Research progress on Drosophila visual cognition in China

Visual cognition,as one of the fundamental aspects of cognitive neuroscience,is generally associated with high-order brain functions in animals and human.Drosophila,as a model organism,shares certain features of visual cognition in common with mammals at the genetic,molecular,cellular,and even higher behavioral levels.From learning and memory to decision making,Drosophila covers a broad spectrum of higher cognitive behaviors beyond what we had expected.Armed with powerful tools of genetic manipulation in Drosophila,an increasing number of studies have been conducted in order to elucidate the neural circuit mechanisms underlying these cognitive behaviors from a genes-brain-behavior perspective.The goal of this review is to integrate the most important studies on visual cognition in Drosophila carried out in mainland China during the last decade into a body of knowledge encompassing both the basic neural operations and circuitry of higher brain function in Drosophila.Here,we consider a series of the higher cognitive behaviors beyond learning and memory,such as visual pattern recognition,feature and context generalization,different feature memory traces,salience-based decision,attention-like behavior,and cross-modal leaning and memory.We discuss the possible general gain-gating mechanism implementing by dopamine-mushroom body circuit in fly's visual cognition.We hope that our brief review on this aspect will inspire further study on visual cognition in flies,or even beyond.     

Smart is the new sexy: female mountain chickadees increase reproductive investment when mated to males with better spatial cognition

Understanding the evolution of inter and intraspecific variation in cognitive abilities is one of the main goals in cognitive ecology. In scatter‐caching species, spatial memory is critical for the recovery of food caches and overwinter survival, but its effects on reproduction are less clear. Better spatial cognition may improve pre‐breeding condition allowing for earlier reproduction. Alternatively, when mated to males with better spatial memory, females may be able to invest more in reproduction which may allow increased offspring survival and hence higher fitness. Using wild food‐caching mountain chickadees, we found that when environmental conditions were favourable for breeding, females mated to males with better spatial cognition laid larger clutches and fledged larger broods than females mated to males with worse cognitive performance. Our results support the hypothesis that females may increase their reproductive investment to gain indirect, genetic benefits when mated to high‐quality males with better spatial cognitive abilities.     

Fruit flies and intellectual disability

Mental retardation - more commonly known nowadays as intellectual disability - is a severe neurological condition affecting 3% of the general population. As a result of analysis of familial cases and recent advances in clinical genetic testing great strides have been made in our understanding of the genetic etiologies of mental retardation. Nonetheless, no treatment is currently clinically available to patients suffering from intellectual disability. Several animal models have been used in the study of memory and cognition. Established paradigms in Drosophila have recently captured cognitive defects in fly mutants for orthologs of genes involved in human intellectual disability. We review here three protocols designed to understand the molecular genetic basis of learning and memory in Drosophila and the genes identified so far with relation to mental retardation. In addition, we explore the mental retardation genes for which evidence of neuronal dysfunction other than memory has been established in Drosophila. Finally, we summarize the findings in Drosophila for mental retardation genes for which no neuronal information is yet available. All in all, this review illustrates the impressive overlap between genes identified in human mental retardation and genes involved in physiological learning and memory.     

Serine racemase deletion disrupts memory for order and alters cortical dendritic morphology

There is substantial evidence implicating N-methyl-D-aspartate receptors (NMDARs) in memory and cognition. It has also been suggested that NMDAR hypofunction might underlie the cognitive deficits observed in schizophrenia as morphological changes, including alterations in the dendritic architecture of pyramidal neurons in the prefrontal cortex (PFC), have been reported in the schizophrenic brain post mortem. Here, we used a genetic model of NMDAR hypofunction, a serine racemase knockout (SR-/-) mouse in which the first coding exon of the mouse SR gene has been deleted, to explore the role of D-serine in regulating cognitive functions as well as dendritic architecture. SR-/- mice exhibited a significantly disrupted representation of the order of events in distinct experiences as showed by object recognition and odor sequence tests; however, SR-/- animals were unimpaired in the detection of novel objects and in spatial displacement, and showed intact relational memory in a test of transitive inference. In addition, SR-/- mice exhibited normal sociability and preference for social novelty. Neurons in the medial PFC of SR-/- mice displayed reductions in the complexity, total length and spine density of apical dendrites. These findings show that D-serine is important for specific aspects of cognition, as well as in regulating dendritic morphology of pyramidal neurons in the medial PFC (mPFC). Moreover, they suggest that NMDAR hypofunction might, in part, be responsible for the cognitive deficits and synaptic changes associated with schizophrenia, and highlight this signaling pathway as a potential target for therapeutic intervention.     

Lifelong rapamycin administration ameliorates age-dependent cognitive deficits by reducing IL-1β and enhancing NMDA signaling

Understanding the factors that contribute to age-related cognitive decline is imperative, particularly as age is the major risk factor for several neurodegenerative disorders. Levels of several cytokines increase in the brain during aging, including IL-1β, whose levels positively correlate with cognitive deficits. Previous reports show that reducing the activity of the mammalian target of rapamycin (mTOR) extends lifespan in yeast, nematodes, Drosophila, and mice. It remains to be established, however, whether extending lifespan with rapamycin is accompanied by an improvement in cognitive function. In this study, we show that 18-month-old mice treated with rapamycin starting at 2 months of age perform significantly better on a task measuring spatial learning and memory compared to age-matched mice on the control diet. In contrast, rapamycin does not improve cognition when given to 15-month-old mice with pre-existing, age-dependent learning and memory deficits. We further show that the rapamycin-mediated improvement in learning and memory is associated with a decrease in IL-1β levels and an increase in NMDA signaling. This is the first evidence to show that a small molecule known to increase lifespan also ameliorates age-dependent learning and memory deficits.     

The “online brain”: how the Internet may be changing our cognition

The impact of the Internet across multiple aspects of modern society is clear. However, the influence that it may have on our brain structure and functioning remains a central topic of investigation. Here we draw on recent psychological, psychiatric and neuroimaging findings to examine several key hypotheses on how the Internet may be changing our cognition. Specifically, we explore how unique features of the online world may be influencing: a) attentional capacities, as the constantly evolving stream of online information encourages our divided attention across multiple media sources, at the expense of sustained concentration; b) memory processes, as this vast and ubiquitous source of online information begins to shift the way we retrieve, store, and even value knowledge; and c) social cognition, as the ability for online social settings to resemble and evoke real‐world social processes creates a new interplay between the Internet and our social lives, including our self‐concepts and self‐esteem. Overall, the available evidence indicates that the Internet can produce both acute and sustained alterations in each of these areas of cognition, which may be reflected in changes in the brain. However, an emerging priority for future research is to determine the effects of extensive online media usage on cognitive development in youth, and examine how this may differ from cognitive outcomes and brain impact of uses of Internet in the elderly. We conclude by proposing how Internet research could be integrated into broader research settings to study how this unprecedented new facet of society can affect our cognition and the brain across the life course.     

The expert Neandertal mind

Cognitive neuropsychology, cognitive anthropology, and cognitive archaeology are combined to yield a picture of Neandertal cognition in which expert performance via long-term working memory is the centerpiece of problem solving. This component of Neandertal cognition appears to have been modern in scope. However, Neandertals' working memory capacity, which is the ability to hold a variety of information in active attention, may not have been as large as that of modern humans. This characteristic helps us understand features of the archaeological record, such as the rarity of innovation, and allows us to make empirically based speculations about Neandertal personality.     

What is driving the relationship between height and cognition? Evidence from the Twins Early Development Study

Taller children tend to have better cognitive ability, and the relationship between height and cognition has been proposed as an explanation for the height-wage labor market premium. Height-cognition associations may arise due to social factors that favor taller individuals or be driven by “common factors” that are correlated with height and cognition. Indeed, there is now evidence of a genetic correlation between height and cognition that provides specific evidence for this concern. We examine whether genetic factors explain the relationship by estimating associations between childhood height and cognition in the Twins Early Development Study. We find that height is associated with better cognition even after controlling for genetic and environmental factors shared by twins. The association between height and cognition within fraternal twin pairs is also robust to controlling for individual genetic predictors of height and cognition. These results suggest that genetic factors are not solely responsible for driving the relationship between height and cognition.     

X-linked mental retardation and epigenetics

The search for the genetic defects in constitutional diseases has so far been restricted to direct methods for the identification of genetic mutations in the patients' genome. Traditional methods such as karyotyping, FISH, mutation screening, positional cloning and CGH, have been complemented with newer methods including array-CGH and PCR-based approaches (MLPA, qPCR). These methods have revealed a high number of genetic or genomic aberrations that result in an altered expression or reduced functional activity of key proteins. For a significant percentage of patients with congenital disease however, the underlying cause has not been resolved strongly suggesting that yet other mechanisms could play important roles in their etiology. Alterations of the 'native' epigenetic imprint might constitute such a novel mechanism. Epigenetics, heritable changes that do not rely on the nucleotide sequence, has already been shown to play a determining role in embryonic development, X-inactivation, and cell differentiation in mammals. Recent progress in the development of techniques to study these processes on full genome scale has stimulated researchers to investigate the role of epigenetic modifications in cancer as well as in constitutional diseases. We will focus on mental impairment because of the growing evidence for the contribution of epigenetics in memory formation and cognition. Disturbance of the epigenetic profile due to direct alterations at genomic regions, or failure of the epigenetic machinery due to genetic mutations in one of its components, has been demonstrated in cognitive derangements in a number of neurological disorders now. It is therefore tempting to speculate that the cognitive deficit in a significant percentage of patients with unexplained mental retardation results from epigenetic modifications.     

Architecture of the X chromosome, expression of LIM kinase 1, and recombination in the agnostic mutants of Drosophila: a model of human Williams syndrome

As the Human Genome and Drosophila Genome Projects were completed, it became clear that functions of human disease-associated genes may be elucidated by studying the phenotypic expression of mutations affecting their structural or functional homologs in Drosophila. Genomic diseases were identified as a new class of human disorders. Their cause is recombination, which takes place at gene-flanking duplicons to generate chromosome aberrations such as deletions, duplications, inversions, and translocations. The resulting imbalance of the dosage of developmentally important genes arises at a frequency of 10(-3) (higher than the mutation rate of individual genes) and leads to syndromes with multiple manifestations, including cognitive defects. Genomic DNA fragments were cloned from the Drosophila melanogaster agnostic locus, whose mutations impair learning ability and memory. As a result, the locus was exactly localized in X-chromosome region 11A containing the LIM kinase 1 (LIMK1) gene (CG1848), which is conserved among many species. Hemizygosity for the LIMK1 gene, which is caused by recombination at neighboring extended repeats, underlies cognitive disorders in human Williams syndrome. LIMK1 is a component of the integrin signaling cascade, which regulates the functions of the actin cytoskeleton, synaptogenesis, and morphogenesis in the developing brain. Immunofluorescence analysis revealed LIMK1 in all subdomains of the central complex and the visual system of Drosophila melanogaster. Like in the human genome, the D. melanogaster region is flanked by numerous repeats, which were detected by molecular genetic methods and analysis of ectopic chromosome pairing. The repeats determined a higher rate of spontaneous and induced recombination. including unequal crossing over, in the agnostic gene region. Hence, the agnostic locus was considered as the first D. melanogaster model suitable for studying the genetic defect associated with Williams syndrome in human.     

Complex Study of Drosophila Mutants in the agnostic Locus: A Model for Coupling Chromosomal Architecture and Cognitive Functions

After the devastation of genetics in our country, Academician Leon A. Orbeli has provided an opportunity for the studies on evolutionary conservatism of genes controlling the main properties of the higher nervous activity and conditioning. For the last few years, determination and bioinformatic analysis of genome sequences in the plant, worm, Drosophila, and human genome have revealed, indeed, a high interspecies homology of genes. Studies on Drosophila mutants have shown that components of intracellular signalization systems regulating neuronal functions and gene expression are organized in supramolecular complexes. It has become evident that the chromosomal architecture predetermines the appearance of deletions, duplications, insertions, and translocations and, therefore, plays an important role not only in evolution but also in generating human pathological syndromes with multiple manifestations, including cognitive dysfunctions. There appeared a new approach, comparative genomics, that allows revealing functions of human disease genes on the basis of their sequence homology to the known Drosophila gene with various well-studied mutant phenotypes. For this reason, the Drosophila genes should be saturated with mutant phenotypes, and these are to be studied in comparison with the chromosomal architecture. Our complex behavioral and molecular-genetic study of spontaneous, induced, and P-insertional mutations in the Drosophila agnostic locus and the bioinformatic analyses of genomic sequences has allowed us to assign the locus to the Drosophila genomic scaffold AE003489 from the 11AB X-chromosomal region that contains the CG1848 gene coding for LIM-kinase 1. Mutations, insertions, and deletions in the agnostic locus lead to an increased activity of Ca²⁺/calmodulin-dependent PDE1, resistance to ether, an inactivator of synaptic transmission, impairments of the brain structures, learning and memory defects in conditioned courtship suppression paradigm, alterations in sound production and in structural-functional chromosomal organization. Therefore, the agnostic locus represents a model to study the human Williams syndrome with multiple dysfunctions due to a contiguous deletion in the 7q11.23 spanning 17 genes, among them the gene for LIM-kinase 1 presumed to be responsible for cognitive defects. The Williams syndrome is considered to be a most efficient model to study human cognition, human genome organization, and evolution.     

Evidence that androgenic and estrogenic metabolites contribute to the effects of dehydroepiandrosterone on cognition in postmenopausal women

Prior studies of the effects of dehydroepiandrosterone (DHEA) on cognition have produced complex and inconsistent results. We hypothesize that these results may arise, in part, because of DHEA's metabolism into estrogens and androgens that produce opposing effects on cognition. Our study administered 50 mg of oral DHEA daily for 4 weeks in a placebo-controlled crossover design to six postmenopausal women. We measured blood levels of androgens (total testosterone, free testosterone, DHEA, DHEAS), estrogens (estradiol, estrone), and cognitive performance on recognition memory, perceptual identification, digit span memory, and visual attentional vigilance under both drug and placebo conditions. Multiple regression models incorporating the factors of age and body mass index (BMI) were used to ascertain the relation between sex steroids and cognitive performance. Our results demonstrated that estrogens produced a positive effect on recognition memory, while androgens produced a negative effect. This pattern reversed in perceptual identification with estrogens producing a negative effect and androgens producing a positive effect. In addition, BMI produced a negative effect on digit span memory, age produced a negative effect on perceptual identification, and androgens produced a negative effect on visual attentional vigilance. These results help, in part, to explain DHEA's complex effects on cognition. The diverse effects of sex steroids across tasks underscore the importance of identifying the specific cognitive mechanisms influenced by sex steroids and emphasizes that one should not expect sex steroids to produce homogeneous effects across cognitive tasks.     

果蝇长时程记忆缺陷型突变体的鉴定

长时程记忆作为依赖蛋白合成的记忆组分,对于了解高等认知活动的分子机制有着重要意义.与此同时,细胞粘连分子作为影响突触可塑性的重要因子在学习与记忆研究领域也日益得到重视.为探索作用于长时程记忆的细胞粘连分子,利用P因子在果蝇基因组随机插入制造突变体,并通过大规模行为筛选得到了一个可能的长时程记忆突变体RUO. 测序结果表明,突变体RUO的P因子位于果蝇中selectin超家族对应的furrowed同源基因功能片段和未知功能的CG1806基因编码片段之间,且更靠近furrowed片段.RT-PCR结果和互补遗传学实验均表明,突变体RUO主要影响furrowed基因的表达.为了进一步确认furrowed基因与长时程记忆的相关性,引入已知的furrowed基因突变体fw1.结果表明,fw1同样具有长时程记忆缺陷,同时具备正常的学习能力.荧光共聚焦扫描成像显示,该基因特异性的表达在果蝇大脑两个对称的未知神经元中.此项工作不仅证明了furrowed基因在果蝇长时程记忆中的重要作用,而且在解剖学上揭示了果蝇神经系统中可能参与长时程记忆形成的新的神经元.     

Challenging the classical notion of time in cognition: a quantum perspective

All mental representations change with time. A baseline intuition is that mental representations have specific values at different time points, which may be more or less accessible, depending on noise, forgetting processes, etc. We present a radical alternative, motivated by recent research using the mathematics from quantum theory for cognitive modelling. Such cognitive models raise the possibility that certain possibilities or events may be incompatible, so that perfect knowledge of one necessitates uncertainty for the others. In the context of time-dependence, in physics, this issue is explored with the so-called temporal Bell (TB) or Leggett–Garg inequalities. We consider in detail the theoretical and empirical challenges involved in exploring the TB inequalities in the context of cognitive systems. One interesting conclusion is that we believe the study of the TB inequalities to be empirically more constrained in psychology than in physics. Specifically, we show how the TB inequalities, as applied to cognitive systems, can be derived from two simple assumptions: cognitive realism and cognitive completeness. We discuss possible implications of putative violations of the TB inequalities for cognitive models and our understanding of time in cognition in general. Overall, this paper provides a surprising, novel direction in relation to how time should be conceptualized in cognition.     

Drosophila modeling of heritable neurodevelopmental disorders

Heritable neurodevelopmental disorders are multifaceted disease conditions encompassing a wide range of symptoms including intellectual disability, cognitive dysfunction, autism and myriad other behavioral impairments. In cases where single, causative genetic defects have been identified, such as Angelman syndrome, Rett syndrome, Neurofibromatosis Type 1 and Fragile X syndrome, the classical Drosophila genetic system has provided fruitful disease models. Recent Drosophila studies have advanced our understanding of UBE3A, MECP2, NF1 and FMR1 function, respectively, in genetic, biochemical, anatomical, physiological and behavioral contexts. Investigations in Drosophila continue to provide the essential mechanistic understanding required to facilitate the conception of rational therapeutic treatments.     

COMT Val158Met and cognition: main effects and interaction with educational attainment

Studies in children have shown that the genetic influence on cognition is positively correlated with socioeconomic status. Catechol- O -methyltransferase (COMT) Val158Met, a common, functional polymorphism, has been implicated in executive cognition and working memory. Imaging studies have shown that the variant Met allele is associated with more efficient prefrontal cortical processing and better attention but also emotional vulnerability to stress. We hypothesized that COMT Val158Met genotype would interact with years of education (yrs ed), one indicator of socioeconomic adversity, to predict cognitive task performance. We therefore administered the Wechsler Adult Intelligence Scale-Revised (WAIS-R) to 328 community-derived, genotyped, Plains American Indians (mean yrs ed = 12; range = 5–18). We found significant genotypic effects on WAIS-R measures of long-term memory, working memory and attention. The Met allele was associated with improved performance in the Information and Picture Completion subscales; Met/Met homozygotes performed the best. COMT genotype interacted with yrs ed to influence Information and Block Design scores: Met allele carriers' scores improved markedly with increasing yrs ed, whereas the scores of Val/Val individuals were only marginally influenced by yrs ed. There was a crossover of effects at 11–12 yrs ed: in the less educated group, Met allele carriers actually performed worse than Val/Val individuals perhaps because of emotional vulnerability to educational adversity, but in the better educated group, Met allele carriers excelled. Our study in Plains American Indians has shown that COMT Val158Met influences several aspects of cognition and some of its effects are moderated by educational adversity.     

Studying the evolutionary ecology of cognition in the wild: a review of practical and conceptual challenges

Cognition is defined as the processes by which animals collect, retain and use information from their environment to guide their behaviour. Thus cognition is essential in a wide range of behaviours, including foraging, avoiding predators and mating. Despite this pivotal role, the evolutionary processes shaping variation in cognitive performance among individuals in wild populations remain very poorly understood. Selection experiments in captivity suggest that cognitive traits can have substantial heritability and can undergo rapid evolution. However only a handful of studies have attempted to explore how cognition influences life‐history variation and fitness in the wild, and direct evidence for the action of natural or sexual selection on cognition is still lacking, reasons for which are diverse. Here we review the current literature with a view to: (i) highlighting the key practical and conceptual challenges faced by the field; (ii) describing how to define and measure cognitive traits in natural populations, and suggesting which species, populations and cognitive traits might be examined to greatest effect; emphasis is placed on selecting traits that are linked to functional behaviour; (iii) discussing how to deal with confounding factors such as personality and motivation in field as well as captive studies; (iv) describing how to measure and interpret relationships between cognitive performance, functional behaviour and fitness, offering some suggestions as to when and what kind of selection might be predicted; and (v) showing how an evolutionary ecological framework, more generally, along with innovative technologies has the potential to revolutionise the study of cognition in the wild. We conclude that the evolutionary ecology of cognition in wild populations is a rapidly expanding interdisciplinary field providing many opportunities for advancing the understanding of how cognitive abilities have evolved.     

Working memory deficits in neuronal nitric oxide synthase knockout mice: potential impairments in prefrontal cortex mediated cognitive function

Neuronal nitric oxide synthase (nNOS) forms nitric oxide (NO), which functions as a signaling molecule via S-nitrosylation of various proteins and regulation of soluble guanylate cyclase (cGC)/cyclic guanosine monophosphate (cGMP) pathway in the central nervous system. nNOS signaling regulates diverse cellular processes during brain development and molecular mechanisms required for higher brain function. Human genetics have identified nNOS and several downstream effectors of nNOS as risk genes for schizophrenia. Besides the disease itself, nNOS has also been associated with prefrontal cortical functioning, including cognition, of which disturbances are a core feature of schizophrenia. Although mice with genetic deletion of nNOS display various behavioral deficits, no studies have investigated prefrontal cortex-associated behaviors. Here, we report that nNOS knockout (KO) mice exhibit hyperactivity and impairments in contextual fear conditioning, results consistent with previous reports. nNOS KO mice also display mild impairments in object recognition memory. Most importantly, we report for the first time working memory deficits, potential impairments in prefrontal cortex mediated cognitive function in nNOS KO mice. Furthermore, we demonstrate Disrupted-in-Schizophrenia 1 (DISC1), another genetic risk factor for schizophrenia that plays roles for cortical development and prefrontal cortex functioning, including working memory, is a novel protein binding partner of nNOS in the developing cerebral cortex. Of note, genetic deletion of nNOS appears to increase the binding of DISC1 to NDEL1, regulating neurite outgrowth as previously reported. These results suggest that nNOS KO mice are useful tools in studying the role of nNOS signaling in cortical development and prefrontal cortical functioning.