehabilitation treatment and sham tDCS. Both groups will receive the intervention for 4 weeks, during which time they will undergo either active or sham tDCS 20 min a day, 6 days a week. PRIMARY OUTCOME: Fatigue Severity Scale (FSS) will be measured at baseline every weekend during the intervention period. Secondary results: Fatigue Impact Scale (FIS), Functional Assessment Chronic Illness Therapy (Fatigue) (FACIT-F), and Specialized Quality of Life Scale in Stroke (SS-QOL) will be measured at baseline and at the end of the intervention time of 4 weeks. Throughout the study, adverse events and adverse reactions will be measured during every treatment. The research study "Effects of transcranial direct current stimulation on patients with post-stroke fatigue" has been approved by the Ethics Committee of the First Affiliated Hospital of Nanchang University: Clinical Medicine Ethics Review [2015]043 in Nov 2015. DISCUSSION: This study will provide insight into the efficacy of transcranial direct-current stimulation for post-stroke fatigue. This is a double-blind randomized controlled trial whose aim is to assess the effects of tDCS on PSF. This study can provide more information about the treatment of PSF. This study has a period of follow-up, which allows for greater accuracy. It is a single-center trial, and this may be a limitation. The other limitation of this study is the relatively small number of participants; thus, the influence of chance on experimental results cannot be completely ruled out. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000031120 . Registered on March 22, 2020. This protocol version number is V1.1.

Polygalasaponin F protects hippocampal neurons against glutamate-induced cytotoxicity.

Excess extracellular glutamate leads to excitotoxicity, which induces neuronal death through the overactivation of N-methyl-D-aspartate receptors (NMDARs). Excitotoxicity is thought to be closely related to various acute and chronic neurological disorders, such as stroke and Alzheimer's disease. Polygalasaponin F (PGSF) is a triterpenoid saponin monomer that can be isolated from Polygala japonica, and has been reported to protect cells against apoptosis. To investigate the mechanisms underlying the neuroprotective effects of PGSF against glutamate-induced cytotoxicity, PGSF-pretreated hippocampal neurons were exposed to glutamate for 24 hours. The results demonstrated that PGSF inhibited glutamate-induced hippocampal neuron death in a concentration-dependent manner and reduced glutamate-induced Ca2+ overload in the cultured neurons. In addition, PGSF partially blocked the excess activity of NMDARs, inhibited both the downregulation of NMDAR subunit NR2A expression and the upregulation of NMDAR subunit NR2B expression, and upregulated the expression of phosphorylated cyclic adenosine monophosphate-responsive element-binding protein and brain-derived neurotrophic factor. These findings suggest that PGSF protects cultured hippocampal neurons against glutamate-induced cytotoxicity by regulating NMDARs. The study was approved by the Institutional Animal Care Committee of Nanchang University (approval No. 2017-0006) on December 29, 2017.

Transmembrane protein 108 inhibits the proliferation and myelination of oligodendrocyte lineage cells in the corpus callosum.

BACKGROUND: Abnormal white matter is a common neurobiological change in bipolar disorder, and dysregulation of myelination in oligodendrocytes (OLs) is the cause. Transmembrane protein 108 (Tmem108), as a susceptible gene of bipolar disorder, is expressed higher in OL lineage cells than any other lineage cells in the central nervous system. Moreover, Tmem108 mutant mice exhibit mania-like behaviors, belonging to one of the signs of bipolar disorder. However, it is unknown whether Tmem108 regulates the myelination of the OLs. RESULTS: Tmem108 expression in the corpus callosum decreased with the development, and OL progenitor cell proliferation and OL myelination were enhanced in the mutant mice. Moreover, the mutant mice exhibited mania-like behavior after acute restraint stress and were susceptible to drug-induced epilepsy. CONCLUSIONS: Tmem108 inhibited OL progenitor cell proliferation and mitigated OL maturation in the corpus callosum, which may also provide a new role of Tmem108 involving bipolar disorder pathogenesis.

Rhesus Monkeys Have a Counting Ability and Can Count from One to Six.

Counting ability is one of the many aspects of animal cognition and has enjoyed great interest over the last couple of decades. The impetus for studying counting ability in nonhuman animals has likely come from more than a general interest in animal cognition, as the analysis of animal abilities amplifies our understanding of human cognition. In addition, a model animal with the ability to count could be used to replace human subjects in related studies. Here we designed a behavioral paradigm to train rhesus monkeys to count 1-to-6 visual patterns presented sequentially with long and irregular interpattern intervals on a touch screen. The monkeys were required to make a response to the sixth pattern exclusively, inhibiting response to any patterns appearing at other ordinal positions. All stimulus patterns were of the same size, color, location, and shape to prevent monkeys making the right choice due to non-number physical cues. In the long delay period, the monkey had to enumerate how many patterns had been presented sequentially and had to remember in which ordinal position the current pattern was located. Otherwise, it was impossible for them to know which pattern was the target one. The results show that all three monkeys learned to correctly choose the sixth pattern within 3 months. This study provides convincing behavioral evidence that rhesus monkeys may have the capacity to count.