Propofol exposure during early gestation impairs learning and memory in rat offspring by inhibiting the acetylation of histone

Propofol is widely used in clinical practice, including non‐obstetric surgery in pregnant women. Previously, we found that propofol anaesthesia in maternal rats during the third trimester (E18) caused learning and memory impairment to the offspring rats, but how about the exposure during early pregnancy and the underlying mechanisms? Histone acetylation plays an important role in synaptic plasticity. In this study, propofol was administered to the pregnant rats in the early pregnancy (E7). The learning and memory function of the offspring were tested by Morris water maze (MWM) test on post‐natal day 30. Two hours before each MWM trial, histone deacetylase 2 (HDAC2) inhibitor, suberoylanilide hydroxamic acid (SAHA), Senegenin (SEN, traditional Chinese medicine), hippyragranin (HGN) antisense oligonucleotide (HGNA) or vehicle were given to the offspring. The protein levels of HDAC2, acetylated histone 3 (H3) and 4 (H4), cyclic adenosine monophosphate (cAMP) response element‐binding protein (CREB), N‐methyl‐D‐aspartate receptor (NMDAR) 2 subunit B (NR2B), HGN and synaptophysin in offspring's hippocampus were determined by Western blot or immunofluorescence test. It was discovered that infusion with propofol in maternal rats on E7 leads to impairment of learning and memory in offspring, increased the protein levels of HDAC2 and HGN, decreased the levels of acetylated H3 and H4 and phosphorylated CREB, NR2B and synaptophysin. HDAC2 inhibitor SAHA, Senegenin or HGN antisense oligonucleotide reversed all the changes. Thus, present results indicate exposure to propofol during the early gestation impairs offspring's learning and memory via inhibiting histone acetylation. SAHA, Senegenin and HGN antisense oligonucleotide might have therapeutic value for the adverse effect of propofol.     

An anti-HIV-1 V3 loop antibody fully protects cross-clade and elicits T-cell immunity in macaques mucosally challenged with an R5 clade C SHIV

Neutralizing antibodies have been shown to protect macaques against SHIV challenge. However, genetically diverse HIV-1 clades have evolved, and a key question left unanswered is whether neutralizing antibodies can confer cross-clade protection in vivo. The novel human monoclonal antibody HGN194 was isolated from an individual infected with an HIV-1 clade AG recombinant circulating recombinant form (CRF). HGN194 targets an epitope in the third hypervariable loop (V3) of HIV-1 gp120 and neutralizes a range of relatively neutralization-sensitive and resistant viruses. We evaluated the potential of HGN194 to protect infant rhesus monkeys against a SHIV encoding a primary CCR5-tropic HIV-1 clade C envelope. After high-dose mucosal challenge, all untreated controls became highly viremic while all HGN194-treated animals (50 mg/kg) were completely protected. When HGN194 was given at 1 mg/kg, one out of two monkeys remained aviremic, whereas the other had delayed, lower peak viremia. Interestingly, all protected monkeys given high-dose HGN194 developed Gag-specific proliferative responses of both CD4+ and CD8+ T cells. To test whether generation of the latter involved cryptic infection, we ablated CD8+ cells after HGN194 clearance. No viremia was detected in any protected monkeys, thus ruling out virus reservoirs. Thus, induction of CD8 T-cell immunity may have resulted from transient "Hit and Run" infection or cross priming via Ag-Ab-mediated cross-presentation. Together, our data identified the HGN194 epitope as protective and provide proof-of-concept that this anti-V3 loop mAb can prevent infection with sterilizing immunity after challenge with virus of a different clade, implying that V3 is a potential vaccine target.     

Dissociation of rugose‐dependent short‐term memory component from memory consolidation in Drosophila

Extensive investigations show several molecular and neuroanatomical mechanisms underlying short‐lived and long‐lasting memory in Drosophila. At the molecular level, the genetic pathway of memory formation, which was obtained through mutant research, seems to occur sequentially. So far, studies of Drosophila mutants appear to support the idea that mutants defective in short‐term memory (STM) are always associated with long‐term memory (LTM) impairment. At the neuroanatomical level, distinct memory traces are partially independently distributed. However, whether memory phase dissociation also exists at the molecular level remains unclear. Here, we report on molecular separation of STM and consolidated memory through genetic dissection of rugose mutants. Mutants in the rugose gene, which encodes an evolutionarily conserved A‐kinase anchor protein, show immediate memory defects as assayed through aversive olfactory conditioning. Intriguingly, two well‐defined consolidated memory components, anesthesia‐resistant memory and protein synthesis‐dependent LTM, are both normal in spite of the defective immediate memory after 10‐session massed and spaced training. Moreover, rugose genetically interacts with cyclic AMP‐protein kinase A signaling during STM formation. Considering our previous study that AKAP Yu specifically participates in LTM formation, these results suggest that there exists a molecular level of memory phase dissociation with distinct AKAPs in Drosophila.     

Taste memory formation: role of nucleus accumbens

When a novel taste has been associated with postingestive malaise, animals recognize this taste as aversive. This associative learning is known as conditioned taste aversion. However, when an animal consumes a novel taste and no aversive consequences follow, it becomes recognized as a safe signal, leading to an increase in its consumption in subsequent presentations. In this review, we will discuss the results related to the taste memory formation focusing particularly on the nucleus accumbens (NAcc). The NAcc keeps projections with amygdala, insular cortex, parabrachial nucleus, and nucleus of the solitary tract areas important for taste memory formation. We will review the evidence relating to how the NAcc could be involved in taste memory formation, due to its role in the taste memory trace formation and its role in the association of the conditioned stimulus-unconditioned stimulus, and finally the retrieval of taste memory. In this context, we will review the participation of the cholinergic, dopaminergic, and glutamatergic systems in the NAcc during taste memory formation.     

昆虫记忆的形成机制及生态适应性

介绍近十几年来利用蜜蜂Apis mellifera L.、果蝇Drosophila melanogaster Meigen和寄生蜂等昆虫对学习和记忆行为研究的成果。这些研究表明昆虫的记忆形成是多阶段的。从短时记忆向长时记忆的形成过程中,cAMP反应元件结合蛋白(cAMP response element-bindingprotein,CREB)起重要的作用;而蘑菇体是学习、记忆形成的主要位点。已有的研究还表明昆虫记忆的动态是适应于不同物种的生态学需要。这些研究为探索昆虫和其它动物记忆的形成和生态适应性提供了理论基础。     

生态学中的植物记忆研究

近年来,植物记忆研究为深入理解种群分布格局、群落构建、群落演替等生态学过程提供了新的视角,因此备受生态学家的关注。在介绍生态胁迫记忆、表观遗传记忆、生态记忆、土壤记忆概念的基础上,综述了近几年来相关领域在生态学研究中的最新进展,并提出了植物记忆在生态学研究中值得关注的方向,以期为全面深入的理解生态学过程提供一个新的角度。     

A study of visuospatial working memory pre- and post-Gonadotropin Hormone Releasing Hormone agonists (GnRHa) in young women

Gonadotropin Hormone Releasing Hormone agonists (GnRHa) produce an acute decline in ovarian hormone production leading to a ‘pseudo’ menopause. This is therapeutically useful in the management of a variety of gynaecological conditions but also serves as a powerful model to study the effects of ovarian hormones on cognition. Animal and human behavioral studies report that memory is particularly sensitive to the effects ovarian hormone suppression (e.g. post GnRHa). Further, it has recently been reported that ovariectomy in young women increases the risk of cognitive impairment in later life. However, the underlying brain networks and/or stages of memory processing that might be modulated by acute ovarian hormone suppression remain poorly understood. We used event-related fMRI to examine the effect of GnRHa on visual working memory (VWM). Neuroimaging outcomes from 17 pre-menopausal healthy women were assessed at baseline and 8 weeks after GnRHa treatment. Seventeen matched wait-listed volunteers served as the control group and were assessed at similar intervals during the late follicular phase of the menstrual cycle. We report GnRHa was associated with attenuation of left parahippocampal (BA 35) and middle temporal gyri (BA 21 ,22, 39) activation, with a significant group-by-time interaction at left precuneus (BA 7) and posterior cingulate cortex (PCC) (BA 31) at encoding, and with cerebellar activation at recognition in the context of unimpaired behavioral responses. Our study suggests that acute ovarian hormone withdrawal following GnRHa, and perhaps at other times, (e.g. following surgical menopause and postpartum) alters the neural circuitry underlying performance of VWM.     

不同训练方式建立大鼠空间记忆后海马结构NMDA受体表达的变化

短期强化训练能否建立可靠的空间长时记忆？用不同训练方式建立空间记忆后,大鼠海马结构NMDA受体的表达发生怎样的变化？目前尚未见明确报道。本研究应用Morris水迷宫方法分别采用以下模式对大鼠进行训练：空间长时记忆训练模式（LT组）、空间短时记忆训练模式（ST组）以及短期强化训练模式（SRT组）,对不同训练模式建立的空间记忆进行了比较,应用免疫荧光组织化学方法检测各组大鼠海马结构NMDA／NR1受体表达的变化。结果表明,Morris水迷宫训练过程中,LT和SRT组大鼠寻找站台的半均潜伏期和策略均无显著性差异：记忆检测发现,除LT组大鼠在站台所在象限的停留时间明显长于SRT组大鼠外,两组大鼠寻找站台的潜伏期和策略以及穿越站台的次数均无显著性差异。ST组大鼠海马结构NMDA／NR1的免疫反应强度与对照组相比,无显著差异。但是,LT和SRT组大鼠海马CA1区锥体细胞联及齿状回的颗粒细胞层NMDA／NR1免疫荧光反应都明显增强,两组之间比较无显著差异,但是两组分别与对照组和ST组相比均有显著性差异。上述结果提示,短期强化训练可建立与长期训练基本相同的空间长时记忆。大鼠海马结构CA1区和齿状回NMDA受体表达的增加,可能是空间长时记忆形成的机制之一。     

Molecular mechanisms of memory retrieval

Memory retrieval is a fundamental component or stage of memory processing. In fact, retrieval is the only possible measure of memory. The ability to recall past events is a major determinant of survival strategies in all species and is of paramount importance in determining our uniqueness as individuals. Most biological studies of memory using brain lesion and/or gene manipulation techniques cannot distinguish between effects on the molecular mechanisms of the encoding or consolidation of memories and those responsible for their retrieval from storage. Here we examine recent findings indicating the major molecular steps involved in memory retrieval in selected brain regions of the mammalian brain. Together the findings strongly suggest that memory formation and retrieval may share some molecular mechanisms in the hippocampus and that retrieval initiates extinction requiring activation of several signaling cascades and protein synthesis.     

Glycogen phosphorylase inhibition improves cognitive function of aged mice

Inhibition of glycogen breakdown blocks memory formation in young animals, but it stimulates the maintenance of the long-term potentiation, a cellular mechanism of memory formation, in hippocampal slices of old animals. Here, we report that a 2-week treatment with glycogen phosphorylase inhibitor BAY U6751 alleviated memory deficits and stimulated neuroplasticity in old mice. Using the 2-Novel Object Recognition and Novel Object Location tests, we discovered that the prolonged intraperitoneal administration of BAY U6751 improved memory formation in old mice. This was accompanied by changes in morphology of dendritic spines in hippocampal neurons, and by “rejuvenation” of hippocampal proteome. In contrast, in young animals, inhibition of glycogen degradation impaired memory formation; however, as in old mice, it did not alter significantly the morphology and density of cortical dendritic spines. Our findings provide evidence that prolonged inhibition of glycogen phosphorolysis improves memory formation of old animals. This could lead to the development of new strategies for treatment of age-related memory deficits.     

Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces.

To examine the in vivo function of presenilin-1 (PS1), we selectively deleted the PS1 gene in excitatory neurons of the adult mouse forebrain. These conditional knockout mice were viable and grew normally, but they exhibited a pronounced deficiency in enrichment-induced neurogenesis in the dentate gyrus. This reduction in neurogenesis did not result in appreciable learning deficits, indicating that addition of new neurons is not required for memory formation. However, our postlearning enrichment experiments lead us to postulate that adult dentate neurogenesis may play a role in the periodic clearance of outdated hippocampal memory traces after cortical memory consolidation, thereby ensuring that the hippocampus is continuously available to process new memories. A chronic, abnormal clearance process in the hippocampus may conceivably lead to memory disorders in the mammalian brain.     

Role for brain-derived neurotrophic factor in learning and memory

In addition to its actions on neuronal survival and differentiation, brain-derived neurotrophic factor (BDNF) has a role in the regulation of synaptic strength. Long-term potentiation, a form of synaptic plasticity, is markedly impaired in BDNF mutant mice, but the changes were restored by the re-expression of BDNF. BDNF also influences the development of patterned connections and the growth and complexity of dendrites in the cerebral cortex. These results suggest a role for BDNF in learning and memory processes, since memory acquisition is considered to involve both short-term changes in electrical properties and long-term structural alterations in synapses. Memory acquisition is associated with an increase in BDNF mRNA and TrkB receptor activation in specific brain areas. Moreover, the pharmacologic and genetic deprivation of BDNF or its receptor TrkB results in severe impairment of learning and memory in mice, rats and chicks. The effect of BDNF on learning and memory may be linked to the modulation of NMDA and non-NMDA receptor functions as well as the expression of synaptic proteins required for exocytosis. Activation of the mitogen-associated protein kinase and/or phosphatidylinositol 3-kinase signaling pathways may be involved in BDNF-dependent learning and memory formation. It is concluded that BDNF/TrkB signaling plays an important role in learning and memory.     

Learning in honeybees: from molecules to behaviour

Studies in a variety of organisms as diverse as molluscs, insects, birds and mammals have shown that memories can exist in a variety of temporal domains ranging from short-term memories in the range of minutes to long-term memories lasting a lifetime. While transient covalent modifications of proteins underlie short-term memory, the formation of long-term memory requires gene expression and protein synthesis. Different intracellular signalling cascades have been implicated in distinct aspects of learning and memory formation. Little is known however, about how learning in intact animals is related to the modulation of these signalling cascades and how this contributes to distinct neuronal and behavioural changes in vivo. Associative learning in the honeybee provides the opportunity to study processes of memory formation by analysing its progression through different phases, across levels of behaviour, neural circuits, and cellular signalling pathways. The findings reveal evidence that various cellular signalling pathways in the neuronal circuit of distinct brain areas play a role in different processes during learning and memory formation.     

选择方向强化学习的神经网络模型

提出了神经网络模型的一种选择方向强化学习规则,定义并导出了新模型与Hopfield模型两种不同的筛选曲线,由此表明新模型对相关图样的分辨力优于Hopfield模型。在微机上模拟了由100个神经元构成的网络,结果显示新模型具有重复记忆这一神经生理学特点。定义并分行了记忆强度因子,模拟结果表明记忆强度因子愈大的记忆态,联想性能愈好,学习周期愈短。     

Identification of Genes That Promote or Inhibit Olfactory Memory Formation in Drosophila

Genetic screens in Drosophila melanogaster and other organisms have been pursued to filter the genome for genetic functions important for memory formation. Such screens have employed primarily chemical or transposon-mediated mutagenesis and have identified numerous mutants including classical memory mutants, dunce and rutabaga. Here, we report the results of a large screen using panneuronal RNAi expression to identify additional genes critical for memory formation. We identified >500 genes that compromise memory when inhibited (low hits), either by disrupting the development and normal function of the adult animal or by participating in the neurophysiological mechanisms underlying memory formation. We also identified >40 genes that enhance memory when inhibited (high hits). The dunce gene was identified as one of the low hits and further experiments were performed to map the effects of the dunce RNAi to the α/β and γ mushroom body neurons. Additional behavioral experiments suggest that dunce knockdown in the mushroom body neurons impairs memory without significantly affecting acquisition. We also characterized one high hit, sickie, to show that RNAi knockdown of this gene enhances memory through effects in dopaminergic neurons without apparent effects on acquisition. These studies further our understanding of two genes involved in memory formation, provide a valuable list of genes that impair memory that may be important for understanding the neurophysiology of memory or neurodevelopmental disorders, and offer a new resource of memory suppressor genes that will aid in understanding restraint mechanisms employed by the brain to optimize resources.     

染色质修饰酶在记忆中的作用

学习记忆的形成依赖于转录机制.近年研究发现,染色质修饰在基因表达调节中起重要作用.组蛋白乙酰化和去乙酰化是染色质修饰中最为常见调节方式,参与基因的转录调控.乙酰化可以激活转录,促进记忆的形成.组蛋白去乙酰化酶抑制剂可以增强突触可塑性,改善记忆损伤.因此,对于染色质修饰的深入研究,不仅有助于阐明记忆形成的分子机制,而且对记忆相关疾病的治疗以及新药物研发也具有重要指导意义.本文主要就组蛋白乙酰转移酶调节基因转录以及组蛋白去乙酰化酶抑制剂促进记忆形成的作用机理进行综述.     

Molecular Signals into the Insular Cortex and Amygdala During Aversive Gustatory Memory Formation

In this paper, we will provide evidence of the putative molecular signals and biochemical events that mediate the formation of long-lasting gustatory memory trace. When an animal drinks a novel taste (the conditioned stimulus; CS) and it is later associated with malaise (unconditioned stimulus; US), the animal will reject it in the next presentation, developing a long-lasting taste aversion, i.e., the taste cue becomes an aversive signal, and this is referred to as conditioning taste aversion. Different evidence indicates that the novel stimulus (taste) induces a rapid and strong cortical acetylcholine activity that decreases when the stimulus becomes familiar after several presentations. Cholinergic activation via muscarinic receptors initiates a series of intracellular events leading to plastic changes that could be related to short- and/or long-term memory gustatory trace. Such plastic changes facilitate the incoming US signals carried out by, in part, the glutamate release induced by the US. Altogether, these events could produce the cellular changes related to the switch from safe to aversive taste memory trace. A proposed working model to explain the biochemical sequence of signals during taste memory formation will be discussed.