Memory-related Genes Research Articles

Chronic Sleep Deprivation Altered the Expression of Memory-Related Genes and Caused Cognitive Memory Dysfunction in Mice.

Lack of sleep, whether acute or chronic, is quite common and negatively affects an individual's memory and cognitive function. The question of whether chronic sleep deprivation (CSD) causes cognitive impairment to arise and progress is not well studied. To investigate the effects of CSD on memory and cognition, this study began by establishing a CSD mouse model. Behavioral experiments on animals revealed that CSD induced cognitive behavioral abnormalities reminiscent of Alzheimer's disease. Western blot experiments further demonstrated a considerable increase in amyloid-β (Aβ) expression in the mouse brain following CSD. Meanwhile, the hub gene Prkcg was searched for in the cerebellum using RNA-seq and bioinformatics analysis. PKCγ (Prkcg) expression was significantly reduced, as demonstrated by RT-qPCR and Western blot validations. Additionally, CSD was associated with downregulated CREB expression, decreased expression of the endothelin-converting enzyme (ECE1), and increased phosphorylation of ERK1/2 downstream of PKCγ. These findings suggested that CSD down-regulated PKCγ expression, decreased ECE1 expression, impaired Aβ degradation, and affected the PKCγ/ERK/CREB pathway and the synthesis of memory-related proteins. Overall, this study highlighted how CSD modulated PKCγ-related metabolism, impacting Aβ clearance and the production of memory-related proteins. Such insights are crucial for understanding and preventing sporadic Alzheimer's disease (sAD) associated with CSD.

Theoretical framework for the difference of two negative binomial distributions and its application in comparative analysis of sequencing data.

High-throughput sequencing (HTS) technologies have been instrumental in investigating biological questions at the bulk and single-cell levels. Comparative analysis of two HTS data sets often relies on testing the statistical significance for the difference of two negative binomial distributions (DOTNB). Although negative binomial distributions are well studied, the theoretical results for DOTNB remain largely unexplored. Here, we derive basic analytical results for DOTNB and examine its asymptotic properties. As a state-of-the-art application of DOTNB, we introduce DEGage, a computational method for detecting differentially expressed genes (DEGs) in scRNA-seq data. DEGage calculates the mean of the sample-wise differences of gene expression levels as the test statistic and determines significant differential expression by computing the P-value with DOTNB. Extensive validation using simulated and real scRNA-seq data sets demonstrates that DEGage outperforms five popular DEG analysis tools: DEGseq2, DEsingle, edgeR, Monocle3, and scDD. DEGage is robust against high dropout levels and exhibits superior sensitivity when applied to balanced and imbalanced data sets, even with small sample sizes. We utilize DEGage to analyze prostate cancer scRNA-seq data sets and identify marker genes for 17 cell types. Furthermore, we apply DEGage to scRNA-seq data sets of mouse neurons with and without fear memory and reveal eight potential memory-related genes overlooked in previous analyses. The theoretical results and supporting software for DOTNB can be widely applied to comparative analyses of dispersed count data in HTS and broad research questions.

Blockade of histone deacetylase activity affects transcription and splicing of neuronal and glial genes

The study of the molecular mechanisms underlying plastic processes in the nervous system is of great interest in modern neuroscience. It is important to understand that epigenetic modifications, which are crucial for the development and cellular differentiation, can also be involved in plastic processes in the adult nervous system. In our early work, we provided evidence that the expression of important memory-related genes, such as Prkcz and Prkci, can be regulated epigenetically [1]. In the current study, we extended the previous work to the systemic level by applying the RNA sequencing approach to evaluate global changes in the expression patterns of various genes during the induction of epigenetic rearrangements. Rat cortical neuron cultures were incubated with one of the nonselective histone deacetylase inhibitors (trichostatin A, TSA; sodium butyrate, NaB) to change the level of epigenetic regulation. Next, the total RNA was extracted and subjected to RNA-Seq libraries preparation and subsequent NGS-sequencing. Bioinformatics analysis of transcriptomic data revealed substantial overlapping of differentially expressed genes (DEGs) in NaB-treated and TSA-treated groups, indicating that different histone deacetylase (HDAC) inhibitors induce transcriptional changes in primary neuron cultures through common regulatory pathways irrespective of chemical structure of applied inhibitor. We found that histone deacetylase blockade is accompanied by a transition from proliferative processes to cellular differentiation. Gene Ontology (GO) analysis of DEGs datasets revealed that the upregulated genes were engaged in cell differentiation and specialization, tissue and embryonic morphogenesis, and the development of various peripheral tissues and organs. On the contrary, genes that reduce the expression under induction of epigenetic rearrangements were involved in biological processes associated with cell proliferation and, most interestingly, the specialization of various brain cells (neurons, astrocytes, oligodendrocytes). It was shown that the expression of a number of glial markers typical for astrocytes and oligodendrocytes was significantly reduced after application of HDAC inhibitors, which was also confirmed by quantitative PCR using specific primer pairs on selected target genes. During the data analysis, we also found a significant decrease in the expression of various neuronal markers associated with the cytoskeleton, the organization of pre- and postsynaptic endings, synaptic transmission. It is known that fine-tuning of various processes in the central nervous system is due to the production of different isoforms of proteins from the same gene due to the process of alternative splicing of the resulting mRNA. According to the literature, epigenetic rearrangements create a certain environment for the regulation of alternative splicing of different genes [2, 3]. It is shown that production of alternative isoforms can play an important role in various plastic processes [4, 5]. Therefore, using IsoformSwitchAnalyzeR and DEXSeq packages we analyzed the possibility of alternative splicing during the induction of epigenetic rearrangements in rat cortical neuron cultures by evaluating the abundance of various transcripts based on exon usage. We found that some glial genes and a large number of neuronal genes, especially those associated with postsynaptic organization and cell communication, were alternatively spliced after application of histone deacetylase inhibitors. Inhibition of HDAC activity in cortical neuron cultures mainly affected the choice of alternative transcription starts (ATSS) and terminators (ATTS), and to a lesser extent alternative splicing of exons. Obtained results were selectively confirmed by the quantitative PCR using specific pairs of primers for individual exons of different transcript isoforms. Thus, within this study, it was found that histone deacetylases play an important role in the specialization of various brain cells, and the suppression of their activity affects the expression and alternative splicing of various glial and neuronal marker genes. We do not exclude that global transcriptome changes caused by alternative splicing will lead to qualitative rearrangements of the neuron network, and this is the direction of future research.

Pyrus pashia fruit extract and its major phytometabolite chrysin prevent hippocampal apoptosis and memory impairment in PTZ-kindled mice

ABSTRACT Objectives Epilepsy is a chronic neurological condition with recurrent seizures. One-third of epilepsy patients experience unacceptable side effects from antiepileptic drugs. Pyrus pashia is a deciduous tree from southern Asia. Ethnomedicinally, Malakand tribes use its fruits for epilepsy treatment. Our prior research demonstrated the anticonvulsive properties of ethanolic extract of Pyrus pashia (EPP) and its bioactive compound chrysin in acute seizure tests. This study aims to investigate the impact of EPP and chrysin on cognitive impairment in a PTZ-induced kindling mice model of epilepsy. Methods Swiss albino male mice were equally divided into four groups. The first group received 0.5% carboxy methyl cellulose dissolved in normal saline while the other three groups were pre-treated with Diazepam (DZP) (1 mg/kg, i.p.), EPP (200 mg/kg, p.o.) and chrysin (5 mg/kg, p.o.). After 30 min, all groups were administered PTZ (35 mg/kg, i.p.) and evaluated for seizure severity, cognitive function, and neuronal apoptosis. Western blot analysis was conducted to analyze the expressions of apoptosis biomarkers and memory-related genes, including cAMP response element-binding protein (CREB) and Brain Derived Neurotrophic Factor (BDNF). Results The therapeutic effects of EPP and Chrysin were comparable to DZP in terms of reducing seizure severity, but unlike DZP, they prevented PTZ-induced memory impairment in experimental animals. Additionally, they increased the levels of BDNF and CREB while reducing apoptotic biomarkers in the hippocampus of experimental animals. Conclusions Based on the leads offered by this study EPP and its major bioactive constituent, could be developed as the treatment option for epilepsy.

THU494 VHL Protein Deficiency Alters The Immune Microenvironment Of Pancreatic Neuroendocrine Neoplasms

Abstract Disclosure: A. Chmelnik: None. A. Telerman: None. A. Tirosh: None. Introduction - Pancreatic neuroendocrine tumors (PanNENs) may develop sporadically or as part of an inherited disease, such as von Hippel-Lindau (VHL). VHL disease is caused by a germline pathogenic variant in the VHL gene encoding VHL protein (pVHL). Hypoxia inducible factor (HIF) is responsible for cellular oxygen supply. Its degradation is mediated by pVHL via ubiquitination in normoxic states. In pVHL-deficient state leads to HIF overexpression and pseudohypoxia. Several studies suggested immunomodulatory role for HIF in kidney cancer. Aims- To assess the impact of pseudohypoxia on PanNEN immune tumor microenvironment (iTME). Methods- A total of 16 vPanNEN and 23 sPanNEN were processed. Whole genome DNA methylation was performed by Illumine Infinium EPIC Array and analyzed using ChAMP on RStudio. Immune cells composition was compared using methylation-based deconvolution algorithms (MethylResolver, Robust Partial Correlations, Constrained Projection and Cibersort), and gene set enrichment analysis identified pathways affected in each group based on promoter methylation analysis. Results- Unsupervised hierarchical analysis of immune-related gene promoter methylation demonstrated separation of vPanNEN vs. sPanNEN. In GSEA analysis methylation was altered in immune memory-related genes in vPanNEN, and in T cells receptors-related genes in sPanNEN. Deconvolution algorithms revealed a lower fraction of CD4 and NK cells (p<0.05) and a lower PD-L1 expression in vPanNENs (p=0.037). Conclusion- Pseudohypoxic vPanNEN have distinct iTME than sPanNEN, in immune cells composition and PD-L1 expression. Presentation: Thursday, June 15, 2023

Thiacloprid impairs honeybee worker learning and memory with inducing neuronal apoptosis and downregulating memory-related genes

Neonicotinoids are among the most widely used insecticides in the world and are recognized as a potential cause of pollinator decline. Previous studies have demonstrated that the neonicotinoid thiacloprid has adverse effects on foraging and memory behaviors. However, there is no direct evidence linking thiacloprid-induced neuronal cell damage in the brains of honeybees to learning and memory dysfunction. Adult honeybee (Apis mellifera L.) workers were chronically exposed to sub-lethal concentrations of thiacloprid. We discovered that thiacloprid negatively affected their survival, food consumption, and body weight. In addition, sucrose sensitivity and memory performance were impaired. We evaluated the apoptosis of honeybee brain cells using TUNEL (Terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP-biotin nick-end labeling) and Caspase-3 assays, which revealed that thiacloprid increases the dose-dependent apoptosis of neurons in the mushroom bodies (MB) and antennal lobes (AL). We also determined the abnormal transcripts of multiple genes, including vitellogenin (Vg), immune system genes (apidaecin and catalase), and memory-associated genes (pka, creb, Nmdar1, Dop2, Oa1, Oa-2R, and Oa-3R). These results indicate that exposure to sublethal concentrations of thiacloprid cause abnormal expression of memory-related genes and apoptosis of brain cells in the AL and MB, which may contribute to the memory disorder induced by thiacloprid exposure.

Effect of induced diabetes on morphometric indexes of the cerebellar cortex and gene expression in C57BL mice.

Diabetes is a metabolic disorder that affects the development of the central nervous system and plays an important role in learning and memory. Diabetes increases the reactive oxygen species (ROS) level in cells and changes the expression of several genes, including SYP, BDNF, PAX7, and SYNCAM1, through the FOXO transcription factor. This study was done to assess the effect of diabetes on morphometric indexes of the cerebellar cortex and gene expression in mice. Diabetes was induced in twelve adult, male C57BL mice using an injection of streptozotocin. After two months, the mice were dissected, and the cerebellum was stored for further analysis. For the morphometric analysis, tissue sections were stained with cresyl violet and examined with a light microscope. For gene expression analysis, the RNA was extracted, and cDNA was synthesized. The mRNA levels of SYP, BDNF, PAX7, and SYNCAM1 genes were measured by the real-time PCR method. The thickness of the molecular layer and Purkinje layer, and the number of Purkinje and granular cells in the diabetic group were significantly reduced compared to controls P<0.0 1). The area, perimeter, and diameter of Purkinje cells in the diabetic group were significantly reduced compared to controls P<0.0 1). The expression of PAX7, SYP, and BDNF genes of the diabetic group was significantly reduced. However, SYNCAM1 expression in the cerebellum of the diabetic group was significantly increased compared to controls (P<0.05). Induced diabetes in mice can decrease the expression of memory-related genes in the cerebellum. Also, these genes affect the morphology and thickness of the cerebellum.

Astrocyte L-Lactate Signaling in the ACC Regulates Visceral Pain Aversive Memory in Rats.

Pain involves both sensory and affective elements. An aspect of the affective dimension of pain is its sustained unpleasantness, characterized by emotional feelings. Pain results from interactions between memory, attentional, and affective brain circuitry, and it has attracted enormous interest in pain research. However, the brain targets and signaling mechanism involved in pain remain elusive. Using a conditioned place avoidance (CPA) paradigm, we show that colorectal distention (CRD magnitude ≤ 35 mmHg, a subthreshold for pain) paired with a distinct environment can cause significant aversion to a location associated with pain-related insults in rats. We show a substantial increase in the L-lactate concentration in the anterior cingulate cortex (ACC) following CPA training. Local exogenous infusion of lactate into the ACC enhances aversive memory and induces the expression of the memory-related plasticity genes pCREB, CREB, and Erk1/2. The pharmacological experiments revealed that the glycogen phosphorylation inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) impairs memory consolidation. Furthermore, short-term Gi pathway activation of ACC astrocytes before CPA training significantly decreases the lactate level and suppresses pain-related aversive learning. The effects were reversed by the local infusion of lactate into the ACC. Our study demonstrates that lactate is released from astrocytes in vivo following visceral pain-related aversive learning and memory retrieval and induces the expression of the plasticity-related immediate early genes CREB, pCREB, and Erk1/2 in the ACC. Chronic visceral pain is an important factor in the pathophysiology of irritable bowel syndrome (IBS). The current study provides evidence that astrocytic activity in the ACC is required for visceral pain-related aversive learning and memory.

Comparison between relative and absolute quantitative real-time PCR applied to single-cell analyses: Transcriptional levels in a key neuron for long-term memory in the pond snail.

Quantitative real-time PCR (qPCR) is a powerful method for measuring nucleic acid levels and quantifying mRNA levels, even in single cells. In the present study, we compared the results of single-cell qPCR obtained by different quantification methods (relative and absolute) and different reverse transcription methods. In the experiments, we focused on the cerebral giant cell (CGC), a key neuron required for the acquisition of conditioned taste aversion in the pond snail Lymnaea stagnalis, and examined changes in the mRNA levels of 3 memory-related genes, cAMP-response element binding proteins (LymCREB1 and LymCREB2) and CREB-binding protein (LymCBP), during memory formation. The results obtained by relative quantification showed similar patterns for the 3 genes. For absolute quantification, reverse transcription was performed using 2 different methods: a mixture of oligo d(T) primers and random primers (RT method 1); and gene-specific primers (RT method 2). These methods yielded different results and did not show consistent changes related to conditioning. The mRNA levels in the samples prepared by RT method 2 were up to 3.3 times higher than those in samples prepared by RT method 1. These results suggest that for qPCR of single neurons, the efficacy and validity do not differ between relative and absolute quantification methods, but the reverse transcription step critically influences the results of mRNA quantification.

The Enrichment of T-Cell Proliferation and Memory Gene Signatures of CD79A/CD40 Co-Stimulatory Domain Enhances CD19CAR-T Cell Efficacy

Introduction: CD28 or 4-1BB co-stimulated CD19 chimeric antigen receptor (CAR) T-cell has demonstrated remarkable outcomes in B-cell malignancies. Recently, we reported that a novel CD19CAR-T cell incorporated B-cell co-stimulatory molecules; CD79A/CD40 (CD19.79a.40z), exhibited superior anti-tumor activity in B-cell lymphoma model compared to CD28 or 4-1BB co-stimulated CAR-T cell. Despite these promising results, the molecular signatures of this novel CAR-T cell and its effects on the overall cellular state are not well understood. This study assessed mRNA expression using RNA-sequencing (RNA-seq) to interrogate the intrinsic transcriptional gene underlying CD19.79a.40z CAR-T cell response and identify the differentially expressed genes (DEGs) compared to CD19.28z or CD19.BBz CAR-T cell upon CD19-specific antigen exposure. Methods: We generated three CD19CAR structures contained different co-stimulatory domain (CD19.28z, CD19.BBz, CD19.79a.40z).The CAR genes were transfected into retroviral packaging cells and transduced into human CD3+ cells. We first screened the functions of each CAR-T cell structure in in vitro assay including cytotoxicity assay, T-cell proliferation assay, and T-cell phenotype assay to confirm whether each CAR-T cell structure contained proper functions. Total CAR-T 3 - 6 x 106 cells were harvested and extracted for RNA at post-stimulation with the target cell line on day seven. Nine samples were RNA-seq using Illumina Hiseq 4000. The short sequence reads were mapped to reference genome from GENCODE (GRCh38) and the expression count matrix was then computed using HTSeq. EdgeR program was used to perform DEGs analysis between three groups: CD19.79a.40z vs. CD19.28z, CD19.79a.40z vs. CD19.BBz and CD19.28z vs. CD19.BBz. The DEGs were selected at FDR <0.05 and fold change ≥ 1.5-fold difference. To identify the regulation of functionally enriched pathways, we performed both ranked gene list analyses on the whole gene expression level using the gene set enrichment analysis (GSEA) software from the Broad Institute and DEGs list separately analyzed for up- and down-regulated genes using g:Profiler. Results: A total of 374 DEGs (232 up-regulated and 142 down-regulated DEGs) and one up-regulated DEG were identified in CD19.79a.40z vs. CD19.28z CAR-T cell groups and CD19.79a.40z vs. CD19.BBz CAR-T cell groups respectively. We found 104 DEGs in which 32 DEGs were up-regulated and 72 DEGs were down-regulated in CD19.28z CAR-T cell compared to CD19.BBz CAR-T cell.Functional enrichment analysis using g;Profiler illustrated that CD19.79a.40z CAR-T cells consisted of down-regulated genes mediating apoptosis and exhaustion while up-regulated genes correlated with T-cell activation, proliferation, positive regulation of interferon production, and NF-κB pathway. Compared to either CD19.28z or CD19.BBz CAR-T cells, CD19.79a.40z CAR-T cells strongly enriched in genes associated with T-cell proliferation at the transcription level supported by the expression of BATF3, IL2, ZP3, TFRC,IRF1 and CD70. In addition, CD19.79a.40z CAR-T cell contained many down-regulated apoptosis-related genes, including ID3, PDCD1 and EOMES (Figure). GSEA revealed that CD19.79a.40z CAR-T cells enriched in both glycolysis and fatty acid metabolism, which are the underlying metabolic pathway closely linked to T-cell activation and proliferation. Regarding T-cell differentiation, CD19.79a.40z CAR-T cells were particularly enriched in naïve and memory-related genes compared to CD19.BBz CAR-T cell. Conclusions: This study provides a comprehensive insight into the understanding of gene expression and its related pathways that potentiates the superior anti-tumor functions by CD19CAR-T cell incorporated B-cell co-stimulatory domain. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Lactate-mediated neural plasticity genes emerged during the evolution of memory systems

The ability to record experiences and learning is present to different degrees in several species; however, the complexity and diversity of memory processes are cognitive function features that differentiate humans from other species. Lactate has recently been discovered to act as a signaling molecule for neuronal plasticity linked to long-term memory. Because lactate is not only an energy substrate for neurons but also a signaling molecule for plasticity (Magistretti and Allaman in Nat Rev Neurosci 19:235–249, 2018. https://doi.org/10.1038/nrn.2018.19), it is of particular interest to understand how and when memory-related genes and lactate-mediated neural plasticity (LMNP) genes emerged and evolved in humans. To understand the evolutionary origin and processes of memory and LMNP genes, we first collected information on genes related to memory and LMNP from the literature and then conducted a comparative analysis of these genes. We found that the memory and LMNP genes have different origins, suggesting that these genes may have become established gradually in evolutionarily and functional terms and not at the same time. We also found that memory and LMNP systems have a similar evolutionary history, having been formed with the gradual participation of newly emerging genes throughout their evolution. We propose that the function of LMNP as a signaling process may be evolutionarily associated with memory systems through an unidentified system that is linked by 13 common genes between memory and LMNP gene sets. This study provides evolutionary insight into the possible relationship between memory and the LMNP systems that deepens our understanding of the evolution of memory systems.

The negative effect of flumethrin stress on honey bee (Apis mellifera) worker from larvae to adults

Flumethrin is a highly effective acaricide, but its lipophilic characteristic has some negative effects, such as accumulation in bee hives and bee products. However, studies on the survival stress of honey bees subsequent to chronic flumethrin exposure are limited. To answer this question, a study was carried out on the stress to honey bee (Apis mellifera) workers from larvae to adults by chronic exposure to sublethal concentrations of flumethrin. Three flumethrin treatment groups (1, 0.1, 0.01 mg/L) and one control group (with no added flumethrin) were established and divided the worker larvae into four groups. Then, starting with 2-day-old larvae, larvae and subsequent emerged worker bees of the four groups were orally fed with the corresponding concentrations of flumethrin until all the adult worker bees died, respectively. When the concentration was at 0.01 mg/L of flumethrin, the lifespan of adult worker bees decreased, and a down-regulation of detoxification-related genes (CYP450,GSTS) was induced in 1-day-old pupae. When it is at 0.1 mg/L flumethrin, the lifespan of adult worker bees was again shortened, and down-regulation of memory-related genes (GluRA1, Nmdar1, Tyr1) in 1-day-old pupae and gene Tyr1 in 1-day-old worker bees, detoxification-related genes (CYP450,GSTS) in 1-day-old pupae, and immunity genes (Defensin1, Hymenoptaecin) in 7-day-old worker bees were observed. When the concentration is at 1 mg/L flumethrin, lighter birth weight of newly emerged honeybee was found and deficiencies in olfactory learning and memory were observed in 7-day-old worker bees. Memory-related genes (GluRA1, Nmdar1, Tyr1) were down-regulated in 1-day-old pupae and genes (Nmdar1,Tyr1)in 1-day-old worker bees, as were detoxification-related genes (CYP450,GSTS) in 1-day-old pupae and gene CPY450 in 7-day-old worker bees, and immune genes (Defensin1, Hymenoptaecin) in 7-day-old worker bees. There was no significant difference in pupal weight, capping rate, emergence rate, expression of immune-related genes of 1-day-old pupae, expression of immune-related genes and detoxification-related genes of 1-day-old worker bees, expression of memory-related genes and detoxification-related gene GSTS of 7-day-old worker bees. These data provide an ominous warning about the unintended consequences on apiaries, and underscore the need for careful control of flumethrin residues in bee hives.

Wolbachia-Driven Memory Loss in a Parasitic Wasp Increases Superparasitism to Enhance Horizontal Transmission.

Horizontal transmission of the endosymbiont, Wolbachia, may occur during superparasitism when parasitoid females deposit a second clutch of eggs on a host. Wolbachia may increase the superparasitism tendency of Trichogramma wasps by depriving their memory. To test this hypothesis, we investigated the effects of conditioning experience and memory inhibitors (actinomycin D [ACD] and anisomycin [ANI]) on memory capacity, and expressions of memory-related genes (CREB1 and PKA), and superparasitism frequency of Wolbachia-infected (TDW) and uninfected (TD) lines of Trichogramma dendrolimi after conditioning with lemon or peppermint odor. We detected the presence of Wolbachia in eggs, larvae, pre-pupae, pupae, and adults of Trichogramma by using fluorescence in situ hybridization. The results showed that TDW females had a more reduced memory capacity than TD females after conditioning. Compared with TD females, TDW females showed a higher proportion of superparasitism and a downregulation of CREB1 and PKA genes after conditioning. TD females fed ACD or ANI showed a higher tendency for superparasitism and a downregulation of CREB1 and PKA, along with memory loss after conditioning than TD females fed honey solution only. The presence of Wolbachia was detected in the anterior region of the larva, pre-pupa, and pupa, but was not found in the head of the adult. The results provide evidence of host behavioral manipulation of Wolbachia by depriving memory of host Trichogramma wasps based on Poulin' s criteria. These host behavioral changes led by Wolbachia may be caused by the virulence of Wolbachia on the nervous system of the host. IMPORTANCE The endosymbiotic bacteria, Wolbachia, live widely within cells of arthropods. Wolbachia are not only transmitted vertically from host mother to offspring, but are also transmitted horizontally among host individuals. Horizontal transmission is expected to occur during superparasitism when host parasitoid females deposit a clutch of eggs on a host previously parasitized by the same parasitoid species. Thus, a question is proposed regarding whether superparasitism behavior is a behavior modification induced by the symbiont to favor symbiont transmission. This study highlights behavioral mechanisms of Wolbachia-induced superparasitism in Trichogramma wasps and the manipulation of symbionts on host parasitoids.

Glucose derived carbon nanosphere (CSP) conjugated TTK21, an activator of the histone acetyltransferases CBP/p300, ameliorates amyloid-beta 1-42 induced deficits in plasticity and associativity in hippocampal CA1 pyramidal neurons.

The master epigenetic regulator lysine acetyltransferase (KAT) p300/CBP plays a pivotal role in neuroplasticity and cognitive functions. Recent evidence has shown that in several neurodegenerative diseases, including Alzheimer's disease (AD), the expression level and function of p300/CBP are severely compromised, leading to altered gene expression causing pathological conditions. Here, we show that p300/CBP activation by a small‐molecule TTK21, conjugated to carbon nanosphere (CSP) ameliorates Aβ‐impaired long‐term potentiation (LTP) induced by high‐frequency stimulation, theta burst stimulation, and synaptic tagging/capture (STC). This functional rescue was correlated with CSP‐TTK21‐induced changes in transcription and translation. Mechanistically, we observed that the expression of a large number of synaptic plasticity‐ and memory‐related genes was rescued, presumably by the restoration of p300/CBP mediated acetylation. Collectively, these results suggest that small‐molecule activators of p300/CBP could be a potential therapeutic molecule for neurodegenerative diseases like AD.

Targeting acetyl-CoA metabolism attenuates the formation of fear memories through reduced activity-dependent histone acetylation

Histone acetylation is a key component in the consolidation of long-term fear memories. Histone acetylation is fueled by acetyl-coenzyme A (acetyl-CoA), and recently, nuclear-localized metabolic enzymes that produce this metabolite have emerged as direct and local regulators of chromatin. In particular, acetyl-CoA synthetase 2 (ACSS2) mediates histone acetylation in the mouse hippocampus. However, whether ACSS2 regulates long-term fear memory remains to be determined. Here, we show that Acss2 knockout is well tolerated in mice, yet the Acss2-null mouse exhibits reduced acquisition of long-term fear memory. Loss of Acss2 leads to reductions in both histone acetylation and expression of critical learning and memory-related genes in the dorsal hippocampus, specifically following fear conditioning. Furthermore, systemic administration of blood-brain barrier-permeable Acss2 inhibitors during the consolidation window reduces fear-memory formation in mice and rats and reduces anxiety in a predator-scent stress paradigm. Our findings suggest that nuclear acetyl-CoA metabolism via ACSS2 plays a critical, previously unappreciated, role in the formation of fear memories.

Simvastatin rescues memory and granule cell maturation through the Wnt/\u03b2-catenin signaling pathway in a mouse model of Alzheimer\u2019s disease

We previously showed that simvastatin (SV) restored memory in a mouse model of Alzheimer disease (AD) concomitantly with normalization in protein levels of memory-related immediate early genes in hippocampal CA1 neurons. Here, we investigated age-related changes in the hippocampal memory pathway, and whether the beneficial effects of SV could be related to enhanced neurogenesis and signaling in the Wnt/β-catenin pathway. APP mice and wild-type (WT) littermate controls showed comparable number of proliferating (Ki67-positive nuclei) and immature (doublecortin (DCX)-positive) granule cells in the dentate gyrus until 3 months of age. At 4 months, Ki67 or DCX positive cells decreased sharply and remained less numerous until the endpoint (6 months) in both SV-treated and untreated APP mice. In 6 month-old APP mice, dendritic extensions of DCX immature neurons in the molecular layer were shorter, a deficit fully normalized by SV. Similarly, whereas mature granule cells (calbindin-immunopositive) were decreased in APP mice and not restored by SV, their dendritic arborizations were normalized to control levels by SV treatment. SV increased Prox1 protein levels (↑67.7%, p < 0.01), a Wnt/β-catenin signaling target, while significantly decreasing (↓61.2%, p < 0.05) the upregulated levels of the β-catenin-dependent Wnt pathway inhibitor DKK1 seen in APP mice. In APP mice, SV benefits were recapitulated by treatment with the Wnt/β-catenin specific agonist WAY-262611, whereas they were fully abolished in mice that received the Wnt/β-catenin pathway inhibitor XAV939 during the last month of SV treatment. Our results indicate that activation of the Wnt-β-catenin pathway through downregulation of DKK1 underlies SV neuronal and cognitive benefits.

Treatment-Free Intervals during CD19xCD3 BiTE ® Construct-Mediated T-Cell Stimulation Induce Functional Reinvigoration and Transcriptional Reprogramming of Exhausted T Cells

Treatment-Free Intervals during CD19xCD3 BiTE ® Construct-Mediated T-Cell Stimulation Induce Functional Reinvigoration and Transcriptional Reprogramming of Exhausted T Cells

Deformed wing virus infection affects the neurological function of Apis mellifera by altering extracellular adenosine signaling

Deformed wing virus (DWV) infection is believed to be closely associated with colony losses of honeybee (Apis mellifera) due to reduced learning and memory of infected bees. The adenosine (Ado) pathway is important for maintaining immunity and memory function in animals, and it enhances antivirus responses by regulating carbohydrate metabolism in insects. Nevertheless, its effect on the memory of invertebrates is not yet clear. This study investigated how the Ado pathway regulates energy metabolism and memory in honeybees following DWV infection. Decreased Ado receptor (Ado-R) expression in the brain of infected bees resulted in a carbohydrate imbalance as well as impairments of glutamate-glutamine (Glu-Gln) cycle and long-term memory. Dietary supplementation with Ado not only increased the brain energy metabolism but also rescued long-term memory loss by upregulating the expression of memory-related genes. The present study demonstrated the regulation of the Ado pathway upon DWV infection and provides insights into the mechanisms underlying energy regulation and the neurological function of honeybees.

Memory regulation in feeding habit transformation to dead prey fish of Chinese perch (Siniperca chuatsi).

Memory drove a critical process of feeding habit transformation in Chinese perch when they re-trained to eat dead prey fish. To investigate the regulatory mechanism of cAMP-response element-binding protein (CREB) signaling pathway on the memory of Chinese perch during feeding habit transformation, the phosphorylation levels of upstream signal proteins of CREB between the control group (trained once) and the experimental group (trained twice) were measured. The results illustrated that the re-training was correlated to phosphorylation of extracellular regulated protein kinase (ERK1/2) and calcium/calmodulin-dependent protein kinase II (CaMKII), and dephosphorylation of protein kinase A (PKA) of Chinese perch. Inhibition of ERK1/2-CREB pathway decreased the mRNA levels of memory-related genes ((fos-related antigen 2 (fra2), CCAAT enhancer-binding protein delta (c/ebpb), immediate-early gene zif268 (zif268), proto-oncogenes c-fos (c-fox) and synaptotagmin-IV (sytIV)) and mRNA levels of appetite-related genes (agouti-related peptide (agrp) and ghrelin), and activation of PP1-CREB pathway increased the phosphorylated levels of CREB, the mRNA levels of memory-related genes (fra2, c/ebpb, zif268, and c-fox), and the mRNA levels of appetite-related genes (pro-opiomelanocortin (pomc) and leptin) in primary brain cells of Chinese perch. The memory in Chinese perch feeding habit transformation was associated with the ERK1/2-CREB and PP1-CREB pathways, which could regulate the transcription of memory-related genes and appetite-related genes.

RETRACTED ARTICLE: Using a new HSPC senescence model in vitro to explore the mechanism of cellular memory in aging HSPCs

BackgroundAge-associated changes attenuate human blood system functionality through the aging of hematopoietic stem and progenitor cells (HSPCs), manifested in human populations an increase in myeloproliferative disease and even leukemia; therefore, study on HSPC senescence bears great significance to treat hematopoietic-associated disease. Furthermore, the mechanism of HSPC aging is lacking, especially the cellular memory mechanism. Here, we not only reported a new HSPC senescence model in vitro, but also propose and verify the cellular memory mechanism of HSPC aging of the Polycomb/Trithorax system.MethodsHSPCs (Lin−c-kit+ cells) were isolated and purified by magnetic cell sorting (MACS). The proportions and cell cycle distribution of cells were determined by flow cytometry; senescence-related β-galactosidase assay, transmission electron microscope (TEM), and colony-forming unit (CFU)-mix assay were detected for identification of the old HSPC model. Proteomic tests and RNA-seq were applied to analyze differential pathways and genes in the model cells. qPCR, Western blot (WB), and chromatin immunoprecipitation PCR (CHIP-PCR) were used to detect the gene expression of cell memory-related proteins. Knockdown of cell memory-related key genes was performed with shRNA interference.ResultsIn the model old HSPCs, β-gal activity, cell cycle, colony-forming ability, aging-related cell morphology, and metabolic pathway were significantly changed compared to the young HSPCs. Furthermore, we found the model HSPCs have more obvious aging manifestations than those of natural mice, and IL3 is the major factor contributing to HSPC aging in the model. We also observed dramatic changes in the expression level of PRC/TrxG complexes. After further exploring the downstream molecules of PRC/TrxG complexes, we found that Uhrf1 and TopII played critical roles in HSPC aging based on the HSPC senescence model.ConclusionsThese findings proposed a new HSPC senescence model in vitro which we forecasted could be used to preliminary screen the drugs of the HSPC aging-related hemopathy and suggested cellular memory mechanism of HSPC aging.