Neuron-Specific Regulation of Associative Learning and Memory by MAGI-1 in C. elegans

Background: Identifying the molecular mechanisms and neural circuits that control learning and memory are major challenges in neuroscience. Mammalian MAGI/S-SCAM is a multi-PDZ domain synaptic scaffolding protein that interacts with a number of postsynaptic signaling proteins and is thereby thought to regulate synaptic plasticity [1,2,3]. Principal Findings: While investigating the behavioral defects of C. elegans nematodes carrying a mutation in the single MAGI ortholog magi-1, we have identified specific neurons that require MAGI-1 function for different aspects of associative learning and memory. Various sensory stimuli and a food deprivation signal are associated in RIA interneurons during learning, while additional expression of MAGI-1 in glutamatergic AVA, AVD and possibly AVE interneurons is required for efficient memory consolidation, i.e. the ability to retain the conditioned changes in behavior over time. During associative learning, MAGI-1 in RIA neurons controls in a cell non-autonomous fashion the dynamic remodeling of AVA, AVD and AVE synapses containing the ionotropic glutamate receptor (iGluR) GLR-1 [4]. During memory consolidation, however, MAGI-1 controls GLR-1 clustering in AVA and AVD interneurons cell-autonomously and depends on the ability to interact with the b-catenin HMP-2. Significance: Together, these results indicate that different aspects of associative learning and memory in C. elegans are likely carried out by distinct subsets of interneurons. The synaptic scaffolding protein MAGI-1 plays a critical role in thes

Evolutionary conserved role of neural cell adhesion molecule-1 in memory.

Vukojevic V, Mastrandreas P, Arnold A, et al. Evolutionary conserved role of neural cell adhesion molecule-1 in memory. Translational psychiatry. 2020;10(1): 217.The neural cell adhesion molecule 1 (NCAM-1) has been implicated in several brain-related biological processes, including neuronal migration, axonal branching, fasciculation, and synaptogenesis, with a pivotal role in synaptic plasticity. Here, we investigated the evolutionary conserved role of NCAM-1 in learning and memory. First, we investigated sustained changes in ncam-1 expression following aversive olfactory conditioning in C. elegans using molecular genetic methods. Furthermore, we examined the link between epigenetic signatures of the NCAM1 gene and memory in two human samples of healthy individuals (N=568 and N=319) and in two samples of traumatized individuals (N=350 and N=463). We found that olfactory conditioning in C. elegans induced ncam-1 expression and that loss of ncam-1 function selectively impaired associative long-term memory, without causing acquisition, sensory, or short-term memory deficits. Reintroduction of the C. elegans or human NCAM1 fully rescued memory impairment, suggesting a conserved role of NCAM1 for memory. In parallel, DNA methylation of the NCAM1 promoter in two independent healthy Swiss cohorts was associated with memory performance. In two independent Sub-Saharan populations of conflict zone survivors who had faced severe trauma, DNA methylation at an alternative promoter of the NCAM1 gene was associated with traumatic memories. Our results support a role of NCAM1 in associative memory in nematodes and humans, and might, ultimately, be helpful in elucidating diagnostic markers or suggest novel therapy targets for memory-related disorders, like PTSD

Functional characterization of C. elegans Y-box-binding proteins reveals tissue-specific functions and a critical role in the formation of polysomes

The cold shock domain is one of the most highly conserved motifs between bacteria and higher eukaryotes. Y-box-binding proteins represent a subfamily of cold shock domain proteins with pleiotropic functions, ranging from transcription in the nucleus to translation in the cytoplasm. These proteins have been investigated in all major model organisms except Caenorhabditis elegans. In this study, we set out to fill this gap and present a functional characterization of CEYs, the C. elegans Y-box-binding proteins. We find that, similar to other organisms, CEYs are essential for proper gametogenesis. However, we also report a novel function of these proteins in the formation of large polysomes in the soma. In the absence of the somatic CEYs, polysomes are dramatically reduced with a simultaneous increase in monosomes and disomes, which, unexpectedly, has no obvious impact on animal biology. Because transcripts that are enriched in polysomes in wild-type animals tend to be less abundant in the absence of CEYs, our findings suggest that large polysomes might depend on transcript stabilization mediated by CEY protein

Common epigenetic variation in a European population of mentally healthy young adults

DNA methylation represents an important link between structural genetic variation and complex phenotypes. The study of genome-wide CpG methylation and its relation to traits relevant to psychiatry has become increasingly important. Here, we analyzed quality metrics of 394,043 CpG sites in two samples of 568 and 319 mentally healthy young adults. For 25% of all CpGs we observed medium to large common epigenetic variation. These CpGs were overrepresented in open sea and shore regions, as well as in intergenic regions. They also showed a strong enrichment of significant hits in association analyses. Furthermore, a significant proportion of common DNA methylation is at least partially genetically driven and thus may be observed similarly across tissues. These findings could be of particular relevance for studies of complex neuropsychiatric traits, which often rely on proxy tissues

Microarray-Based Maps of Copy-Number Variant Regions in European and Sub-Saharan Populations

The genetic basis of phenotypic variation can be partially explained by the presence of copy-number variations (CNVs). Currently available methods for CNV assessment include high-density single-nucleotide polymorphism (SNP) microarrays that have become an indispensable tool in genome-wide association studies (GWAS). However, insufficient concordance rates between different CNV assessment methods call for cautious interpretation of results from CNV-based genetic association studies. Here we provide a cross-population, microarray-based map of copy-number variant regions (CNVRs) to enable reliable interpretation of CNV association findings. We used the Affymetrix Genome-Wide Human SNP Array 6.0 to scan the genomes of 1167 individuals from two ethnically distinct populations (Europe, N = 717; Rwanda, N = 450). Three different CNV-finding algorithms were tested and compared for sensitivity, specificity, and feasibility. Two algorithms were subsequently used to construct CNVR maps, which were also validated by processing subsamples with additional microarray platforms (Illumina 1M-Duo BeadChip, Nimblegen 385K aCGH array) and by comparing our data with publicly available information. Both algorithms detected a total of 42669 CNVs, 74% of which clustered in 385 CNVRs of a cross-population map. These CNVRs overlap with 862 annotated genes and account for approximately 3.3% of the haploid human genome

OCUPAÇÃO IRREGULAR: OS ENTRAVES AO PROCESSO DE REGULARIZAÇÃO FUNDIÁRIA EM GOIÂNIA - O Residencial JK.

Made available in DSpace on 2016-08-10T10:49:51Z (GMT). No. of bitstreams: 1 GLADES MARIA DE JESUS DA SILVA SOARES.pdf: 34738059 bytes, checksum: 31cca2a56f989c45052ddde1e3dd31fd (MD5) Previous issue date: 2013-03-14This research seeks to understand the relationship between the occupations of town formal and informal, having as its object of study the process of irregular occupation in the city of Goiânia, and the restrictions of regularization of these possessions. The occupations are irregular phenomena in urban growth in Brazil and reflection of this reality in Goiânia, that the last ten years there has been an increase of more than 50,000 irregular occupations. Thus, faced with such a perspective, this paper is of a dialectical approach of urban space in Goiânia, in order to investigate the barriers of the regularization process, which derive other social problems such as violence, social exclusion, and urban segregation social. In such aspects and the full regularization process comprises three aspects: urban, environmental and legal which involve different public institutions that need to be coordinated and integrated, making the management of these actions, one of the main barriers for effective regularization, which has as main objective, to recover the land from the city, making it perform its function social. In this sense, the research finds that urban planning needs to engage with this conception of town, so the applicability of urban instruments is effectively guided in order to value the human person and not primarily urban space, and are aiming to obtain information on socio-spatial diversity and its complexities in social relations, such as temporality, specificity of relations, the progression to historicities understand and explain each existing group, taking into consideration all the experiences, setting the understanding of social relations of possessions so elucidated. Only then will it be possible to think that the regularization in the city of Goiânia effectively and fully.A presente pesquisa busca compreender as relações entre as ocupações formal e informal da cidade, tendo como objeto de estudo o processo de ocupação irregular no Município de Goiânia, bem como os entraves da regularização dessas posses. As ocupações irregulares urbanas são fenômenos em crescimento no Brasil, e Goiânia reflete essa realidade. Constata-se um aumento de mais de 50.000 ocupações irregulares nos últimos dez anos. Diante de tal perspectiva, a presente dissertação reveste-se de uma abordagem dialética do espaço urbano em Goiânia, de forma a investigar os entraves do processo de regularização, dos quais decorrem outros problemas sociais, tais como: violência, exclusão social, segregação urbana e social. Ressalte-se que o processo de regularização plena compreende três dimensões urbanística, ambiental e jurídica , as quais envolvem ações de diferentes instituições públicas de uma maneira coordenada e integrada. Quando isto não acontece, surgem entraves para a efetivação da regularização fundiária, que tem como objetivo principal recuperar o ordenamento da cidade, fazendo com que ela cumpra a sua função social. Neste sentido, a presente pesquisa constata que o planejamento urbano necessita dialogar com esta concepção de cidade, para que a aplicação dos instrumentos urbanísticos seja efetivamente norteada de forma a valorizar a pessoa humana e não prioritariamente o espaço urbano. Esse diálogo deve também objetivar a coleta de informações sobre a diversidade socioespacial e suas complexidades nas relações sociais, como temporalidade, especificidades das relações, progressão das historicidades para compreender e explicar cada grupo existente, levando em consideração todas as experiências vividas e configurando a compreensão das relações sociais das posses de forma elucidada. Só a partir daí será possível pensar a regularização fundiária no município de Goiânia de forma efetiva e plena. Para tal, será utilizada teoria consistente centrada em Lefebvre (1980), Villaça (1995) e Santos (1995)

(-)- Gossypol Inhibition of Musashi-Mediated Forgetting Improves Memory and Age-Dependent Memory Decline in Caenorhabditis elegans

Musashi RNA-binding proteins (MSIs) retain a pivotal role in stem cell maintenance, tumorigenesis, and nervous system development. Recently, we showed in C. elegans that Musashi (MSI-1) actively promotes forgetting upon associative learning via a 3'UTR-dependent translational expression of the Arp2/3 actin branching complex. Here, we investigated the evolutionary conserved role of MSI proteins and the effect of their pharmacological inhibition on memory. Expression of human Musashi 1 (MSI1) and Musashi 2 (MSI2) under the endogenous Musashi promoter fully rescued the phenotype of msi-1(lf) worms. Furthermore, pharmacological inhibition of human MSI1 and MSI2 activity using (-)- gossypol resulted in improved memory retention, without causing locomotor, chemotactic, or learning deficits. No drug effect was observed in msi-1(lf) treated worms. Using Western blotting and confocal microscopy, we found no changes in MSI-1 protein abundance following (-)- gossypol treatment, suggesting that Musashi gene expression remains unaltered and that the compound exerts its inhibitory effect post-translationally. Additionally, (-)- gossypol suppressed the previously seen rescue of the msi-1(lf) phenotype in worms expressing human MSI1 specifically in the AVA neuron, indicating that (-)- gossypol can regulate the Musashi pathway in a memory-related neuronal circuit in worms. Finally, treating aged worms with (-)- gossypol reversed physiological age-dependent memory decline. Taken together, our findings indicate that pharmacological inhibition of Musashi might represent a promising approach for memory modulation

Cell fate-specific regulation of EGF receptor trafficking during Caenorhabditis elegans vulval development

By controlling the subcellular localization of growth factor receptors, cells can modulate the activity of intracellular signal transduction pathways. During Caenorhabditis elegans vulval development, a ternary complex consisting of the LIN-7, LIN-2 and LIN-10 PDZ domain proteins localizes the epidermal growth factor receptor (EGFR) to the basolateral compartment of the vulval precursor cells (VPCs) to allow efficient receptor activation by the inductive EGF signal from the anchor cell. We have identified EGFR substrate protein-8 (EPS-8) as a novel component of the EGFR localization complex that links receptor trafficking to cell fate specification. EPS-8 expression is upregulated in the primary VPCs, where it creates a positive feedback loop in the EGFR/RAS/MAPK pathway. The membrane-associated guanylate kinase LIN-2 recruits EPS-8 into the receptor localization complex to retain the EGFR on the basolateral plasma membrane, and thus allow maximal receptor activation in the primary cell lineage. Low levels of EPS-8 in the neighboring secondary VPCs result in the rapid degradation of the EGFR, allowing these cells to adopt the secondary cell fate. Extracellular signals thus regulate EGFR trafficking in a cell type-specific manner to control pattern formation during organogenesis

A role for alpha-adducin (ADD-1) in nematode and human memory

Identifying molecular mechanisms that underlie learning and memory is one of the major challenges in neuroscience. Taken the advantages of the nematode Caenorhabditis elegans, we investigated ?-adducin (add-1) in aversive olfactory associative learning and memory. Loss of add-1 function selectively impaired short- and long-term memory without causing acquisition, sensory, or motor deficits. We showed that ?-adducin is required for consolidation of synaptic plasticity, for sustained synaptic increase of AMPA-type glutamate receptor (GLR-1) content and altered GLR-1 turnover dynamics. ADD-1, in a splice-form- and tissue-specific manner, controlled the storage of memories presumably through actin-capping activity. In support of the C. elegans results, genetic variability of the human ADD1 gene was significantly associated with episodic memory performance in healthy young subjects. Finally, human ADD1 expression in nematodes restored loss of C. elegans add-1 gene function. Taken together, our findings support a role for ?-adducin in memory from nematodes to humans. Studying the molecular and genetic underpinnings of memory across distinct species may be helpful in the development of novel strategies to treat memory-related diseases

Phosphorylation of MSI-1 is implicated in the regulation of associative memory in Caenorhabditis elegans

The Musashi family of RNA-binding proteins controls several biological processes including stem cell maintenance, cell division and neural function. Previously, we demonstrated that the C. elegans Musashi ortholog, msi-1, regulates forgetting via translational repression of the Arp2/3 actin-branching complex. However, the mechanisms controlling MSI-1 activity during the regulation of forgetting are currently unknown. Here we investigated the effects of protein phosphorylation on MSI-1 activity. We showed that MSI-1 function is likely controlled by alterations of its activity rather than its expression levels. Furthermore, we found that MSI-1 is phosphorylated and using mass spectrometry we identified MSI-1 phosphorylation at three residues (T18, S19 and S34). CRISPR-based manipulations of MSI-1 phosphorylation sites revealed that phosphorylation is necessary for MSI-1 function in both short- and long-term aversive olfactory associative memory. Thus, our study provides insight into the mechanisms regulating memory-related MSI-1 activity and may facilitate the development of novel therapeutic approaches