Netrin-1 signaling pathway mechanisms in neurodegenerative diseases

Netrin-1 and its receptors play crucial roles in inducing axonal growth and neuronal migration during neuronal development.Their profound impacts then extend into adulthood to encompass the maintenance of neuronal survival and synaptic function.Increasing amounts of evidence highlight several key points:(1)Diminished Netrin-1 levels exacerbate pathological progression in animal models of Alzheimer’s disease and Parkinson’s disease,and potentially,similar alterations occur in humans.(2)Genetic mutations of Netrin-1 receptors increase an individuals’susceptibility to neurodegenerative disorders.(3)Therapeutic approaches targeting Netrin-1 and its receptors offer the benefits of enhancing memory and motor function.(4)Netrin-1 and its receptors show genetic and epigenetic alterations in a variety of cancers.These findings provide compelling evidence that Netrin-1 and its receptors are crucial targets in neurodegenerative diseases.Through a comprehensive review of Netrin-1 signaling pathways,our objective is to uncover potential therapeutic avenues for neurodegenerative disorders.

CD34^(+ )progenitor cells as diagnostic and therapeutic targets in Alzheimer's disease

Alzheimer’s disease(AD)is the main neurodegenerative disease leading to dementia and cognitive impairment in the elderly.Considering AD to be an epidemic,an increase from the current 50 million to more than 150 million patients is expected by the year 2050.

A novel model of drug cue-induced behaviours in rhesus macaque subjected to chronic ketamine exposure

To the Editor,Non-human primate(NHP)models are advantageous for mimicking human addiction with high behavioural validity.1 However,current NHP drug addiction models(eg,self-administration)often require a comprehensive behavioural training paradigm,relatively expensive apparatus and invasive surgical procedures.

Enriched environment elevates expression of growth associated protein-43 in the substantia nigra of SAMP8 mice

An enriched environment protects dopaminergic neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine（MPTP）-induced neuronal injury, but the underlying mechanism for this is not clear. Growth associated protein-43（GAP-43） is closely associated with neurite outgrowth and axon regeneration during neural development. We speculate that an enriched environment can reduce damage to dopaminergic neurons by affecting the expression of GAP-43. This study is designed to test this hypothesis. Three-month-old female senescence-accelerated mouse prone 8（SAMP8） mice were housed for 3 months in an enriched environment or a standard environment. These mice were then subcutaneously injected in the abdomen with 14 mg/kg MPTP four times at 2-hour intervals. Morris water maze testing demonstrated that learning and memory abilities were better in the enriched environment group than in the standard environment group. Reverse-transcription polymerase chain reaction, immunohistochemistry and western blot assays showed that m RNA and protein levels of GAP-43 in the substantia nigra were higher after MPTP application in the enriched environment group compared with the standard environment group. These findings indicate that an enriched environment can increase GAP-43 expression in SAMP8 mice. The upregulation of GAP-43 may be a mechanism by which an enriched environment protects against MPTP-induced neuronal damage.

Endothelial progenitor cells as a therapeutic option in intracerebral hemorrhage

Intracerebral hemorrhage （ICH） is the most severe cerebrovascular disease, which represents a leading cause of death and disability in developed countries. However, therapeutic options are limited, so is mandatory to investigate repairing processes after stroke in order to develop new therapeutic strategies able to promote brain repair processes. Therapeutic angiogenesis and vasculogenesis hold promise to improve outcome of ICH patients. In this regard, circulating endothelial progenitor cells （EPCs） have recently been suggested to be a marker of vascular risk and endothelial function. Moreover, EPC levels have been associated with good neurological and functional outcome as well as reduced residual hematoma volume in ICH patients. Finally, experimental and clinical studies indicate that EPC might mediate endothelial cell regeneration and neovascularization. Therefore, EPC-based therapy could be an excellent therapeutic option in ICH. In this mini-review, we discuss the present status of knowledge about the possible therapeutic role of EPCs in ICH, molecular mechanisms, and the future perspectives and strategies for their use in clinical practice.

An enriched environment improves cognitive performance in mice from the senescence-accelerated prone mouse 8 strain Role of upregulated neurotrophic factor expression in the hippocampus

In this study,we examined 3-month-old female mice from the senescence-accelerated prone mouse 8 strain and age-matched homologous normal aging female mice from the senescence accelerated-resistant mouse 1 strain.Mice from each strain were housed in an enriched environment（including a platform,running wheels,tunnel,and some toys）or a standard environment for 3 months.The mice housed in the enriched environment exhibited shorter escape latencies and a greater percentage of time in the target quadrant in the Morris water maze test,and they exhibited reduced errors and longer latencies in step-down avoidance experiments compared with mice housed in the standard environment.Correspondently,brain-derived neurotrophic factor mRNA and protein ex- pression in the hippocampus was significantly higher in mice housed in the enriched environment compared with those housed in the standard environment,and the level of hippocampal brain-derived neurotrophic factor protein was positively correlated with the learning and memory abilities of mice from the senescence-accelerated prone mouse 8 strain.These results suggest that an enriched environment improved cognitive performance in mice form the senescence-accelerated prone mouse 8 strain by increasing brain-derived neurotrophic factor expression in the hippocampus.

精神分裂症患者的情感体验和表达（英文）

背景:精神分裂症存在情感体验和表达障碍。然而,大多数以往研究往往只局限于情感体验(尤其是快感缺乏)或只针对表达。较少有同时研究精神分裂症患者情感体验和表达。目的 :本研究旨在考察精神分裂症患者的快感体验和情感表达。尤其是,特别关注精神分裂症患者的情感障碍(包括快感体验和表达)和阴性症状之间的关系。方法 :150例患者完成了愉快情绪体验量表(Temporal Experience of Pleasure Scale)和情感表达量表(Emotional Expressivity Scale)的评估。结果 :精神分裂症患者表现出快感缺乏,但情感表达的能力完整。以阴性症状为主的精神分裂症患者在期待性愉快体验,尤其是抽象性期待愉快体验上的缺损更为明显结论:研究结果表明,精神分裂症患者存在出快感缺乏,但他们表达情感的能力似乎完好无损。快感缺乏尤以阴性症状为主的精神分裂症患者更为突出。

Poor CD4 count is a predictor of untreated depression in human immunodeficiency virus-positive African-Americans

AIM: To determine if efforts to improve antiretroviral therapy(ART) adherence minimizes the negative impact of depression on human immunodeficiency virus(HIV) outcomes. METHODS: A cross-sectional study of a clinic-based cohort of 158 HIV seropositive(HIV+) African Americans screened for major depressive disorder(MDD) in 2012. CD4 T lymphocyte(CD4+) counts were obtained from these individuals. Self-report on adherence to ART was determined from questionnaire administered during clinic visits. The primary outcome measure was conditional odds of having a poorer CD4+ count(< 350 cells/mm3). Association between CD4+ count and antidepressant-treated or untreated MDD subjects was examined controlling for self-reported adherence and other potential confounders. RESULTS: Out of 147 individuals with available CD4+ T lymphocyte data, 31% had CD4+ count < 350 cells/mm^3 and 28% reported poor ART adherence. As expected the group with > 350 cells/mm^3 CD4+ T lymphocyte endorsed significantly greater ART adherence compared to the group with < 350 cells/mm3 CD4+ T lymphocyte count(P < 0.004). Prevalence of MDD was 39.5% and 66% of individuals with MDD took antidepressants. Poor CD4+ T lymphocyte count was associated with poor ART adherence and MDD. Adjusting for ART adherence, age, sex and education, which were potential confounders, the association between MDD and poor CD4+ T lymphocyte remained significant only in the untreated MDD group.CONCLUSION: Therefore, CD4+ count could be a clinical marker of untreated depression in HIV+. Also, mental health care may be relevant to primary care of HIV+ patients.

Acute exercise and cognitive function:Emerging research issues

The effect of acute exercise, a single bout of exercise, on cognitive performance has attracted much attention. The first narrative review of this literature was conducted by Tomporowski and Ellis.1 In their summary, the authors concluded that acute exercise facilitates cognitive performance; however, they emphasized that the studies at that time were atheoretical and suffered from methodological limitations, making the reliability of the conclusions uncertain. In a meta-analytic review conducted approximately a decade later, Etnier et al.2 concluded that acute exercise results in a positive significant effect on cognitive performance that was of small magnitude （effect size, ES = 0.16）.

New strategies for ischemic stroke: internal photobiomodulation therapy

Epidemiology and physiopathology of ischemic stroke:Every year, around 15 million of people suffer a stroke event all around the world. Among those, around 6.7 million will die, and most of the survivors will suffer some grade of disability.

Exergames： neuroplastic hypothesis about cognitive improvement and biological effects on physical function of institutionalized older persons

Exergames can be considered a dual task because the games are performed by a man-videogame interface, requiring cognitive and motor functions simultaneously. Although the literature has shown improvements of cognitive and physical functions due to exergames, the intrinsic mechanisms involved in these functional changes have still not been elucidated. The aims of the present study were（1） to demonstrate the known biological mechanisms of physical exercise regarding muscle adaptation and establish a relationship with exergames; and（2） to present a neurobiological hypothesis about the neuroplastic effects of exergames on the cognitive function of institutionalized older persons. These hypotheses are discussed.

Transplanting embryonic stem cells onto damaged human corneal endothelium

AIM To investigate whether human embryonic stem cells(hESCs) could be made to attach, grow and differentiate on a human Descemet's membrane(DM).METHODS Spontaneously differentiated hESCs were transferred onto a human corneal button with the endothelial layer removed using ocular sticks. The cells were cultured on a DM for up to 15 d. The genetically engineered hESC line expressed green fluorescent protein, which facilitated identification during the culture experiments, tissue preparation, and analysis. To detect any differentiation into human corneal endothelial-like cells, we analysed the transplanted cells by immunohistochemistry using specific antibodies.RESULTS We found transplanted cells form a single layer of cells with a hexagonal shape in the periphery of the DM. The majority of the cells were negative for octamer-binding transcription factor 4 but positive for paired box 6 protein, sodium potassium adenosine triphosphatase(NaKATPase), and Zona Occludens protein 1. In four of the 18 trials, the transplanted cells were found to express CK3, which indicates that the stem cells differentiated into corneal epithelial cells in these cases. CONCLUSION It is possible to get cells originating from hESCs to become established on a human DM, where they grow and differentiate into corneal endothelial-like cells in vitro.

A new visual acuity test on touchpad for vision screening in children

AIM:To validate a visual acuity(VA)test application on touchpad in the screening of pediatric population by comparing VA results obtained with conventional tests.METHODS:A cohort of 101 patients,44 girls and 57 boys with a median of 6.5 years old(3-10 years of age),presenting for eye examinations in Ophthalmology Department(Strasbourg,France)between November 1st,2018,and February 1st,2019 were enrolled.Monocular and binocular VA testing was performed on the subject using both a standard test and the touchpad application(Monoyer,"E"or,Pigassou depending of children s capacities).Patients were excluded if they were physically or mentally unable to use the touchpad.The duration of each tests,the painfulness,the comprehension,the attention of children during the test and test’s preferences were also evaluated.RESULTS:There was a good linear correlation and intra-class correlation coefficient[ICC=0.50(0.34.0.64)for binocular acuity,0.74(0.64.0.82)for right eyes and 0.525(0.37.0.66)for left eye].The standard errors of measurement were very low(0.08.0.05.0.08 for binocular VA,right eyes VA and left eyes VA,respectively).There was no difference between two tests for right eye(P=0.126);left eye(P=0.098)and binocular acuity(P=0.085).Non inferiority was proved for all binocular[-0.06(-0.09.-0.03)],right eye[-0.04(-0.07.-0.01)]and left eye[-0.06(-0.09,-0.02)]VA.The sensitivity and specificity,which correspond to the ability for our app to detect amblyopia,were 92%and 80%respectively.CONCLUSION:Our touchpad application represents an efficient and valid test of VA in children with a high specificity to detect visual impairment.

Spatial Memory Deficits and Their Correlations with Clusters of Shrunken Neuronal Soma in the Cortices and Limbic System Following a “Mild’’ Mechanical Impact to the Dorsal Skull in Female Rats

Background: Previous results showed that quantitative changes in behavioural accuracies by rats that sustained a “mild” closed head injury were moderately correlated with the total areas (numbers) of anomalous neuronal soma within regions below the impact. Method: Water maze behavioural measures within one day or two months after a single impact of mechanical force over the right dorsal skull, with or without stunning and with or without subsequent pregnancy, were measured and compared to proportions of anomalous neurons under the impact site. Results: The consequences of the impact accommodated about 20% of the variance in the rats’ scores for less proficient spatial learning and memory. There were significantly more anomalous cells within right hemisphere below the impact site that were correlated with poorer initial maze learning. Maternal experience reduced the numbers of anomalous cells in the right limbic area only. Conclusion: These results suggest weak mechanical impacts produce changes in histomorphology within some neurons that are still evident two months later and that the presence of these anomalous clusters, corresponding to less than 1% of the cross-sectional area and below the resolution of contemporary MRI in human cases, are strongly correlated with specific behavioural impairments.

Intracerebroventricular transplanted bone marrow stem cells survive and migrate into the brain of rats with Parkinson's disease

In this study, 6-hydroxydopamine was stereotaxically injected into the right substantia nigra compact and ventral tegmental area of rats to establish Parkinson＇s disease models. The rats then received a transplantation of bone marrow stromal cells that were previously isolated, cultured and labeled with 5-bromo-2＇-deoxyuridine in vitro. Transplantation of the bone marrow stromal cells significantly decreased apomorphine-induced rotation time and the escape latency in the Morris water maze test as compared with rats with untreated Parkinson＇s disease. Immunohistochemical staining showed that, 5-bromo-2＇-deoxyuridine-immunoreactive cells were present in the lateral ventricular wall and the choroid plexus 1 day after transplantation. These immunoreactive cells migrated to the surrounding areas of the lateral cerebral ventricle along the corpus callosum. The results indicated that bone marrow stromal cells could migrate to tissues surround the cerebral ventricle via the cerebrospinal fluid circulation and fuse with cells in the brain, thus altering the phenotype of cells or forming neuron-like cells or astrocytes capable of expressing neuron-specific proteins. Taken together, the present findings indicate that bone marrow stromal cells transplanted intracerebroventricularly could survive, migrate and significantly improve the rotational behavior and cognitive function of rats with experimentally induced Parkinson＇s disease.

Neural activation while perceiving biological motion in dynamic facial expressions and point-light body action animations

BACKGROUND： The interpretation of non-verbal social signals relies heavily on the ability to perceive biological motion. The posterior superior temporal sulcus is an important part of a network involved in biological motion processing. However, the underlying functional organization remains poorly understood. Several studies have suggested topographical representation of motion from different body parts within this region. However, other studies have shown that the posterior superior temporal sulcus responds equally to any body part. OBJECTIVE： Through the use of functional magnetic resonance imaging, the effects of socially relevant biological motion stimuli to activate a specific cortical area within posterior superior temporal sulcus, even if different body parts are involved in motion, will be analyzed. DESIGN, TIME AND SETTING： A functional magnetic resonance imaging, block-design was performed at the Magnetic Resonance Imaging, Surgical Medical Investigation Center, Havana, Cuba between 2004 and 2005. PARTICIPANTS： Thirteen healthy volunteers, from 19 to 55 years of age and compris!ng eight males and five females, were included in the study. METHODS： A conjunction analysis of responses to natural, dynamic, fearful, facial expressions and point-light, body-motion animations. MAIN OUTCOME MEASURES： The corresponding functionally specialized areas, as well as neural areas significant for both types of stimuli, were identified. RESULTS： One region within the posterior superior temporal sulcus of the right hemisphere was equally activated by facial and body complex motion. CONCLUSION： A site of common neural activity existed within the posterior superior temporal sulcus, which was not specific to a biological motion type. In addition, the activity was not related to a topographically organized body-part map, which suggested high-level visual representation of biological motion in this region.

Imagery perspective among young athletes: Differentiation between external and internal visual imagery

Purpose： This study aimed to investigate the construct of external visual imagery （EVI） vs. internal visual imagery （IV/） by comparing the athletes＇ imagery ability with their levels of skill and types of sports. Methods： Seventy-two young athletes in open （n = 45） or closed （n = 27） sports and with different skill levels completed 2 custom-designed tasks. The EVI task involved the subject generating and visualizing the rotated images of different body parts, whereas the IVI task involved the subject visualizing himself or herself performing specific movements. Results： The significant Skill-Level x Sport Type interactions for the EVI task revealed that participants who specialized in open sports and had higher skill-levels had a higher accuracy rate as compared to the other subgroups. For the IVI task, the differences between the groups were less clear： those with higher skill-levels or open sports had a higher accuracy rate than those with lower skill-levels or closed sports. Conclusion： EVI involves the visualization of others and the environment, and would be relevant to higher skill-level athletes who engage in open sports. IVI, in contrast, tends to be more self-oriented and would be relevant for utilization by higher skill-level athletes regardless of sport type.

Small scale adeno-associated virusvector production for preclinical gene delivery based on chloroform precipitation

Gene therapy aims to introduce genetic information into a cell-type of interest to replace,correct,silence,or modify defective genes.Gene therapy in its broadest sense can theoretically prevent,halt,or cure any condition that affects mankind.In addition to that,the introduction and/or manipulation of genes is one of the major research areas in biological sciences,aimed to deepen our knowledge on how biological systems work.Scientific advances have made it possible to induce changes ranging from manipulations of large stretches of the genome to the change of single nucleotides.The gold-standard vehicles to bring this genetic information into the target cells are viral vectors.

Adolescent Exposure of JWH-018 “Spice” Produces Subtle Effects on Learning and Memory Performance in Adulthood

The active components associated with the bio-designer drugs known variously as “Spice” or “K2” have rapidly gained in popularity among recreational users, forcing the United States Drug Enforcement Administration to classify these compounds as Schedule I drugs in the Spring of 2011. However, although there is some information about many of the synthetic cannabinoids used in Spice products, little is known about the consequences of the main constituent, (1-pentyl-3-(1-naphthoyl)indole;JWH-018), on neuropsychological development or behavior. In the present experiment, adolescent rats were given repeated injections of either saline or 100 μg/kg of JWH-018. Once the animals were 75 days of age, they were trained using tasks with spatial components of various levels of difficulty and a spatial learning set task. On early trials with water maze tasks of varying difficulty, the JWH-018 treated rats were impaired relative to controls. However, by the end of each phase of testing, drug and control animals were comparable, although on probe trials the drug-treated animals spent significantly less time in the target quadrant. In addition, the performance of the drug-treated rats was inferior to that of the control animals on a learning set task, suggesting some difficulty in adapting their responses to changing task demands. The results suggest that chronic exposure to this potent cannabinoid CB1 receptor agonist during adolescence is capable of producing a variety of subtle changes affecting spatial learning and memory performance in adulthood, well after the drug exposure period.

Longitudinal Examination of Learning and Memory in Rats Following Adolescent Exposure to 3,4-Methylenedioxymethamphetamine or 5-Methoxy-N,N-Diisopropyltryptamine

A drug of abuse, Foxy or Methoxy Foxy gained popularity among recreational users as an alternative to MDMA (Ecstasy). Considerable research into the consequences of MDMA use is available, yet much remains unknown about the neurobiological consequences of Foxy use. In addition, research into the long-term neuropsychological repercussions associated with these two compounds remains incomplete. The goal of the present research was to explore the effects of MDMA or Foxy on cognitive processes associated with adolescent exposure considered over much of the lifespan. Here we investigated whether the reported effects following adolescent exposure resolved in early adulthood or continued throughout life. The protocol involved repeated doses of either MDMA or Foxy during the period defined as mid-adolescence (postnatal days 34 - 46) in rats, followed by the use of four series of learning and memory tasks repeated at different points in the rodent lifespan. At four time points in adulthood, the animals were trained and tested on a on a series of spatial and non-spatial memory tasks designed to assess the impact and severity of Foxy and MDMA. Oddly, MDMA-treated rats were impaired on a step down passive avoidance task. The performance of the drug-treated rats was markedly inferior to that of the control animals on more demanding water maze tasks, with some results suggesting a lack of flexibility in adapting to changing task demands. MDMA rats were the most impaired. While some persistent cognitive deficits were found, no significant group differences in serotonin or dopamine levels were found in any of the measured regions of the brain changes, cortical or subcortical. These results provide evidence for compromised neurocognition that continues long after drug exposure in the absence of any discernable changes in neurotransmitter levels. Several possible physiological and neurochemical mechanisms associated with these compounds requiring further study are also outlined.