Mouse neurexin-1alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments.
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ABSTRACT:
SUBMITTER: Etherton MR
PROVIDER: S-EPMC2764944 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cognitive control--the ability to exert control over thoughts, attention and behavior in order to achieve a goal--is essential to adaptive functioning and its disruption characterizes various neuropsychiatric and neurodegenerative disorders. In recent years, increased attention has been devoted to investigating the effects of training on performance and brain function, but little is known about whether cognitive control can be improved through training. To fill this gap, we designed a brief training targeting various components of cognitive control, including conflict monitoring and interference resolution. Twenty participants performed a 3-day training protocol, preceded and followed by identical pre- and post-training sessions, respectively, which included event-related potential (ERP) recordings. To detect transfer effects, the training and pre-/post-training sessions employed different tasks hypothesized to rely on similar interference resolution mechanisms. We hypothesized that training would selectively improve performance for high-interference (i.e., incongruent) trials and be associated with reduced amplitudes in the N2 component, a waveform known to index interference. Trial-to-trial behavioral adjustments were also analyzed to assess potential mechanisms of training-induced improvements. Relative to pre-training, participants showed reduced reaction time (RT) and N2 amplitude for incongruent, but not congruent, trials, suggesting improved interference resolution. Critically, participants showing the greatest reductions in interference effects during the course of the training displayed the largest pre- to post-training reductions in N2 amplitudes in a separate task, highlighting transfer effects. Overall, results suggest that a brief training can improve cognitive control, specifically the ability to inhibit task-irrelevant information.
| S-EPMC3601637 | biostudies-literature
Project description:Epigenomic abnormalities caused by genetic mutation in epigenetic regulators can result in neurodevelopmental disorders, deficiency in neural plasticity and mental retardation. As a histone demethylase, plant homeodomain finger protein 8 (Phf8) is a candidate gene for syndromal and non-specific forms of X-chromosome-linked intellectual disability (XLID). Here we report that Phf8 knockout mice displayed impaired learning and memory, and impaired hippocampal long-term potentiation (LTP) without gross morphological defects. We also show that mTOR signaling pathway is hyperactive in hippocampus in Phf8 knockout mouse. Mechanistically, we show that demethylation of H4K20me1 by Phf8 results in transcriptional suppression of RSK1 and homeostasis of mTOR signaling. Pharmacological suppression of mTOR signaling with rapamycin in Phf8 knockout mice recovers the weakened LTP and cognitive deficits. Together, our results indicate that loss of Phf8 in animals causes deficient learning and memory by epigenetic disruption of mTOR signaling, and provides a potential therapeutic drug target to treat XLID.
| S-EPMC5760733 | biostudies-literature
Project description:Background: The long-term high-fat, high-sugar diet exacerbates type 2 diabetes mellitus (T2DM)-related cognitive impairments. The negative impact of poor dietary patterns on brain development and neurological function may be related to gut microbiota disturbance. The role of phlorizin in mitigating glucose and lipid metabolism disorders is well documented. However, the protective effect of phlorizin on diabetes-related cognitive dysfunction is unclear. Therefore, the present study aimed to investigate the effect of dietary supplementation of phlorizin on high-fat and high-fructose diet (HFFD)-induced cognitive dysfunction and evaluate the crucial role of the microbiota-gut-brain axis. Results: Dietary supplementation of phlorizin for 14 weeks effectively prevented glucolipid metabolism disorder, spatial learning impairment, and memory impairment in HFFD mice. In addition, phlorizin improved the HFFD-induced decrease in synaptic plasticity, neuroinflammation, and excessive activation of microglia in the hippocampus. Transcriptomics analysis shows that the protective effect of phlorizin on cognitive impairment was associated with increased expression of neurotransmitters and synapse-related genes in the hippocampus. Phlorizin treatment alleviated colon microbiota disturbance, mainly manifested by an increase in gut microbiota diversity and the abundance of short-chain fatty acid (SCFA)-producing bacteria. The level of microbial metabolites, including SCFA, inosine 5'-monophosphate (IMP), and D (-)-beta-hydroxybutyric acid (BHB) were also significantly increased after phlorizin treatment. Moreover, integrating multiomics analysis observed tight connections between phlorizin-regulated genes, microbiota, and metabolites. Furthermore, removal of the gut microbiota via antibiotics treatment diminished the protective effect of phlorizin against HFFD-induced cognitive impairment, underscoring the critical role of the gut microbiota in mediating cognitive behavior. Importantly, supplementation with SCFA and BHB alone mimicked the regulatory effects of phlorizin on cognitive function. Conclusions: These results indicate that gut microbiota and their metabolites mediate the ameliorative effect of phlorizin on HFFD-induced cognitive impairment. Therefore, phlorizin can be used as an easy-to-implement nutritional therapy to prevent and alleviate metabolism-related neurodegenerative diseases by targeting the regulation of the microbiome-gut-brain axis.
2024-03-20 | GSE261887 | GEO
Project description:BackgroundPersistent psychological stress often leads to anxiety disorders and depression. Benzodiazepines and selective serotonin reuptake inhibitors are popular treatment options but have limited efficacy, supporting the need for alternative treatment. Based on our recent preclinical work suggesting a causal link between neurobehavioral deficits and elevated oxidative stress, we hypothesized that interventions that mitigate oxidative stress can attenuate/overcome neurobehavioral deficits.MethodsHere, we employed the rat social defeat model of psychological stress to determine whether increasing antioxidant levels using grape powder would prevent and/or reverse social defeat-induced behavioral and cognitive deficits. Furthermore, a hippocampal-derived HT22 cell culture model of oxidative stress was employed to identify the individual beneficial constituent(s) of grape powder and the underlying mechanism(s) of action.ResultsGrape powder treatment prevented and reversed social defeat-induced behavioral and cognitive deficits and also decreased social defeat-induced increase in plasma corticosterone and 8-isoprostane (systemic and oxidative stress markers, respectively). And grape powder treatment replenished social defeat-induced depleted pool of key antioxidant enzymes glyoxalase-1, glutathione reducatse-1, and superoxide dismutase. Grape powder constituents, quercetin and resveratrol, were most effective in preventing oxidative stress-induced decreased cellular antioxidant capacity. Grape powder protected oxidative stress-induced cell death by preventing calcium influx, mitochondrial dysfunction, and release of cytochrome c.ConclusionsGrape powder treatment by increasing antioxidant pool and preventing cell damage and death prevented and reversed social defeat-induced behavioral and cognitive deficits in rats. Quercetin and resveratrol are the major contributors towards beneficial effects of grape powder.
| S-EPMC5492781 | biostudies-literature
Project description:The dysfunction of the small-conductance calcium-activated K+ channel SK3 has been described as one of the factors responsible for the progress of psychoneurological diseases, but the molecular basis of this is largely unknown. This report reveals through use of immunohistochemistry and computational tomography that long-term increased expression of the SK3 small-conductance calcium-activated potassium channel (SK3-T/T) in mice induces a notable bilateral reduction of the hippocampal area (more than 50 %). Histological analysis showed that SK3-T/T mice have cellular disarrangements and neuron discontinuities in the hippocampal formation CA1 and CA3 neuronal layer. SK3 overexpression resulted in cognitive loss as determined by the object recognition test. Electrophysiological examination of hippocampal slices revealed that SK3 channel overexpression induced deficiency of long-term potentiation in hippocampal microcircuits. In association with these results, there were changes at the mRNA levels of some genes involved in Alzheimer's disease and/or linked to schizophrenia, epilepsy, and autism. Taken together, these features suggest that augmenting the function of SK3 ion channel in mice may present a unique opportunity to investigate the neural basis of central nervous system dysfunctions associated with schizophrenia, Alzheimer's disease, or other neuropsychiatric/neurodegenerative disorders in this model system. As a more detailed understanding of the role of the SK3 channel in brain disorders is limited by the lack of specific SK3 antagonists and agonists, the results observed in this study are of significant interest; they suggest a new approach for the development of neuroprotective strategies in neuropsychiatric/neurodegenerative diseases with SK3 representing a potential drug target.
| S-EPMC5310555 | biostudies-literature
Project description:BackgroundThe serine/threonine protein phosphatase, PP2A, is thought to play a central role in the molecular pathogenesis of Alzheimer's disease (AD), and the activity and substrate specificity of PP2A is regulated, in part, through methylation and demethylation of its catalytic subunit. Previously, we found that transgenic overexpression of the PP2A methyltransferase, LCMT-1, or the PP2A methylesterase, PME-1, altered the sensitivity of mice to impairments caused by acute exposure to synthetic oligomeric amyloid-β (Aβ).ObjectiveHere we sought to test the possibility that these molecules also controlled sensitivity to impairments caused by chronically elevated levels of Aβ produced in vivo.MethodsTo do this, we examined the effects of transgenic LCMT-1, or PME-1 overexpression on cognitive and electrophysiological impairments caused by chronic overexpression of mutant human APP in Tg2576 mice.ResultsWe found that LCMT-1 overexpression prevented impairments in short-term spatial memory and synaptic plasticity in Tg2576 mice, without altering APP expression or soluble Aβ levels. While the magnitude of the effects of PME-1 overexpression in Tg2576 mice was small and potentially confounded by the emergence of non-cognitive impairments, Tg2576 mice that overexpressed PME-1 showed a trend toward earlier onset and/or increased severity of cognitive and electrophysiological impairments.ConclusionThese data suggest that the PP2A methyltransferase, LCMT-1, and the PP2A methylesterase, PME-1, may participate in the molecular pathogenesis of AD by regulating sensitivity to the pathogenic effects of chronically elevated levels of Aβ.
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Project description:The neurexins are a family of presynaptic cell adhesion molecules. Human genetic studies have found heterozygous deletions affecting NRXN1 and NRXN2, encoding ?-neurexin I (Nrxn1?) and ?-neurexin II (Nrxn2?), in individuals with autism spectrum disorders and schizophrenia. However, the link between ?-neurexin deficiency and the manifestation of psychiatric disorders remain unclear. To assess whether the heterozygous loss of neurexins results in behaviors relevant to autism or schizophrenia, we used mice with heterozygous (HET) deletion of Nrxn1? or Nrxn2?. We found that in a test of social approach, Nrxn1? HET mice show no social memory for familiar versus novel conspecifics. In a passive avoidance test, female Nrxn1? HET mice cross to the conditioned chamber sooner than female wild-type and Nrxn2? HET mice. Nrxn2? HET mice also express a lack of long-term object discrimination, indicating a deficit in cognition. The observed Nrxn1? and Nrxn2? genotypic effects were specific, as neither HET deletion had effects on a wide range of other behavioral measures, including several measures of anxiety. Our findings demonstrate that the heterozygous loss of ?-neurexin I and ?-neurexin II in mice leads to phenotypes relevant to autism and schizophrenia.
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Project description:Emerging epidemiology studies indicate that maternal immune activation (MIA) resulting from inflammatory stimuli such as viral or bacterial infections during pregnancy serves as a risk factor for multiple neurodevelopmental disorders including autism spectrum disorders and schizophrenia. Although alterations in the cortex and hippocampus of MIA offspring have been described, less evidence exists on the impact on the cerebellum. Here, we report altered expression of cytokines and chemokines in the cerebellum of MIA offspring, including increase in the neuroinflammatory cytokine TNF? and its receptor TNFR1. We also report reduced expression of the synaptic organizing proteins cerebellin-1 and GluR?2. These synaptic protein alterations are associated with a deficit in the ability of cerebellar neurons to form synapses and an increased number of dendritic spines that are not in contact with a presynaptic terminal. These impairments are likely contributing to the behavioral deficits in the MIA exposed offspring.
| S-EPMC5436129 | biostudies-literature
Project description:The limbic system-associated membrane protein (LAMP) is a GPI-anchored cell adhesion molecule expressed heavily in limbic and limbic-associated regions of the developing and adult brain. Experimental studies show that LAMP promotes the growth of limbic neurons and guides the projections of limbic fibers. In order to examine the functional consequences of disrupting limbic circuit assembly, we generated a mouse line in which the Lsamp gene encoding LAMP was deleted. Basic neuroanatomical organization and sensory and motor development are normal in Lsamp(-/-) mice. The most profound change in behavior in both male and female Lsamp(-/-) mice is a heightened reactivity to novelty exhibited in several behavioral tests. Lsamp(-/-) mice display hyperactivity in a novel arena and both sexes habituate to the same activity levels as their wild type littermates, but at different rates. In the elevated plus maze, Lsamp(-/-) mice exhibit increased total arm entries, with a bias towards the open arms; they spend more time in the open arms and have a substantial increase in the amount of risk assessment in unprotected areas of the maze. In the y-maze, Lsamp(-/-) mice exhibit characteristic hyperactivity and a decreased level of spontaneous alternation during the period when their novelty-induced hyperactivity is at its peak. We hypothesize that Lsamp(-/-) mice may not simply exhibit a decrease in anxiety, but may have a heightened, and possibly maladaptive, response to novel environmental stressors. Genetic deletion of Lsamp may thus cause circumscribed changes in the fine connectivity of specific circuits that underlie these behaviors.
| S-EPMC2275759 | biostudies-literature
Project description:Binge drinking is common in adolescence. Rodent studies modeling adolescent binge drinking find persistent effects on the brain's physiology, including increased expression of neuroimmune genes, impaired neurogenesis, and changes in behavioral flexibility. This study used females and males to investigate the effects of adolescent intermittent ethanol (AIE) on a battery of behaviors assessing spatial navigation using a radial arm water maze, working memory using the Hebb-Williams maze, non-spatial long-term memory using novel object recognition, and dominance using a tube dominance test. Results indicate that AIE impairs adult acquisition in spatial navigational learning with deficits predominantly driven by females. Surprisingly, AIE slowed the transition from random to serial search strategies in both sexes, suggesting AIE impairs flexibility in problem-solving processing. In the Hebb-Williams maze working memory task, adult AIE rats exhibited deficits in problem solving, resulting in more errors across the 12 maze configurations, independent of sex. Conversely, AIE decreased dominance behaviors in female rats, and at 7 months post-alcohol, female AIE rats continued to exhibit deficits in novel object recognition. These results suggest that cognitive-behavioral alterations after adolescent binge drinking persist well into middle age, despite abstinence. Future studies should focus on intervening treatment strategies in both females and males.
| S-EPMC7692738 | biostudies-literature