Microglia are the resident macrophages of the central nervous system. Microglia possess varied morphologies and functions. Under normal physiological conditions, microglia mainly exist in a resting ...state and constantly monitor their microenvironment and survey neuronal and synaptic activity. Through the C1q, C3 and CR3 "Eat Me" and CD47 and SIRPα "Don't Eat Me" complement pathways, as well as other pathways such as CX3CR1 signaling, resting microglia regulate synaptic pruning, a process crucial for the promotion of synapse formation and the regulation of neuronal activity and synaptic plasticity. By mediating synaptic pruning, resting microglia play an important role in the regulation of experience-dependent plasticity in the barrel cortex and visual cortex after whisker removal or monocular deprivation, and also in the regulation of learning and memory, including the modulation of memory strength, forgetfulness, and memory quality. As a response to brain injury, infection or neuroinflammation, microglia become activated and increase in number. Activated microglia change to an amoeboid shape, migrate to sites of inflammation and secrete proteins such as cytokines, chemokines and reactive oxygen species. These molecules released by microglia can lead to synaptic plasticity and learning and memory deficits associated with aging, Alzheimer's disease, traumatic brain injury, HIV-associated neurocognitive disorder, and other neurological or mental disorders such as autism, depression and post-traumatic stress disorder. With a focus mainly on recently published literature, here we reviewed the studies investigating the role of resting microglia in synaptic plasticity and learning and memory, as well as how activated microglia modulate disease-related plasticity and learning and memory deficits. By summarizing the function of microglia in these processes, we aim to provide an overview of microglia regulation of synaptic plasticity and learning and memory, and to discuss the possibility of microglia manipulation as a therapeutic to ameliorate cognitive deficits associated with aging, Alzheimer's disease, traumatic brain injury, HIV-associated neurocognitive disorder, and mental disorders.
Cognitive impairment is the strongest predictor of functional outcomes in schizophrenia and is hypothesized to result from synaptic dysfunction. However, targeting synaptic plasticity and cognitive ...deficits in patients remains a significant clinical challenge. A comprehensive understanding of synaptic plasticity and the molecular basis of learning and memory in a disease context can provide specific targets for the development of novel therapeutics targeting cognitive impairments in schizophrenia. Here, we describe the role of synaptic plasticity in cognition, summarize evidence for synaptic dysfunction in schizophrenia and demonstrate the use of patient derived induced-pluripotent stem cells for studying synaptic plasticity in vitro. Lastly, we discuss current advances and future technologies for bridging basic science research of synaptic dysfunction with clinical and translational research that can be used to predict treatment response and develop novel therapeutics.
Neuroinflammation is thought to contribute to the onset and progression of Alzheimer's disease (AD). Galectin-3 (Gal-3), the only member of the galectin chimeric subfamily, is a key regulator of ...neuroinflammation and microglial activation. However, the effects of Gal-3 inhibition in AD-related neuroinflammation are unclear. Here, we investigated whether hippocampal Gal-3 knockdown alleviated lipopolysaccharide (LPS)-induced neurotoxicity and cognitive deficits, as well as the underlying mechanisms. First, we bilaterally injected aged mice (23 months old) with anti-Gal-3 short hairpin RNA into the hippocampus dentate gyrus, followed by systemic LPS administration. To determine the effects of hippocampal Gal-3 knockdown on neuroinflammatory response and neuronal apoptosis, we assessed the effects of Gal-3 silencing on the levels of pro-inflammatory cytokines, microglial activation, and apoptosis in the hippocampus of LPS-exposed aged mice. Behavioral tests were used to access the cognitive function of the mice. To explore the potential signaling, protein extracts from the brains of mice were subjected to analyze the expression levels of key molecules (including Toll-like receptor 4 (TLR4), myeloid differentiation factor 88, and nuclear transcription factor-κB (NF-κB) p65) of the TLR4/NF-кB pathway, and BV2 cells were pretreated with TLR4 inhibitor or NF-κB inhibitor before Gal-3 stimulation. These analyses showed that hippocampal Gal-3 knockdown attenuated neuroinflammation and neuronal apoptosis in the hippocampus of LPS-challenged aged mice, and this was associated with improved cognitive function. Hippocampal Gal-3 knockdown may protect against LPS-induced neurotoxicity by inhibiting the TLR4/NF-кB pathway. Our findings highlight Gal-3 as a potential therapeutic target against AD-associated neuroinflammation.
The fetus and infants are particularly vulnerable to Cadmium (Cd) due to the immaturity of the blood-brain barrier. In utero and early life exposure to Cd is associated with cognitive deficits. ...Although such exposure has attracted widespread attention, its gender-specificity remains controversial, and there are no reports disclosing the underlying mechanism of gender‑specific neurotoxicity. We extensively evaluated the learning and cognitive functions and synaptic plasticity of male and female rats exposed to maternal Cd. Maternal Cd exposure induced learning and memory deficits in male offspring rats, but not in female offspring rats. PLCβ4 was identified as a critical protein, which might be related to the gender‑specific cognitive deficits in male rats. The up-regulated PLCβ4 competed with PLCγ1 to bind to PIP2, which counteracted the hydrolysis of PIP2 by PLCγ1. The decreased activation of PLCγ1 inhibited the phosphorylation of CREB to reduce BDNF transcription, which consequently resulted in the damage of hippocampal neurons and cognitive deficiency. Moreover, the low level of BDNF promoted AEP activation to induce Aβ deposition in the hippocampus. These findings highlight that PLCβ4 might be a potential target for the therapy of learning and cognitive deficits caused by Cd exposure in early life.
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•Maternal Cd exposure induced learning and memory deficits in male offspring rats, but not in female offspring rats.•PLCβ4 is related to the gender‑specific neurotoxic effects, which is negatively regulated neurite outgrowth.•PLCβ4 contributes to cognitive deficits by suppressing PIP2/PLCγ1/CREB/BDNF signaling pathway.•PLCβ4 might be a potential target for the therapy of learning and cognitive deficits caused by Cd exposure in early life.
Oxidative stress and mitochondrial dysfunction contribute greatly to fluoride-induced cognitive impairment and behavioural disorders. Honokiol, a natural biphenolic compound, possesses antioxidant ...and mitochondrial protective properties. The present study investigated the protective actions of honokiol on NaF-elicited cognitive deficits and elucidated the possible mechanism of honokiol-mediated protection. The results demonstrated that honokiol administration markedly attenuated fluoride-induced cognitive impairments and neural/synaptic injury in mice. Moreover, honokiol elevated the activity and expression of SOD2 and promoted mtROS scavenging through Sirt3 activation in NaF-treated mice and SH-SY5Y cell lines. Meanwhile, honokiol substantially lowered mtROS production by enhancing Sirt3-mediated mitochondrial DNA (mtDNA) transcription, thereby leading to significant increases in ATP synthesis and complex I activity. Further studies revealed that honokiol activated AMPK and upregulated the PGC-1α and Sirt3 protein expression in vivo and in vitro. Intriguingly, the protective actions of honokiol on oxidative stress and mitochondrial dysfunction were abolished by AMPK shRNA or Sirt3 shRNA. Notably, AMPK knockdown prevented the increase in PGC-1α and Sirt3 expression induced by honokiol, while Sirt3 shRNA suppressed Sirt3 signaling without significant effects on p-AMPK and PGC-1α expression. In conclusion, our findings indicate that honokiol mitigates NaF-induced oxidative stress and mitochondrial dysfunction by regulating mtROS homeostasis, partly via the AMPK/PGC-1α/Sirt3 pathway, which ultimately contributes to neuronal/synaptic injury and cognitive deficits.
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•Honokiol attenuated fluoride-induced cognitive deficits in mice.•Honokiol prevented neuronal/synaptic injury in the hippocampus of fluoride-treated mice.•Honokiol inhibited oxidative stress and mitochondrial abnormalities following fluoride challenge.•The AMPK-PGC-1α-Sirt3 pathway was involved in the honokiol’s positive effects on fluoride-induced mitochondrial dysfunction.
Vascular endothelial growth factor (VEGF) and neuregulin1 (NRG1) are multifunctional trophic factors reported to be dysregulated in schizophrenia. However, the relationships between serum ...concentrations and schizophrenia symptoms have differed markedly across studies, possibly because schizophrenia is a highly heterogenous disorder. The aim of this study was to investigate the associations of serum VEGF and NRG1 with clinical symptoms and cognitive deficits specifically in male patients with chronic schizophrenia.
The study included 79 male patients with chronic schizophrenia and 79 matched healthy individuals. Serum VEGF, NRG1β1, S100B, S100A8, and neuropilin1 were measured using the Luminex liquid suspension chip detection method, psychopathological symptom severity using the Positive and Negative Symptom Scale (PANSS), and cognitive dysfunction using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).
Serum VEGF and NRG1β1 concentrations were significantly lower in male chronic schizophrenic patients than healthy controls (P < 0.05), while serum S100B, S100A8, and neuropilin1 concentrations did not differ between groups (P > 0.05). Serum VEGF concentration was negatively correlated with PANSS negative subscore (beta = −0.220, t = −2.07, P = 0.042), general psychopathology subscore (beta = -0.269, t = −2.55, P = 0.013), and total score (beta = -0.234, t = −2.12, P = 0.038), and positively correlated with RBANS language score (beta = 0.218, t = 2.03, P = 0.045). Alternatively, serum NRG1β1 concentration was not correlated with clinical symptoms or cognitive deficits (all P > 0.05).
Dysregulation of VEGF and NRG1β1 signaling may contribute to the pathogenesis of chronic schizophrenia in males. Moreover, abnormal VEGF signaling may contribute directly or through intermediary processes to neuropsychiatric and cognitive symptom expression.
•Serum VEGF and NRG1 levels were reduced in male patients with chronic schizophrenia.•Reduced serum VEGF was associated with psychopathologic symptoms and language deficits.•Deficient VEGF signaling is a potential therapeutic target for schizophrenia treatment.
•Aspartame metabolised to methanol, aspartic acid, and phenylalanine has detrimental effects on cognitive function.•Methanol derivatives and aspartic acid act as neurotoxins contributing to neuronal ...damage and possible microglia activation.•Elevated phenylalanine hinders tryptophan influx through LAT1, impacting neurotransmitter synthesis inside brain.•Tryptophan supplementation may restore serotonin levels, mitigating excitotoxicity and neuro-inflammation.•Increased 5-HTP and melatonin might help transitioning microglia to a resting state, thereby improving cognitive function.
Aspartame, an artificial sweetener, is consumed by millions of people globally. There are multiple reports of aspartame and its metabolites affecting cognitive functions in animal models and humans, which include learning problems, headaches, seizures, migraines, irritable moods, anxiety, depression, and insomnia. These cognitive deficits and associated symptoms are partly attributed to dysregulated excitatory and inhibitory neurotransmitter balance due to aspartate released from aspartame, resulting in an excitotoxic effect in neurons, leading to neuronal damage. However, microglia, a central immunocompetent cell type in brain tissue and a significant player in inflammation can contribute to the impact. Microglia rapidly respond to changes in CNS homeostasis. Aspartame consumption might affect the microglia phenotype directly via methanol-induced toxic effects and indirectly via aspartic acid-mediated excitotoxicity, exacerbating symptoms of cognitive decline. Long-term oral consumption of aspartame thus might change microglia’s phenotype from ramified to activated, resulting in chronic or sustained activation, releasing excess pro-inflammatory molecules. This pro-inflammatory surge might lead to the degeneration of healthy neurons and other glial cells, impairing cognition. This review will deliberate on possible links and research gaps that need to be explored concerning aspartame consumption, ecotoxicity and microglia-mediated inflammatory cognitive impairment. The study covers a comprehensive analysis of the impact of aspartame consumption on cognitive function, considering both direct and indirect effects, including the involvement of microglia-mediated neuroinflammation. We also propose a novel intervention strategy involving tryptophan supplementation to mitigate cognitive decline symptoms in individuals with prolonged aspartame consumption, providing a potential solution to address the adverse effects of aspartame on cognitive function.
To determine the extent and efficacy of attentional training as a form of neuropsychological rehabilitation to ameliorate attention deficits in adults with moderate-to-severe traumatic brain injury.
...Articles published in Cumulative Index to Nursing and Allied Health Literature, Cochrane Library, PubMed, PsycINFO, Scopus, and Web of Science were searched between January 17, and February 27, 2021.
Two reviewers blindly assessed studies for eligibility according to the following criteria: any article evaluating the efficacy of any type of behavioral intervention that targeted attention (by means of cognitive rehabilitative, psychoeducational, or neuropsychological strategies, at either an individual or group level) in adults who had sustained a formally documented moderate-to-severe traumatic brain injury.
Methodological quality of each article was blindly assessed by 2 reviewers. Data were extracted from each study, including study type, sample size, sample characteristics, summary of intervention, measures used to assess attention, statistical outcomes and results, effect size, conclusion, and limitations.
7314 articles were retrieved from databases, 4325 articles remained after duplicate removal, and finally 21 articles met eligibility criteria and were included in this review. Articles represented varied methodological quality in group or single subject design. Irrespective of the heterogeneity regarding intervention types and attentional outcome measures used across the studies, overall findings suggest that attentional gains can be made in this sample, irrespective of time since injury, age, and injury severity. Further, a growing interest in technology-based interventions is frequently used and holds promise to bettering rehabilitation efforts. However, there is still limited evidence supporting the ecological validity of attentional training interventions (eg, the transfer of treatment effects to daily activities).
This article plays a crucial role in informing ongoing rehabilitation practices, guiding clinicians with evidence-based strategies and shaping future research directions for more effective attentional training guidelines.
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Background
Deficits in theory of mind (ToM) found in individuals with alcohol use disorder (AUD) are often thought to result from prolonged heavy alcohol use. However, links between deficits in ToM ...and greater alcohol problems are often also present in non‐clinical samples (e.g., adolescents and young adults) who may not have a similar long‐lasting history of alcohol consumption as individuals with AUD. The current study is the first to systematically review and meta‐analyze results from studies examining associations between lower ToM and greater alcohol problems in non‐clinical samples. Evidence of reliable associations in these non‐clinical samples would support the idea that deficits in ToM might also precede the emergence of AUD.
Methods
PsycINFO, PubMed, and Google Scholar were searched according to our preregistered International Prospective Register of Systematic Reviews (PROSPERO) protocol (CRD42021225392) and following the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) methodology. We systematically reviewed sample characteristics and ToM measures in identified articles. We then meta‐analyzed the findings of association between ToM and alcohol problems in non‐clinical samples using random effects models.
Results
Nearly all studies used a measure of ToM that assessed the ability to infer the mental states of others based on eye region cues. Meta‐analytic results demonstrated that lower ToM was associated with more alcohol problems (r = −0.16, k = 6, CI = −0.26, −0.04, p < 0.01, Q = 15.55, I2 = 67.85), and there was significant heterogeneity across studies. Gender (ß = 0.0003, CI = −0.006, 0.007, z = 0.09, p = 0.93), age (ß = −0.008, CI = −0.03, 0.01, z = −0.82, p = 0.42), and study quality (ß = −0.10, CI = −0.35, 0.15, z = −0.82, p = 0.41) did not explain the heterogeneity.
Conclusion
In non‐clinical samples, lower ToM is associated with more alcohol problems, indicative of a small effect size. Future longitudinal studies are needed to explore whether socio‐cognitive deficits may also serve as a risk factor for alcohol misuse.
This study is the first to systematically review and meta‐analyze results from studies examining associations between theory of mind (ToM) and alcohol problems in non‐clinical samples. Most studies used a measure of ToM that assessed the ability to infer the mental states of others based on eye region cues. Meta‐analytic results demonstrated that lower ToM was reliably associated with more alcohol problems in non‐clinical samples.
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