Long-term Memory Deficits Research Articles

Modulation of Kynurenic Acid Production by N-acetylcysteine Prevents Cognitive Impairment in Adulthood Induced by Lead Exposure during Lactation in Mice.

Lead (Pb2+) exposure during early life induces cognitive impairment, which was recently associated with an increase in brain kynurenic acid (KYNA), an antagonist of NMDA and alpha-7 nicotinic receptors. It has been described that N-acetylcysteine (NAC) favors an antioxidant environment and inhibits kynurenine aminotransferase II activity (KAT II, the main enzyme of KYNA production), leading to brain KYNA levels decrease and cognitive improvement. This study aimed to investigate whether the NAC modulation of the brain KYNA levels in mice ameliorated Pb2+-induced cognitive impairment. The dams were divided into four groups: Control, Pb2+, NAC, and Pb2++NAC, which were given drinking water or 500 ppm lead acetate in the drinking water ad libitum, from 0 to 23 postnatal days (PNDs). The NAC and Pb2++NAC groups were simultaneously fed NAC (350 mg/day) in their chow from 0 to 23 PNDs. At PND 60, the effect of the treatment with Pb2+ and in combination with NAC on learning and memory performance was evaluated. Immediately after behavioral evaluation, brain tissues were collected to assess the redox environment; KYNA and glutamate levels; and KAT II activity. The NAC treatment prevented the long-term memory deficit exhibited in the Pb2+ group. As expected, Pb2+ group showed redox environment alterations, fluctuations in glutamate levels, and an increase in KYNA levels, which were partially avoided by NAC co-administration. These results confirmed that the excessive KYNA levels induced by Pb2+ were involved in the onset of cognitive impairment and could be successfully prevented by NAC treatment. NAC could be a tool for testing in scenarios in which KYNA levels are associated with the induction of cognitive impairment.

Effect of vitamin E on doxorubicin and paclitaxel-induced memory impairments in male rats.

In addition to peripheral neuronal dysfunction, conventional chemotherapy can be associated with other neurological treatment-limiting adverse effects, including cognitive dysfunction, memory impairment, and anxiety, which are referred to as "chemobrain". This study aimed to investigate the effects of doxorubicin (DOX) and paclitaxel (PAC) on learning and memory in rats using radial arm water maze (RAWM) and investigated a potential beneficial effect of vitamin E(Vit. E). Adult male rats were injected with four doses of 2mg/kg/week DOX, or 2mg/kg PAC every other day intraperitoneally. Vit. Ewas co-administered with these drugs in other groups to study its antioxidative effects. Using the RAWM, each rat was assessed for learning and memory performance through two sets of six trials separated by a 5-min rest period evaluating both short- and long-term effects on memory. There was no deficit in learning or long-term memory in both drug groups compared to control. However, rats in both drug groups made significantly more errors in all short-term memory trials. This effect was mitigated when Vit. E was co-administered with either drug. Moreover, PAC (but not DOX) induced hippocampal lipid peroxidation by increasing the levels of standard biomarker thiobarbituric acid reactive substances(TBARS). Interestingly, Vit. E prevented PAC-induced hippocampal oxidative stress. Furthermore, both DOX and PAC were correlated with reduction in Brain-Derived Neurotrophic Factor (BDNF) expression levelsin the hippocampus, which was overcome by the co-administration of Vit. E. There is a potential role of Vit. E in alleviating short-term memory impairment in rats exposed to chemotherapy, possibly by reducing hippocampal oxidative stress and neurodegeneration.

Behavioral deficits after mild traumatic brain injury by fluid percussion in rats

Mild traumatic brain injury (TBI) can lead to various disorders, encompassing cognitive and psychiatric complications. While pre-clinical studies have long investigated behavioral alterations, the fluid percussion injury (FPI) model still lacks a comprehensive behavioral battery that includes psychiatric-like disorders. To address this gap, we conducted multiple behavioral tasks over two months in adult male Wistar rats, focusing on mild FPI. Statistical analyses revealed that both naive and sham animals exhibited an increase in sweet liquid consumption over time. In contrast, the TBI group did not show any temporal changes, although mild FPI did induce a statistically significant decrease in sucrose consumption compared to control groups during the chronic phase. Additionally, social interaction tasks indicated reduced contact time in TBI animals. The elevated plus maze task demonstrated an increase in open-arm exploration following fluid percussion. Nonetheless, no significant differences were observed in the acute and chronic phases for the forced swim and light–dark box tasks. Evaluation of three distinct memory tasks in the chronic phase revealed that mild FPI led to long-term memory deficits, as assessed by the object recognition task, while the surgical procedure itself resulted in short-term spatial memory deficits, as evaluated by the Y-maze task. Conversely, working memory remained unaffected in the water maze task. Collectively, these findings provide a nuanced characterization of behavioral deficits induced by mild FPI.

Motor and Cognitive Functions in Aging C57BL/6 Mice: Association with Activity of the Monoaminergic Systems in the Cerebellum and Frontal Cortex.

The activity in the open field, short- and long-term memory in the novel object recognition test, and gait features were evaluated in 6- and 12-month-old male C57BL/6 mice. The levels of norepinephrine, dopamine, serotonin, and their metabolites were determined in the cerebellum and frontal cortex. In the observed age range, a decrease in locomotion speed, impairment of gait initiation and stability, and long-term memory deficit were revealed. In the cerebral cortex, reduced levels of dopamine and its metabolites and accelerated metabolism of all neurotransmitters under study were found. In the cerebellum, the content of all studied monoamines was elevated, while dopamine metabolism was decelerated. Analysis of correlations between the neurochemical and behavioral parameters showed that the mechanisms of compensation of brain functions during the early aging may be associated with an increase in activity of the monoaminergic systems in the cerebellum.

Distinct effects of AMPAR subunit depletion on spatial memory

Pharmacological studies established a role for AMPARs in the mammalian forebrain in spatial memory performance. Here we generated global GluA1/3 double knockout mice (Gria1/3-/-) and conditional knockouts lacking GluA1 and GluA3 AMPAR subunits specifically from principal cells across the forebrain (Gria1/3ΔFb). In both models, loss of GluA1 and GluA3 resulted in reduced hippocampal GluA2 and increased levels of the NMDAR subunit GluN2A. Electrically-evoked AMPAR-mediated EPSPs were greatly diminished, and there was an absence of tetanus-induced LTP. Gria1/3-/- mice showed premature mortality. Gria1/3ΔFb mice were viable, and their memory performance could be analyzed. In the Morris water maze (MWM), Gria1/3ΔFb mice showed profound long-term memory deficits, in marked contrast to the normal MWM learning previously seen in single Gria1-/- and Gria3-/- knockout mice. Our results suggest a redundancy of function within the pool of available ionotropic glutamate receptors for long-term spatial memory performance.

Protective action of Cecropia pachystachya extract and enriched flavonoid fraction against memory deficits, inflammation and oxidative damage in lipopolysaccharide challenged mice

Ethnopharmacological relevanceCecropia pachystachya (CP) Trécul is a medicinal plant native to South and Central America with several pharmacological properties, such as anti-inflammatory and neuroprotective. Aim of the studyIn this study, we investigated the effect of CP extract (200 mg/kg) and its enriched flavonoid fraction (EFF-CP) (50 and 100 mg/kg) in a model of lipopolysaccharide (LPS)-induced neuroinflammation. Material and methodsCP and EFF-CP were administered intragastrically for 14 days and LPS (250 μg/kg) was administered intraperitoneally from the 8th to the 14th days. LC/DAD/MS analysis showed the presence of isoorientin, orientin, and isovitexin as major compounds. ResultsThe results demonstrated that CP extract and EFF-CP gave protection against LPS-induced short-term and long-term memory deficits. The treatment with CP and/or EFF-CP protected against LPS-induced increases in reactive species, nitrites, total thiol and lipoperoxidation in the cerebral cortex, hippocampus and striatum. Moreover, CP and EFF-CP restored superoxide dismutase and catalase activities that had been reduced by LPS in the cerebral cortex, hippocampus and striatum. TNF-α levels were increased in the cortex, striatum and hippocampus in the LPS group, while CP treatment prevented this change in the cerebral cortex. EFF-CP decreased the levels of this cytokine in all structures analyzed at both doses. ConclusionCP extract and its EFF-CP are important therapeutic targets for the management of neuroinflammation observed in neurodegenerative diseases.

Sex-Specific Alterations in Spatial Memory and Hippocampal AKT-mTOR Signaling in Adult Mice Pre-exposed to Ketamine and/or Psychological Stress During Adolescence

BackgroundKetamine (KET) is administered to manage major depression in adolescent patients. However, the long-term effects of juvenile KET exposure on memory-related tasks have not been thoroughly assessed. We examined whether exposure to KET, psychological stress, or both results in long-lasting alterations in spatial memory in C57BL/6 mice. Furthermore, we evaluated how KET and/or psychological stress history influenced hippocampal protein kinase B–mechanistic target of rapamycin (AKT-mTOR)–related signaling. MethodsOn postnatal day 35, male and female mice underwent vicarious defeat stress (VDS), a form of psychological stress that reduces sociability in both sexes, with or without KET exposure (20 mg/kg/day, postnatal days 35–44). In adulthood (postnatal day 70), mice were assessed for spatial memory performance on a water maze task or euthanized for hippocampal tissue collection. ResultsJuvenile pre-exposure to KET or VDS individually increased the latency (seconds) to locate the escape platform in adult male, but not female, mice. However, juvenile history of concomitant KET and VDS prevented memory impairment. Furthermore, individual KET or VDS pre-exposure, unlike their combined history, decreased hippocampal AKT-mTOR signaling in adult male mice. Conversely, KET pre-exposure alone increased AKT-mTOR in the hippocampus of adult female mice. Lastly, rapamycin-induced decreases of mTOR in naïve adult female mice induced spatial memory retrieval deficits, mimicking adult male mice with a history of exposure to VDS or KET. ConclusionsOur preclinical model shows how KET treatment for the management of adolescent psychological stress–induced sequelae does not impair spatial memory later in life. However, juvenile recreational KET misuse, like psychological stress history, results in long-term spatial memory deficits and hippocampal AKT-mTOR signaling changes in a sex-specific manner.

Protective effect of Baoyuan Jieyu formula on long-term spaceflight composite stress-induced depressive-like behavior and memory deficits through regulation of Ca2+ channel currents

Long-term spaceflight composite stress (LSCS) can cause adverse effects on human systems, especially the central nervous system. This study aimed to identify the underlying mechanisms of the protective effect of Baoyuan Jieyu Formula (BYJYF) on LSCS-induced depressive-like behavior and memory deficits. In this experiment, we simulated the real space station environment for a period of 42 days. Novel object recognition test and forced swimming test were used to assess the memory abilities and depression level of rats as well as test the therapeutic effects of BYJYF treatment. Results showed LSCS could induce depressive-like behavior and damage short-term memory in the behavioral level, and BYJYF could enhance the ability to resist LSCS. Meanwhile, LSCS increased the levels of CRH, ACTH, and CORT and induced HPA axis hyperactivity, which can be relieved by BYJYF. Further, we predicted and verified the potential signaling pathways of BYJYF. Results showed BYJYF may reverse the inhibition of LSCS on Ca2+ channel currents. And we also found that BYJYF may exert its medicinal effects via four main active components including saikosaponin A. Overall, BYJYF exhibited protective effects against LSCS-induced depressive-like behavior and memory deficits, which might be ascribed to the regulation of Ca2+ channel currents and four active components. And it might become a promising candidate medicine for diseases induced by LSCS.

3'UTR of mRNA Encoding CPEB Protein Orb2 Plays an Essential Role in Intracellular Transport in Neurons.

Intracellular trafficking plays a critical role in the functioning of highly polarized cells, such as neurons. Transport of mRNAs, proteins, and other molecules to synaptic terminals maintains contact between neurons and ensures the transmission of nerve impulses. Cytoplasmic polyadenylation element binding (CPEB) proteins play an essential role in long-term memory (LTM) formation by regulating local translation in synapses. Here, we show that the 3'UTR of the Drosophila CPEB gene orb2 is required for targeting the orb2 mRNA and protein to synapses and that this localization is important for LTM formation. When the orb2 3'UTR is deleted, the orb2 mRNAs and proteins fail to localize in synaptic fractions, and pronounced LTM deficits arise. We found that the phenotypic effects of the orb2 3'UTR deletion were rescued by introducing the 3'UTR from the orb, another Drosophila CPEB gene. In contrast, the phenotypic effects of the 3'UTR deletion were not rescued by the 3'UTR from one of the Drosophila α-tubulin genes. Our results show that the orb2 mRNAs must be targeted to the correct locations in neurons and that proper targeting depends upon sequences in the 3'UTR.

Sex-specific effects of Cre expression in Syn1Cre mice

The Cre-loxP system has been used to generate cell-type specific mutations in mice, allowing researchers to investigate the underlying biological mechanisms of disease. However, the Cre-recombinase alone can induce phenotypes that confound comparisons among genotypes if the appropriate Cre control is not included. In this study, we characterised behavioural, morphological and metabolic phenotypes of the pan-neuronal Syn1Cre line. We found that these mice possess intact neuromuscular parameters but have reduced exploratory activity and a male-specific increase in anxiety-like behaviour. Moreover, we observed a male-specific deficit in learning and long-term memory of Syn1Cre mice that could be a result of decreased visual acuity. Furthermore, we found that over-expression of human growth hormone (hGH) from Syn1Cre results in a male-specific reduction in body weight and femur length, potentially through decreased hepatic Igf1 expression. However, metabolic characteristics of Syn1Cre mice such as glucose metabolism, energy expenditure and feeding were unaffected by the presence of Syn1Cre. In conclusion, our data demonstrate that Syn1Cre expression has effects on behavioural and morphological traits. This finding highlights the importance of including the Cre control in all comparisons, while the male-specific effects on some phenotypes highlight the importance of including both sexes.

Long-term Memory Testing in Children With Typical Development and Neurodevelopmental Disorders: Remote Web-based Image Task Feasibility Study.

Neurodevelopmental disorders (NDD) cause individuals to have difficulty in learning facts, procedures, or social skills. NDD has been linked to several genes, and several animal models have been used to identify potential therapeutic candidates based on specific learning paradigms for long-term and associative memory. In individuals with NDD, however, such testing has not been used so far, resulting in a gap in translating preclinical results to clinical practice. We aim to assess if individuals with NDD could be tested for paired association learning and long-term memory deficit, as shown in previous animal models. We developed an image-based paired association task, which can be performed at different time points using remote web-based testing, and evaluated its feasibility in children with typical development (TD), as well as NDD. We included 2 tasks: object recognition as a simpler task and paired association. Learning was tested immediately after training and also the next day for long-term memory. We found that children aged 5-14 years with TD (n=128) and with NDD of different types (n=57) could complete testing using the Memory Game. Children with NDD showed deficits in both recognition and paired association tasks on the first day of learning, in both 5-9-year old (P<.001 and P=.01, respectively) and 10-14-year old groups (P=.001 and P<.001, respectively). The reaction times to stimuli showed no significant difference between individuals with TD or NDD. Children with NDD exhibited a faster 24-hour memory decay for the recognition task than those with TD in the 5-9-year old group. This trend is reversed for the paired association task. Interestingly, we found that children with NDD had their retention for recognition improved and matched with typically developing individuals by 10-14 years of age. The NDD group also showed improved retention deficits in the paired association task at 10-14 years of age compared to the TD group. We showed that web-based learning testing using simple picture association is feasible for children with TD, as well as with NDD. We showed how web-based testing allows us to train children to learn the association between pictures, as shown in immediate test results and those completed 1 day after. This is important as many models for learning deficits in NDD target both short- and long-term memory for therapeutic intervention. We also demonstrated that despite potential confounding factors, such as self-reported diagnosis bias, technical issues, and varied participation, the Memory Game shows significant differences between typically developing children and those with NDD. Future experiments will leverage this potential of web-based testing for larger cohorts and cross-validation with other clinical or preclinical cognitive tasks.

Maternal Supplementation with N-Acetylcysteine Modulates the Microbiota-Gut-Brain Axis in Offspring of the Poly I:C Rat Model of Schizophrenia.

The microbiota-gut-brain axis is a complex interconnected system altered in schizophrenia. The antioxidant N-acetylcysteine (NAC) has been proposed as an adjunctive therapy to antipsychotics in clinical trials, but its role in the microbiota-gut-brain axis has not been sufficiently explored. We aimed to describe the effect of NAC administration during pregnancy on the gut-brain axis in the offspring from the maternal immune stimulation (MIS) animal model of schizophrenia. Pregnant Wistar rats were treated with PolyI:C/Saline. Six groups of animals were studied according to the study factors: phenotype (Saline, MIS) and treatment (no NAC, NAC 7 days, NAC 21 days). Offspring were subjected to the novel object recognition test and were scanned using MRI. Caecum contents were used for metagenomics 16S rRNA sequencing. NAC treatment prevented hippocampal volume reduction and long-term memory deficits in MIS-offspring. In addition, MIS-animals showed lower bacterial richness, which was prevented by NAC. Moreover, NAC7/NAC21 treatments resulted in a reduction of proinflammatory taxons in MIS-animals and an increase in taxa known to produce anti-inflammatory metabolites. Early approaches, like this one, with anti-inflammatory/anti-oxidative compounds, especially in neurodevelopmental disorders with an inflammatory/oxidative basis, may be useful in modulating bacterial microbiota, hippocampal size, as well as hippocampal-based memory impairments.

Ouabain Reverts CUS-Induced Disruption of the HPA Axis and Avoids Long-Term Spatial Memory Deficits

Ouabain (OUA) is a cardiotonic steroid that modulates Na+, K+ -ATPase activity. OUA has been identified as an endogenous substance that is present in human plasma, and it has been shown to be associated with the response to acute stress in both animals and humans. Chronic stress is a major aggravating factor in psychiatric disorders, including depression and anxiety. The present work investigates the effects of the intermittent administration of OUA (1.8 μg/kg) during the chronic unpredictable stress (CUS) protocol in a rat’s central nervous system (CNS). The results suggest that the intermittent OUA treatment reversed CUS-induced HPA axis hyperactivity through a reduction in (i) glucocorticoids levels, (ii) CRH-CRHR1 expression, and by decreasing neuroinflammation with a reduction in iNOS activity, without interfering with the expression of antioxidant enzymes. These changes in both the hypothalamus and hippocampus may reflect in the rapid extinction of aversive memory. The present data demonstrate the ability of OUA to modulate the HPA axis, as well as to revert CUS-induced long-term spatial memory deficits.

Accelerated long-term forgetting of recall and recognition memory in people with epilepsy

PurposePersons with epilepsy (PWE) report memory deficits as one of the most distressing aspects of their disorder. Recently, a long-term memory deficit known as Accelerated Long-Term Forgetting (ALF) has been described in PWE. ALF is characterized by the initial retention of learned information, followed by an accelerated rate of memory decay. However, the rate of ALF varies widely across literature and it is unclear how it impacts different memory retrieval types. The current study aimed to capture the time course of ALF on both free recall and recognition memory using a movie-based task in PWE. MethodsA sample of 30 PWE and 30 healthy comparison (HC) subjects watched a nature documentary and were tested on their recall and recognition of the film’s content immediately after viewing and at delays of 24 hours, 48 hours, and 72 hours. Participants also rated the confidence they had in their recognition memory trial responses. ResultsFor recall, PWE exhibit ALF at 72 hours (β = −19.840, SE = 3.743, z(226) = −5.301, p < 0.001). For recognition, PWE had decreased performance compared to controls at the 24-hour (β = −10.165, SE = 4.174, z(224) = −3.166, p = 0.004), 48-hour (β = −8.113, SE = 3.701, z(224) = −2.195, p = 0.044), and 72-hour (β = −10.794, SE = 3.017, z(224) = −3.295, p = 0.003) delays. The PWE group showed positive correlations (tau = 0.165, p < 0.001) between confidence ratings and accuracy, with higher confidence reflecting successful recognition. PWE were 49% less likely to answer either retrieval type correctly at 72 hours (OR 0.51, 95% CI [0.35, 0.74], p < 0.001). Left hemispheric seizure onset decreased the odds of successful retrieval by 88% (OR 0.12, 95% CI [0.01, 0.42], p = 0.019). ConclusionsThese findings provide evidence of ALF in PWE, with a differential impact on recall and recognition memory. This further supports the call to include ALF assessments in standard memory evaluations in PWE. Additionally, identifying the neural correlates of ALF in the future will be important in developing targeted therapies to alleviate the burden of memory impairment for PWE.

A Comparative Study of the Impact of NO-Related Agents on MK-801- or Scopolamine-Induced Cognitive Impairments in the Morris Water Maze

Learning and memory deficits accompany numerous brain dysfunctions, including schizophrenia and Alzheimer's disease (AD), and many studies point to the role of nitric oxide (NO) in these processes. The present investigations constitute the follow-up of our previous research, in which we investigated the activity of NO releasers and a selective inhibitor of neuronal NO synthase (nNOS) to prevent short-term memory deficits in novel object recognition and T-maze. Here, the ability of the compounds to prevent the induction of long-term memory deficits by MK-801 or scopolamine administration was investigated. The Morris Water Maze test, a reliable and valid test of spatial learning and memory, was used, in which escape latency in the acquisition phase and nine different parameters in the retention phase were measured. A fast NO releaser (spermine NONOate), a slow NO releaser (DETA NONOate), and a nNOS inhibitor, N(ω)-propyl-L-arginine (NPLA), were used. The compounds were administered i.p. at a dose range of 0.05-0.5 mg/kg. All compounds prevented learning deficits in the acquisition phase and reversed reference memory deficits in the retention phase of the scopolamine-treated mice. Spermine NONOate was the least effective. In contrast, the drugs poorly antagonised MK-801-induced deficits, and only the administration of DETA NONOate induced some improvements in the retention trial.

Abstract TMP112: CD133+Exosome Treatment Improves Neuro-cognitive And Cardiac Function After Stroke In Female Adult Type 2 Diabetic Mice

Background: Cardiac complications post-stroke are common, and diabetes exacerbates post-stroke cardiac injury. In this study, we tested whether treatment with exosomes harvested from human umbilical cord blood derived CD133+ cells (CD133+Exo) improve neuro-cognitive and cardiac function in female type 2 diabetes mellitus (T2DM) mice subjected to ischemic stroke. Methods: Female, adult non-DM and T2DM mice were randomized to: 1) Non-DM (n=6), 2) Non-DM-stroke (n=15), 3) T2DM (n=8), 4) T2DM-stroke (n=12) and 5) T2DM-stroke+Exo (n=13). CD133+Exo (20μg/200μl PBS, i.v.) was administered 3 days after stroke. Evaluation of neurological function (mNSS, adhesive removal test), cognitive function (novel object recognition (NOR) test, odor test) and cardiac function (echocardiography) was performed, and mice were sacrificed at 28 days after stroke. Results: Stroke induces severe neurological deficits and significant short-term and long-term memory deficits which were worse in T2DM mice compared to non-DM mice. CD133+Exo treatment in T2DM-stroke mice significantly improves neurological function and cognitive outcome indicated by improved discrimination index in NOR test and odor test compared to control T2DM-stroke mice. T2DM-stroke induces significant cardiac dysfunction indicated by reduced left ventricular ejection fraction (LVEF) and shortening fraction (LVSF) compared to T2DM-control and non-DM-stroke mice. CD133+Exo treatment significantly improves LVEF, LVSF and heart rate and reduces left ventricular dimension compared to T2DM-stroke mice. T2DM-stroke mice exhibit significantly increased cardiomyocyte hypertrophy, cardiac fibrosis and inflammation compared to T2DM-control and non-DM-stroke mice. Treatment of T2DM-stroke with CD133+Exo significantly reduced cardiomyocyte hypertrophy, cardiac fibrosis and inflammation compared to T2DM-stroke mice. T2DM-stroke increases while CD133+Exo treatment reduces expression of serum inflammatory factors such as MMP-2, DKK-1, CRP, VCAM, CXCL5 and Cystatin-C. Conclusions: In T2DM-stroke mice, CD133+Exo treatment significantly improves neurological, cognitive, and cardiac function, and reduces cardiac pathological remodeling compared to T2DM-stroke control mice.

The ribose methylation enzyme FTSJ1 has a conserved role in neuron morphology and learning performance.

FTSJ1 is a conserved human 2'-O-methyltransferase (Nm-MTase) that modifies several tRNAs at position 32 and the wobble position 34 in the anticodon loop. Its loss of function has been linked to X-linked intellectual disability (XLID), and more recently to cancers. However, the molecular mechanisms underlying these pathologies are currently unclear. Here, we report a novel FTSJ1 pathogenic variant from an X-linked intellectual disability patient. Using blood cells derived from this patient and other affected individuals carrying FTSJ1 mutations, we performed an unbiased and comprehensive RiboMethSeq analysis to map the ribose methylation on all human tRNAs and identify novel targets. In addition, we performed a transcriptome analysis in these cells and found that several genes previously associated with intellectual disability and cancers were deregulated. We also found changes in the miRNA population that suggest potential cross-regulation of some miRNAs with these key mRNA targets. Finally, we show that differentiation of FTSJ1-depleted human neural progenitor cells into neurons displays long and thin spine neurites compared with control cells. These defects are also observed in Drosophila and are associated with long-term memory deficits. Altogether, our study adds insight into FTSJ1 pathologies in humans and flies by the identification of novel FTSJ1 targets and the defect in neuron morphology.

Parvalbumin interneuron loss mediates repeated anesthesia-induced memory deficits in mice.

Repeated or prolonged, but not short-term, general anesthesia during the early postnatal period causes long-lasting impairments in memory formation in various species. The mechanisms underlying long-lasting impairment in cognitive function are poorly understood. Here, we show that repeated general anesthesia in postnatal mice induces preferential apoptosis and subsequent loss of parvalbumin-positive inhibitory interneurons in the hippocampus. Each parvalbumin interneuron controls the activity of multiple pyramidal excitatory neurons, thereby regulating neuronal circuits and memory consolidation. Preventing the loss of parvalbumin neurons by deleting a proapoptotic protein, mitochondrial anchored protein ligase (MAPL), selectively in parvalbumin neurons rescued anesthesia-induced deficits in pyramidal cell inhibition and hippocampus-dependent long-term memory. Conversely, partial depletion of parvalbumin neurons in neonates was sufficient to engender long-lasting memory impairment. Thus, loss of parvalbumin interneurons in postnatal mice following repeated general anesthesia critically contributes to memory deficits in adulthood.

Dietary choline metabolite TMAO impairs cognitive function and induces hippocampal synaptic plasticity declining through the mTOR/P70S6K/4EBP1 pathway.

Mild cognitive impairment (MCI) is an intermediate state between "healthy" and "dementia", which affects memory and cognitive function. Timely intervention and treatment of MCI can effectively prevent it from developing into an incurable neurodegenerative disease. Lifestyle factors, such as dietary habits, were highlighted as risk factors for MCI. The effect of a high-choline diet on cognitive function is contentious. In this study, we focus our attention on the choline metabolite trimethylamine-oxide (TMAO), an acknowledged pathogenic molecule of cardiovascular disease (CVD). With recent studies indicating that TMAO also plays a potential role in the central nervous system (CNS), we aim to explore the effect of TMAO on synaptic plasticity in the hippocampus, the basic structure of studying and memory. Using various hippocampal-dependent spatial references or working memory-related behavioral texts, we found that TMAO treatment caused both long-term memory (LTM) and short-term memory (STM) deficits in vivo. Simultaneously, the plasm and whole brain levels of choline and TMAO were measured by employing liquid phase mass spectrometry (LC/MS). Furthermore, the effects of TMAO on the hippocampus were further explored by applying Nissl staining and transmission electron microscopy (TEM). Moreover, the expression of synaptic plasticity-related proteins, including synaptophysin (SYN), postsynaptic density protein95 (PSD95), and N-methyl-aspartate receptor (NMDAR), was examined by western blotting and immunohistochemical (IHC). The results showed that TMAO treatment contributes to neuron loss, synapse ultrastructure alteration, and synaptic plasticity impairments. In mechanism, the mammalian target of rapamycin (mTOR) regulates synaptic function, and the activation of the mTOR signaling pathway was observed in TMAO groups. In conclusion, this study confirmed that the choline metabolite TMAO can induce hippocampal-dependent learning and memory ability impairment with synaptic plasticity deficits by activating the mTOR signaling pathway. The effects of choline metabolites on cognitive function may provide a theoretical basis for establishing the daily reference intakes (DRIs) of choline.

Ishige okamurae Attenuates Neuroinflammation and Cognitive Deficits in Mice Intracerebroventricularly Injected with LPS via Regulating TLR-4/MyD88-Dependent Pathways.

Neuroinflammation is one of the critical causes of neuronal loss and cognitive impairment. We aimed to evaluate the anti-neuroinflammatory properties of Ishige okamuae using mice intracerebroventricularly injected with lipopolysaccharides (LPS) and LPS-treated C6 glioma cells. We found that the short- and long-term memory deficits of LPS-injected mice were improved by oral administration of Ishige okamurae extracts (IOE). LPS-induced neuronal loss, increase in amyloid-β plaque, and expression of COX-2 and iNOS were restored by IOE. In addition, LPS-induced activation of Toll-like receptor-4 (TLR-4) and its downstream molecules, such as MyD88, NFκB, and mitogen-activated protein kinases (MAPKs), were significantly attenuated in the brains of mice fed with IOE. We found that pretreatment of IOE to C6 glioma cells ameliorated LPS-induced expression of TLR-4 and its inflammatory cascades, such as MyD88 expression, reactive oxygen species production, MAPKs phosphorylation, and NFκB phosphorylation with consequent downregulation of COX-2, iNOS, proinflammatory cytokines, and nitric oxide expression. Furthermore, IOE (0.2 µg/mL) was found to have equivalent efficacy with 10 μM of MyD88 inhibitor in preventing LPS-induced inflammatory responses in C6 glioma cells. Taken together, these results strongly suggest that IOE could be developed as a promising anti-neuroinflammatory agent which is able to control the TLR-4/MyD88-dependent signaling pathways.