Age-linked suppression of lipoxin A4 mediates cognitive deficits in mice and humans

Age increases the risk for cognitive impairment and is the single major risk factor for Alzheimer's disease (AD), the most prevalent form of dementia in the elderly. The pathophysiological processes triggered by aging that render the brain vulnerable to dementia involve, at least in part, changes in inflammatory mediators. Here we show that lipoxin A4 (LXA4), a lipid mediator of inflammation resolution known to stimulate endocannabinoid signaling in the brain, is reduced in the aging central nervous system. We demonstrate that genetic suppression of 5-lipoxygenase (5-LOX), the enzyme mediating LXA4 synthesis, promotes learning impairment in mice. Conversely, administration of exogenous LXA4 attenuated cytokine production and memory loss induced by inflammation in mice. We further show that cerebrospinal fluid LXA4 is reduced in patients with dementia and positively associates with memory performance, brain-derived neurotrophic factor (BDNF), and AD-linked amyloid-β. Our findings suggest that reduced LXA4 levels may lead to vulnerability to age-related cognitive disorders and that promoting LXA4 signaling may comprise an effective strategy to prevent early cognitive decline in AD.

Unraveling the Interconnections Between Statistical Learning and Dyslexia: A Review of Recent Empirical Studies

One important aspect of human cognition involves the learning of structured information encountered in our environment, a phenomenon known as statistical learning. A growing body of research suggests that learning to read print is partially guided by learning the statistical contingencies existing between the letters within a word, and also between the letters and sounds to which the letters refer. Research also suggests that impairments to statistical learning ability may at least partially explain the difficulties experienced by individuals diagnosed with dyslexia. However, the findings regarding impaired learning are not consistent, perhaps partly due to the varied use of methodologies across studies – such as differences in the learning paradigms, stimuli used, and the way that learning is assessed – as well as differences in participant samples such as age and extent of the learning disorder. In this review, we attempt to examine the purported link between statistical learning and dyslexia by assessing a set of the most recent and relevant studies in both adults and children. Based on this review, we conclude that although there is some evidence for a statistical learning impairment in adults with dyslexia, the evidence for an impairment in children is much weaker. We discuss several suggestive trends that emerge from our examination of the research, such as issues related to task heterogeneity, possible age effects, the role of publication bias, and other suggestions for future research such as the use of neural measures and a need to better understand how statistical learning changes across typical development. We conclude that no current theoretical framework of dyslexia fully captures the extant research findings on statistical learning.

Longitudinal Assessment of Tau-Associated Pathology by 18F-THK5351 PET Imaging: A Histological, Biochemical, and Behavioral Study

Several common and debilitating neurodegenerative disorders are characterized by the intracellular accumulation of neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated tau protein. In Alzheimer’s disease (AD), NFTs are accompanied by extracellular amyloid-beta (Aβ), but primary tauopathy disorders are marked by the accumulation of tau protein alone, including forms of frontotemporal dementia (FTD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), among others. 18F-THK5351 has been reported to bind pathological tau as well as associated reactive astrogliosis. The goal of this study was to validate the ability of the PET tracer 18F-THK5351 to detect early changes in tau-related pathology and its relation to other pathological hallmarks. We demonstrated elevated in vivo 18F-THK5351 PET signaling over time in transgenic P301S tau mice from 8 months that had a positive correlation with histological and biochemical tau changes, as well as motor, memory, and learning impairment. This study indicates that 18F-THK5351 may help fill a critical need to develop PET imaging tracers that detect aberrant tau aggregation and related neuropathology in order to diagnose the onset of tauopathies, gain insights into their underlying pathophysiologies, and to have a reliable biomarker to follow during treatment trials.

Postnatal SETD1B is essential for learning and the regulation of neuronal plasticity genes

Histone 3 lysine 4 methylation (H3K4me) is mediated by six different lysine methyltransferases. Amongst these enzymes SET domain containing 1b (SETD1B) has been linked to syndromic intellectual disability but its role in the postnatal brain has not been studied yet. Here we employ mice that lack Setd1b from excitatory neurons of the postnatal forebrain and combine neuron-specific ChIP-seq and RNA-seq approaches to elucidate its role in neuronal gene expression. We observe that SETD1B controls the expression of genes with a broad H3K4me3 peak at their promoters that represent neuronal enriched genes linked to learning and memory function. Comparative analysis to corresponding data from conditional Kmt2a and Kmt2b knockout mice suggests that this function is specific to SETD1B. Moreover, postnatal loss of Setd1b leads to severe learning impairment, suggesting that SETD1B-mediated regulation of H3K4me levels in postnatal neurons is critical for cognitive function.

Reading fluency and statistical learning across modalities and domains: online and offline measures

The vulnerability of statistical learning has been demonstrated in reading difficulties in both the visual and acoustic domains. We examined segmentation abilities of adolescents with three different levels of reading fluency in the acoustic verbal and visual nonverbal domains. We applied online target detection tasks, where the extent of learning is reflected in differences between reaction times to predictable versus unpredictable targets. Explicit judgments of well-formedness were also elicited in an offline two-alternative forced choice task. A significant online learning effect was observed in all groups in both domains, and online patterns were similar in participants with low, medium and high reading fluency. On the offline measures, all groups were at chance in the visual, but not the verbal domain. These findings suggest that there is no robust statistical learning impairment associated with reading problems either in the visual or the acoustic domain in adolescents. Results also imply that offline measures may mask learning abilities, and measuring learning online can provide a deeper understanding of the learning process and of its potential deficits.

Neonatal exposure to sevoflurane caused learning and memory impairment via dysregulating SK2 channel endocytosis

Numerous studies have demonstrated that anesthetics’ exposure to neonates imposes toxicity on the developing brain but the underlying mechanisms need to be further elucidated. Our present study aimed to explore the role of small conductance Ca2+-activated potassium channel type2 in memory and learning dysfunction caused by exposing neonates to sevoflurane. Postnatal day 7 Sprague-Dawley rats and hemagglutinin-tagged small conductance Ca2+-activated potassium channel type2 channel transfected COS-7 cells were exposed to sevoflurane and the trafficking of small conductance Ca2+-activated potassium channel type2 channels was analyzed; furthermore, memory and learning ability was analyzed by the Morris water maze test on postnatal day30–35 (juvenile period). Our results showed that sevoflurane exposure inhibited small conductance Ca2+-activated potassium channel type2 channel endocytosis in both hippocampi of postnatal day 7 rats and hemagglutinin-tagged small conductance Ca2+-activated potassium channel type2 channel transfected COS-7 cells and the memory and learning ability was impaired in the juvenile period after sevoflurane exposure to neonatal rats. Herein, our results demonstrated that exposing neonates to sevoflurane caused memory and learning impairment via dysregulating small conductance Ca2+-activated potassium channel type2 channels endocytosis.

Mechanistic and Efficacy Study on Effects of Fibroin Enzymatic Hydrolysate (FEH) on Memory and Learning Impairments Induced by Scopolamine in Mice

In addition, FEH treatment increased ACh and BDNF levels, and reduced the levels of IL-1β, TNF-α and IL-6 in brain hippocampal tissue of mice with scopolamine-induced memory and learning impairment. Furthermore, FEH treatment enhanced the expression of phosphorylated cAMP response element-binding protein (p-CREB) and BDNF via the stimulation of the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin/postsynaptic density protein 95 (p-PI3K/p-AKT/mTOR/PSD95) pathway, and activation of Extracellular Signal-Regulated Kinases (ERK) and Ca2+/calmodulin-dependent protein kinase II (CaMKII). These results provide extensive information regarding the protective mechanism of action of FEH, and support the potential of FEH supplementation to prevent learning and memory impairment.