Chronic Lead Exposure in Adult Mice: Associations with miR-671/CDR1as Regulation, NF-κB Signaling, and Alzheimer's Disease-like Pathology.

Long-term exposure to lead (Pb) can result in chronic damage to the body through accumulation in the central nervous system (CNS) leading to neurodegenerative diseases, such as Alzheimer's disease (AD). This study delves into the intricate role of miR-671/CDR1as regulation in the etiology of AD-like lesions triggered by chronic Pb exposure in adult mice. To emulate the chronic effects of Pb, we established a rodent model spanning 10 months of controlled Pb administration, dividing 52 C57BL/6J mice into groups receiving varying concentrations of Pb (1, 2, or 4 g/L) alongside an unexposed control. Blood Pb levels were monitored using serum samples to ensure accurate dosing and to correlate with observed toxicological outcomes. Utilizing the Morris water maze, a robust behavioral assay for assessing cognitive functions, we documented a dose-dependent decline in learning and memory capabilities among the Pb-exposed mice. Histopathological examination of the hippocampal tissue revealed tell-tale signs of AD-like neurodegeneration, characterized by the accumulation of amyloid plaques and neurofibrillary tangles. At the molecular level, a significant upregulation of AD-associated genes, namely amyloid precursor protein (APP), ß-secretase 1 (BACE1), and tau, was observed in the hippocampal tissue of Pb-exposed mice. This was accompanied by a corresponding surge in the protein levels of APP, BACE1, amyloid-ß (Aß), and phosphorylated tau (p-tau), further implicating Pb in the dysregulation of these key AD markers. The expression of CDR1as, a long non-coding RNA implicated in AD pathogenesis, was found to be suppressed in Pb-exposed mice. This observation suggests a potential mechanistic link between Pb-induced neurotoxicity and the dysregulation of the CDR1as/miR-671 axis, which warrants further investigation. Moreover, our study identified a dose-dependent alteration in the intracellular and extracellular levels of the transcription factor nuclear factor-kappa B (NF-κB). This finding implicates Pb in the modulation of NF-κB signaling, a pathway that plays a pivotal role in neuroinflammation and neurodegeneration. In conclusion, our findings underscored the deleterious effects of Pb exposure on the CNS, leading to the development of AD-like pathology. The observed modulation of NF-κB signaling and miR-671/CDR1as regulation provides a plausible mechanistic framework for understanding the neurotoxic effects of Pb and its potential contribution to AD pathogenesis.

Durability of Effects of Cognitive Remediation on Cognition and Psychosocial Functioning in Schizophrenia: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

OBJECTIVE: Cognitive remediation provides substantial improvements in cognitive performance and real-world functioning for people living with schizophrenia, but the durability of these benefits needs to be reassessed and better defined. The aims of this study were to provide a comprehensive assessment of the durability of the benefits of cognitive remediation for cognition and functioning in people living with schizophrenia and evaluating potential moderators of effects. METHODS: A systematic search was conducted in PubMed, Scopus, and PsycINFO, and reference lists of included articles and Google Scholar were inspected. Eligible studies were randomized clinical trials of cognitive remediation in patients diagnosed with schizophrenia spectrum disorders in which follow-up assessments were included. Screening and data extraction were performed by at least two independent reviewers. Cohen's d was used to measure outcomes. Primary outcomes were changes in cognition and functioning from baseline to conclusion of follow-up. Moderators of the durability of effects were assessed. RESULTS: Of 2,840 identified reports, 281 full texts were assessed and 130 reports on 67 studies with 5,334 participants were included. Cognitive remediation produced statistically significant positive effects that persisted at the end of follow-up in global cognition (d=0.23) and in global functioning (d=0.26). Smaller study samples and single-center studies were associated with better cognitive outcomes; longer treatment and follow-up duration, techniques for transferring cognitive gains to the real world, integration with psychiatric rehabilitation, group format of delivery, and more female participants in the sample were associated with better functional outcomes. CONCLUSIONS: Cognitive remediation provides durable improvements in cognition and functioning in schizophrenia. This finding corroborates the notion that cognitive remediation should be implemented more widely in clinical and rehabilitation practice.

Attention control in autism: Eye-tracking findings from pre-school children in a low- and middle-income country setting.

LAY ABSTRACT: The development of cognitive processes, such as attention control and learning, has been suggested to be altered in children with a diagnosis of autism spectrum disorder. However, nearly all of our understanding of the development of these cognitive processes comes from studies with school-aged or older children in high-income countries, and from research conducted in a controlled laboratory environment, thereby restricting the potential generalisability of results and away from the majority of the world's population. We need to expand our research to investigate abilities beyond these limited settings. We address shortcomings in the literature by (1) studying attention control and learning in an understudied population of children in a low- and middle-income country setting in India, (2) focusing research on a critical younger age group of children and (3) using portable eye-tracking technology that can be taken into communities and healthcare settings to increase the accessibility of research in hard-to-reach populations. Our results provide novel evidence on differences in attention control and learning responses in groups of children with and without a diagnosis of autism spectrum disorder. We show that learning responses in children that we assessed through a portable eye-tracking task, called the 'antisaccade task', may be specific to autism. This suggests that the methods we use may have the potential to identify and assess autism-specific traits across development, and be used in research in low-resource settings.

Effects of exercise-targeted hippocampal PDE-4 methylation on synaptic plasticity and spatial learning/memory impairments in D-galactose-induced aging rats.

Physical exercise reduces the effects of aging and cognitive decline by improving synaptic plasticity and spatial learning. However, the underlying neurobiological mechanisms are unclear. A total of 45 Male SPF Sprague-Dawley rats were acclimatized and then allocated into three groups, 15 in each group: the saline control (DC) group, D-gal-induced aging (DA) group, and D-gal-induced aging + exercise (DE) group. Six weeks of intraperitoneal injections of D-gal at a concentration of 100 mg/kg body weight/d was injected to establish model of aging in the DA and DE groups. Morris water maze test was implemented to evaluate the hippocampus related cognition. SOD activity and MDA was tested to assess the aging in all groups. H&E and Nissl staining was used to observe the histopathological changes of hippocampal neurons in aging rats. Quantitative real-time polymerase chain reaction, western blotting and immunofluorescence staining techniques were used to investigate the expression of synaptic genes and proteins in the hippocampus. Massarray methylation system was employed to measure the PDE-4 gene methylation level in rat hippocampal tissues. Our results demonstrated that exercise intervention improves cognitive function in D-gal-induced aging rats. The methylation of CpG sites in PDE-4 in the hippocampus was significantly increased. The physical exercise significantly increased PDE-4 gene methylation and effectively decreased PDE-4 gene and protein expression. These beneficial behavioral and morphological effects were attributed to PDE-4 methylation, which was activated cAMP/PKA/CREB pathway and improved synaptic plasticity. Exercise induced PDE-4 methylation is key mechanism underpinning the amelioration of learning/memory impairment, suggesting the potential efficacy of physical exercise training in delaying brain aging.

Disclosing an autism diagnosis improves ratings of candidate performance in employment interviews.

LAY ABSTRACT: Employment interviews are challenging for many autistic people, for example, due to difficulties with interpreting questions. Autistic people also have differences in non-verbal communication, such as emotional expression, eye-contact, and gestures, with research showing that these factors negatively affect first impressions. Some studies have shown that perceptions of autistic people are more positive when the person observing them, such as an interviewer, is already aware of their diagnosis. However, previous research has not studied how disclosing one's autism diagnosis affects perceptions of a candidate undergoing a full employment interview. Participants in this study acted as raters, who watched a video of an autistic person undergoing a mock employment interview with a researcher, and then rated their overall impressions of them on factors important to real-world hiring decisions, such as confidence, motivation, and knowledgeability. Prior to watching the interview, raters were either (1) not aware of the interviewee's diagnosis, (2) made aware of their diagnosis, or (3) made aware of their diagnosis and provided with additional information about autism, such as differences in behaviours and communication. The results show that disclosing an autism diagnosis improved ratings compared to not disclosing the diagnosis. Providing additional information about autism alongside the diagnostic label did not improve ratings further. The findings are important for employers and autistic people; employers should consider improving procedures by which autistic people can disclose their diagnosis prior to interview should they wish, and autistic people may wish to consider the potential benefits of disclosing their diagnosis.

Effect of safflower yellow on learning and memory ability of APP/PS1 at different months based on TLR4/NF-KB signaling pathway / 中国药理学通报

Aim To investigate the effect of safflower yellow (SY) on learning and memory ability of APP/ PS1 mice at different disease stages, and to explore the mechanism of SY anti- Alzheimer's disease by using 3-,6- and 9-month-old APP/PS 1 transgenic mice as experimental animal models. Methods Behavioral experiments were conducted to observe the effects of SY on learning and memory of APP/PS1 mice of different months. ELISA was used to detect the effect of SY on the expression of inflammatory factors in cortex of mice of different months. Western blot was used to detect the microglia activation marker protein, and its mechanism of action was further analyzed. Results SY could enhance the learning and memory ability of mice aged 3, 6 and 9 months, reduce the content of IL-6 and increase the content of TGF-β1 in brain tissue, up-regulate the expression levels of arginase-1 (arg-1) and triggering receptor expressed on myeloid cells 2 (tREM2) in brain tissue of mice of different months, and down-regulate the expression levels of inducible nitric oxide synthase (iNOS), Toll-like receptors 4 (tlr4) and nuclear factor-kappa B (nf-KB). Conclusions Compared with 3- and 9-month-old mice, SY is the most effective in improving learning memory in 6-month-old APP/PS1 mice. SY inhibits TLR4/NF-KB pathway activation by inducing TREM2 expression in brain tissue of APP/PS 1 transgenic mice, promotes microglia phenotype shift to anti-inflammatory phenotype, reduces chronic neuroinflammatory response, and improves learning memory in APP/PS1 mice at all months of age.

Electroacupuncture Pretreatment Attenuates Learning Memory Impairment Induced by Repeated Propofol Exposure and Modulates Hippocampal Synaptic Plasticity in Rats.

Background: Recurrent propofol anesthesia in the peak of neurodevelopment may lead to learning-memory decline. This study aimed to examine the efficacy of electroacupuncture pretreatment in ameliorating the aforementioned learning memory deficits and to explore its underlying mechanisms in a rat model of repeated propofol exposure. Methods: 10-day-old Sprague Dawley rats were randomly assigned to five groups: the control, fat emulsion, propofol, electroacupuncture pretreatment and electroacupuncture pretreatment combined with propofol groups. The electroacupuncture pretreatment involved three consecutive daily sessions, while propofol was received intraperitoneally once daily for five days. Following the modeling period, the rats' learning-memory performance was assessed using the New Novel Arm Y-maze, New Object Recognition, and Morris Water Maze. The Nissl staining method was used to observe the development of hippocampal neurons, while Golgi staining was employed to observe hippocampal synaptic development. Results: The electroacupuncture pretreatment significantly attenuated the learning and memory impairment induced by recurring propofol exposure in rats. Additionally, it facilitated the development of hippocampal neurons and synaptic plasticity in the hippocampus. Immunofluorescence and Western Blot analyses were conducted to detect the expression of proteins related to apoptosis, learning memory, and synaptic plasticity. In the propofol group, the pro-apoptotic factors Caspase-3 and Bax was up-regulated, while the anti-apoptotic factor Bcl-2 was down-regulated, as compared to the blank group. Additionally, the phosphorylated cAMP-response element binding protein (pCREB), brain-derived neurotrophic factor (BDNF), synaptophysin, and growth associated protein-43 (GAP-43) was significantly decreased. In contrast, the electroacupuncture pretreatment combined with propofol group exhibited decreased the Caspase-3 and Bax and increased the Bcl-2, as compared to the propofol group, meanwhile, the pCREB, BDNF, Synaptophysin and GAP-43 was increased. Conclusion: Our findings indicate that electroacupuncture pretreatment can alleviate the learning and memory impairment induced by recurring propofol exposure in rats. This is achieved by enhancing hippocampal synaptic plasticity, activating the pCREB/BDNF pathway and inhibiting neuronal apoptosis.

[Effect of electroacupuncture on proliferation and differentiation of endogenous neural stem cells and Jagged1/Notch1 pathway in hippocampus of APP/PS1 model mice].

OBJECTIVE: To investigate the effect of electroacupuncture(EA) stimulation on proliferation and diffe-rentiation of endogenous neural stem cells as well as Jagged1/Notch1 pathway in AD model mice, so as to explore its mechanism underlying amelioration of AD. METHODS: A total of 40 6-week-old male APP/PS1 transgenic AD mice were randomly divided into EA group (n=20) and AD model group ( n=20), and other 20 normal C57BL/6J mice of the same age were used as the normal control group. The mice in the EA group received EA (10 Hz, 2 mA) at "Baihui"(GV20), "Fengfu"(GV16) and bilateral "Shenshu" (BL23) for 20 min, once daily, 6 days a week for 16 weeks. The mice's learning-memory ability was detected by Morris water maze tests. The Aß senile plaques in the hippocampal CA1 region were detected by Congo red staining, the immunofluorescence double label of BrdU, neuronal nuclear antigen (NeuN) and astrocyte specific protein GFAP in dentate gyrus of hippocampus was performed for detecting the proliferation and differentiation of the endogenous neural stem cells. The expression levels of Nestin (neuron specific protein) and GFAP were detected by Western blot, and those of Jagged1 and Notch1 mRNAs and proteins in the hippocampus were detected by real-time fluorescence quantifative PCR and Western blot. RESULTS: Compared with the normal control group, the escape latencies at 2nd, 3rd and 4th day, and Aß senile plaques were significantly increased (P<0.05, P<0.01), whereas the platform crossing times and time spent in the target quadrant, the expression levels of Jagged1 mRNA and Nestin protein were remarkably down-regulated (P<0.05) in the model group. Following EA intervention, the escape latencies at the 3rd and 4th day, Aß senile plaques, immunofluorescence density of BrdU/GFAP, and GFAP protein expression were pronouncedly decreased (P<0.05, P<0.01), while the platform crossing times, platform quadrant residence time, immunofluorescence density of BrdU/NeuN, expression levels of Jagged1 and Notch1 mRNAs and proteins and Nestin protein evidently increased (P<0.05, P<0.01), suggesting an enhancement of proliferation and diffe-rentiation of endogenous neural stem cells into neurons and a suppression of the proliferation and differentiation towards astrocytes in the hippocampus. CONCLUSION: EA at GV20, GV16 and BL23 can improve the learning-memory ability, promote the proliferation and differentiation of endogenous neural stem cells towards neurons and inhibit the proliferation and differentiation of endogenous neural stem cells towards astrocytes in the hippocampus, which may be achieved by regulating Jagged1/Notch1 pathway.

[Electroacupuncture at "Baihui"（GV20） and "Yongquan"（KI1） improves learning-memory ability of APP/PS1 double transgenic mice by regulating endosomal-lysosomal system].

OBJECTIVE: To explore the mechanism of electroacupuncture（EA） in improving learning-memory ability in Alzheimer's disease （AD） mice from the perspective of endosomal-lysosomal system. METHODS: Male APP/PS1 transgenic mice were randomly divided into model group and EA group （n=10 in each group） and 10 male C57BL/6 wild mice were taken as the normal group. EA （1 Hz/50 Hz, 1 mA） was applied at bilateral "Yongquan"（KI1） and acupuncture was applied at "Baihui" （GV20） for 15 min. The mice of the model and normal groups were subjected to restriction with the same method as those of the EA group for 15 min. The treatment was conducted once every other day for 6 weeks. The spatial learning-memory ability （shown by escape latency of place navigation test and the time of crossing the target platform and total swimming distance in the target quadrant in 1 min of spatial probe test ） was detected by Morris water maze test. The immunoactivity of senile plaques （SP） in the hippocampus tissue was detected by immunohistochemistry. The ultrastructural characters of hippocampal neurons were observed by transmission electron microscope, and the expression levels of Ras-related protein 5 （Rab5）, Ras-related protein 7 （Rab7） and cathepsin D （CTSD） in the hippocampus were detected by Western blot, separately. RESULTS: Compared with the normal group, the escape latency, SP immunoactivity, and protein expression levels of Rab5, Rab7 and CTSD were significantly increased （P<0.05, P<0.01）, while the number of crossing the original platform and the total swimming distance in the platform quadrant were considerably reduced （P<0.05） in the model group. In contrast to the model group, the EA group had a marked decrease in the escape latency, SP immunoactivity, and protein expression levels of Rab5, Rab7 and CTSD （P<0.05, P<0.01）, and a striking increase in the number of crossing the original platform and the swimming distance in the platform quadrant （P<0.05）. Results of transmission electron microscope showed an accumulation of endosome, lysosome, and endolysosomes in the hippocampal neurons in the model group, which was evidently milder in the EA group. CONCLUSION: EA of GV20 and KI1 can improve the learning-memory ability of AD mice, which may be related to its function in reducing hippocampal Aß deposition and down-regulating endosomal-lysosomal system activity.

[Mechanisms of moxibustion preconditioning underlying improving learning-memory ability by regulating polarization of microglia via TLR4/NF-κB signaling pathway in AD rats].

OBJECTIVE: To observe the effect of moxibustion preconditioning on learning-memory ability, Toll like receptor 4(TLR4)/nuclear factor-kappa B(NF-κB) signal pathway related proteins and microglia in rats with Alzheimer's disease (AD), so as to explore its possible mechanisms underlying improvement of AD. METHODS: Male SD rats were randomly divided into normal, sham operation, AD model and pre-moxibustion groups, with 9 rats in each group. Moxibustion was applied to "Baihui"(GV20), "Shenshu"(BL23) and "Zusanli"(ST36) for 15 min, once daily, 6 days as a course of treatment for 3 courses. At the end of moxibustion, the AD model was established by injection of Aß25-35 aggregation solution into the bilateral hippocampus. The sham operation group was only injected with the same amount of 0.9% Nacl solution. The spatial learning-memory ability of rats was detected by Morris water maze test, the ultrastructure of hippocampal neurons was observed by transmission electron microscope (TEM). The histopathological changes of hippocampus tissue were observed by HE staining, and the protein expression levels of TLR4 and NF-κB p65 in the hippocampus detected by Western blot, and the positive expressions of Iba-1, CD80 and CD206 in the hippocampal CA1 region were detected by immunofluorescence labeling. The contents of inflammatory factors IL-1ß, TNF-α and IL-10 in the hippocampus were measured by ELISA. RESULTS: Compared with the sham operation group, the escape latency was significantly increased (P<0.01), and the number of platform quadrant crossing times was decreased (P<0.01) in the model group. In comparison with the model group, the increased escape latency and the decreased platform quadrant crossing times were reversed in the pre-moxibustion group (P<0.01). TEM and light microscope observation showed loose arrangement of cells, enlarged cell space, degeneration, swelling and deformation of hippocampal neurons, rupture of membranes of a large number of cells, reduction of mitochondria, dilation of endoplasmic reticulum, and matrix vacuoles, uneven distribution of organelles and cytoplasm, and being difficult in distinguishing the nuclear cytoplasm in the model group, which was relatively milder in the pre-moxibustion group. The expression levels of hippocampal NF-κB p65 and TLR4, the mean immunofluorescence density of Iba-1 and CD80, as well as the contents of IL-1ß and TNF-α in hippocampal CA1 region were significantly increased in the model group than those in the sham operation group (P<0.01), and obviously decreased in the pre-moxibustion group than those in the model group (P<0.05, P<0.01). Whereas the expression of CD206 and the content of IL-10 were evidently decreased in the model group than those in the sham operation group (P<0.01), and strikingly increased in the pre-moxibustion group than those in the model group (P<0.01). No significant differences were found between the sham operation group and the normal group in all the indexes mention above (P>0.05). CONCLUSION: Pre-moxibustion at GV20, BL23 and ST36 can improve learning-memory ability in AD rats, which may be associated with its functions in promoting the polarization of microglia from M1 to M2 and reducing the neuroinflammatory response by way of TLR4/NF-κB signaling pathway.

A Comprehensive Multilevel Analysis of the Bucharest Early Intervention Project: Causal Effects on Recovery From Early Severe Deprivation.

OBJECTIVE: The Bucharest Early Intervention Project is the first randomized controlled trial of foster care as an alternative to institutional care. The authors synthesized data from nearly 20 years of assessments of the trial to determine the overall intervention effect size across time points and developmental domains. The goal was to quantify the overall effect of the foster care intervention on children's outcomes and examine sources of variation in this effect, including domain, age, and sex assigned at birth. METHODS: An intent-to-treat approach was used to examine the causal effects of the randomized controlled trial for 136 children residing in institutions in Bucharest, Romania (baseline age, 6-31 months) who were randomly assigned to either foster care (N=68) or care as usual (N=68). At ages 30, 42, and 54 months and 8, 12, and 16-18 years, children were assessed for IQ, physical growth, brain electrical activity (EEG), and symptoms of five types of psychopathology. RESULTS: Participants provided 7,088 observations across follow-up waves. Children assigned to foster care had better cognitive and physical outcomes and less severe psychopathology than did those who received care as usual. The magnitude of these effect sizes remained stable across development. The foster care intervention most influenced IQ and disorders of attachment/social relatedness. CONCLUSIONS: Young children benefit from placement in families after institutional care. The benefits of foster care for previously institutionalized children were remarkably stable across development.

The Nature of Prefrontal Cortical GABA Neuron Alterations in Schizophrenia: Markedly Lower Somatostatin and Parvalbumin Gene Expression Without Missing Neurons.

OBJECTIVE: In schizophrenia, somatostatin (SST) and parvalbumin (PV) mRNA levels are lower in the dorsolateral prefrontal cortex (DLPFC), but it remains unclear whether these findings reflect lower transcript levels per neuron, fewer neurons, or both. Distinguishing among these alternatives has implications for understanding the pathogenesis of, and developing new treatments for, DLPFC dysfunction in schizophrenia. METHODS: To identify SST and PV neurons in postmortem human DLPFC, the authors used fluorescent in situ hybridization to label cells expressing two transcripts not altered in schizophrenia: vesicular GABA transporter (VGAT; a marker of all GABA neurons) and SOX6 (a marker of only SST and PV neurons). In cortical layers 2 and 4, where SST and PV neurons, respectively, are differentially enriched, levels of SST and PV mRNA per neuron and the relative densities of SST-, PV-, and VGAT/SOX6-positive neurons were quantified. RESULTS: In individuals with schizophrenia, mRNA levels per positive neuron were markedly and significantly lower for SST in both layers (effect sizes >1.48) and for PV only in layer 4 (effect size=1.14) relative to matched unaffected individuals. In contrast, the relative densities of all SST-, PV-, or VGAT/SOX6-positive neurons were unaltered in schizophrenia. CONCLUSIONS: Novel multiplex fluorescent in situ hybridization techniques permit definitive distinction between cellular levels of transcripts and the presence of neurons expressing those transcripts. In schizophrenia, pronounced SST and PV mRNA deficits are attributable to lower levels of each transcript per neuron, not fewer neurons, arguing against death or abnormal migration of these neurons. Instead, these neurons appear to be functionally altered and thus amenable to therapeutic interventions.