scholarly journals Age-associated changes to neuronal dynamics involve a loss of inhibitory signaling in C. elegans

2021 ◽  
Author(s):  
Gregory S Wirak ◽  
Jeremy Florman ◽  
Mark J Alkema ◽  
Christopher W Connor ◽  
Christopher V Gabel
Keyword(s):  
Nervous System ◽  
Functional Organization ◽  
Functional Decline ◽  
Aging Brain ◽  
Neuronal Dynamics ◽  
Aging Research ◽  
C Elegans ◽  
Activation Data ◽  
Inhibitory Signaling ◽  
Cellular Modifications

In the aging brain, many of the alterations underlying cognitive and behavioral decline remain opaque. C. elegans offers a powerful model for aging research, with a simple, well-studied nervous system to further our understanding of the cellular modifications and functional alterations accompanying senescence. We perform multi-neuronal functional imaging across the aged C. elegans nervous system, measuring an age-associated breakdown in system-wide functional organization. At single-cell resolution, we detect shifts in activity dynamics toward higher frequencies, alongside a specific loss of inhibitory signaling occurring early in the aging process. These effects are partially delayed or accelerated by a long-lived or neurodegenerative mutant background, respectively. We further provide evidence that these effects are partially mediated through degradation of GABA signaling, via a pathway involving UNC-2/CaV2α and caspase activation. Data from mammals are consistent with our findings, suggesting a conserved shift in the balance of excitatory/inhibitory signaling with age leading to functional decline.

scholarly journals UBC-9 Acts in GABA Neurons to Control Neuromuscular Signaling in C. elegans

2020 ◽  
Vol 15 ◽  
pp. 263310552096279
Author(s):  
Victoria A Kreyden ◽  
Elly B Mawi ◽  
Kristen M Rush ◽  
Jennifer R Kowalski
Keyword(s):  
Nervous System ◽  
Synaptic Vesicle ◽  
Motor Neurons ◽  
Protein Function ◽  
Cholinergic Neurons ◽  
Synaptic Proteins ◽  
Inhibitory Synapses ◽  
C Elegans ◽  
Associated Proteins ◽  
Inhibitory Signaling

Regulation of excitatory to inhibitory signaling balance is essential to nervous system health and is maintained by numerous enzyme systems that modulate the activity, localization, and abundance of synaptic proteins. SUMOylation is a key post-translational regulator of protein function in diverse cells, including neurons. There, its role in regulating synaptic transmission through pre- and postsynaptic effects has been shown primarily at glutamatergic central nervous system synapses, where the sole SUMO-conjugating enzyme Ubc9 is a critical player. However, whether Ubc9 functions globally at other synapses, including inhibitory synapses, has not been explored. Here, we investigated the role of UBC-9 and the SUMOylation pathway in controlling the balance of excitatory cholinergic and inhibitory GABAergic signaling required for muscle contraction in Caenorhabditis elegans. We found inhibition or overexpression of UBC-9 in neurons modestly increased muscle excitation. Similar and even stronger phenotypes were seen with UBC-9 overexpression specifically in GABAergic neurons, but not in cholinergic neurons. These effects correlated with accumulation of synaptic vesicle-associated proteins at GABAergic presynapses, where UBC-9 and the C. elegans SUMO ortholog SMO-1 localized, and with defects in GABA-dependent behaviors. Experiments involving expression of catalytically inactive UBC-9 [UBC-9(C93S)], as well as co-expression of UBC-9 and SMO-1, suggested wild type UBC-9 overexpressed alone may act via substrate sequestration in the absence of sufficient free SUMO, underscoring the importance of tightly regulated SUMO enzyme function. Similar effects on muscle excitation, GABAergic signaling, and synaptic vesicle localization occurred with overexpression of the SUMO activating enzyme subunit AOS-1. Together, these data support a model in which UBC-9 and the SUMOylation system act at presynaptic sites in inhibitory motor neurons to control synaptic signaling balance in C. elegans. Future studies will be important to define UBC-9 targets at this synapse, as well as mechanisms by which UBC-9 and the SUMO pathway are regulated.

scholarly journals Health and longevity studies in C. elegans: the “healthy worm database” reveals strengths, weaknesses and gaps of test compound-based studies

2021 ◽  
Vol 22 (2) ◽  
pp. 215-236
Author(s):  
Nadine Saul ◽  
Steffen Möller ◽  
Francesca Cirulli ◽  
Alessandra Berry ◽  
Walter Luyten ◽  
...  
Keyword(s):  
Healthy Aging ◽  
Model Organism ◽  
Research Field ◽  
Aging Research ◽  
Genetic Manipulations ◽  
C Elegans ◽  
Starting Point ◽  
Health Related ◽  
Phenotype Measurement ◽  
Or Gene

AbstractSeveral biogerontology databases exist that focus on genetic or gene expression data linked to health as well as survival, subsequent to compound treatments or genetic manipulations in animal models. However, none of these has yet collected experimental results of compound-related health changes. Since quality of life is often regarded as more valuable than length of life, we aim to fill this gap with the “Healthy Worm Database” (http://healthy-worm-database.eu). Literature describing health-related compound studies in the aging model Caenorhabditis elegans was screened, and data for 440 compounds collected. The database considers 189 publications describing 89 different phenotypes measured in 2995 different conditions. Besides enabling a targeted search for promising compounds for further investigations, this database also offers insights into the research field of studies on healthy aging based on a frequently used model organism. Some weaknesses of C. elegans-based aging studies, like underrepresented phenotypes, especially concerning cognitive functions, as well as the convenience-based use of young worms as the starting point for compound treatment or phenotype measurement are discussed. In conclusion, the database provides an anchor for the search for compounds affecting health, with a link to public databases, and it further highlights some potential shortcomings in current aging research.

Lineage-dependent spatial and functional organization of the mammalian enteric nervous system

Science ◽  
2017 ◽  
Vol 356 (6339) ◽  
pp. 722-726 ◽  
Author(s):  
Reena Lasrado ◽  
Werend Boesmans ◽  
Jens Kleinjung ◽  
Carmen Pin ◽  
Donald Bell ◽  
...  
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
Functional Organization

Behavioral Effects of Volatile Anesthetics in Caenorhabditis elegans

1996 ◽  
Vol 85 (4) ◽  
pp. 901-912 ◽  
Author(s):  
Michael C. Crowder ◽  
Laynie D. Shebester ◽  
Tim Schedl
Keyword(s):  
Nervous System ◽  
Caenorhabditis Elegans ◽  
Time Course ◽  
Model Organism ◽  
Volatile Anesthetic ◽  
Volatile Anesthetics ◽  
Effective Concentration ◽  
Forward Genetics ◽  
C Elegans ◽  
Median Effective Concentration

Background The nematode Caenorhabditis elegans offers many advantages as a model organism for studying volatile anesthetic actions. It has a simple, well-understood nervous system; it allows the researcher to do forward genetics; and its genome will soon be completely sequenced. C. elegans is immobilized by volatile anesthetics only at high concentrations and with an unusually slow time course. Here other behavioral dysfunctions are considered as anesthetic endpoints in C. elegans. Methods The potency of halothane for disrupting eight different behaviors was determined by logistic regression of concentration and response data. Other volatile anesthetics were also tested for some behaviors. Established protocols were used for behavioral endpoints that, except for pharyngeal pumping, were set as complete disruption of the behavior. Time courses were measured for rapid behaviors. Recovery from exposure to 1 or 4 vol% halothane was determined for mating, chemotaxis, and gross movement. All experiments were performed at 20 to 22 degrees C. Results The median effective concentration values for halothane inhibition of mating (0.30 vol%-0.21 mM), chemotaxis (0.34 vol%-0.24 mM), and coordinated movement (0.32 vol% - 0.23 mM) were similar to the human minimum alveolar concentration (MAC; 0.21 mM). In contrast, halothane produced immobility with a median effective concentration of 3.65 vol% (2.6 mM). Other behaviors had intermediate sensitivities. Halothane's effects reached steady-state in 10 min for all behaviors tested except immobility, which required 2 h. Recovery was complete after exposure to 1 vol% halothane but was significantly reduced after exposure to immobilizing concentrations. Conclusions Volatile anesthetics selectively disrupt C. elegans behavior. The potency, time course, and recovery characteristics of halothane's effects on three behaviors are similar to its anesthetic properties in vertebrates. The affected nervous system molecules may express structural motifs similar to those on vertebrate anesthetic targets.

scholarly journals Complementary RNA amplification methods enhance microarray identification of transcripts expressed in the C. elegans nervous system

BMC Genomics ◽  
2008 ◽  
Vol 9 (1) ◽  
Author(s):  
Joseph D Watson ◽  
Shenglong Wang ◽  
Stephen E Von Stetina ◽  
W Clay Spencer ◽  
Shawn Levy ◽  
...  
Keyword(s):  
Nervous System ◽  
Rna Amplification ◽  
C Elegans

scholarly journals Integrated Transcriptome, Proteome, Acetylome, and Metabolome Profiling of Mouse Liver During Normal Aging

2020 ◽  
Author(s):  
Jiang-Feng Liu ◽  
Song-Feng Wu ◽  
Cong Liu ◽  
Hou-Zao Chen ◽  
Juntao Yang
Keyword(s):  
Immune Function ◽  
Mouse Liver ◽  
Functional Decline ◽  
Normal Aging ◽  
Arachidonic Acid Metabolism ◽  
Functional Enrichment ◽  
Metabolome Analysis ◽  
Aging Research ◽  
Complex Biological Process ◽  
Old Mice

Abstract BackgroundAging is a complex biological process accompanied by a time-dependent functional decline that affects most living organisms. We aimed to obtain an integrated aging-associated profile of the mouse liver using a multi-omics approach.ResultsWe performed a combined transcriptome, proteome, acetylome, and metabolome analysis of liver tissues from young and old mice under physiological conditions. Old mice were frequently obese with a fatty liver, and the observed profile changes in different omics were generally moderate. Specifically, transcriptome, proteome, and acetylome analyses revealed different patterns in old and young mice, but metabolome analysis did not. Functional enrichment analysis showed that metabolic pathways were broadly altered during normal aging. Notably, the genes, proteins, and metabolites involved in pyrimidine and glutathione metabolisms were significantly affected in all these four omics. Moreover, we observed increased arachidonic acid metabolism and decreased complement and coagulation cascades in old mice, suggesting an alteration in the immune function during normal aging.ConclusionsWe conducted a multi-omics investigation of normal liver aging in mice and generated comprehensive datasets for aging research. Further analysis revealed that impairment of pyrimidine and glutathione metabolisms and immune function may be critical for hepatic aging and may provide targets for aging interventions.

scholarly journals Heparan sulfate molecules mediate synapse formation and function of male mating neural circuits in C. elegans

2018 ◽  
Author(s):  
María I. Lázaro-Peña ◽  
Carlos A. Díaz-Balzac ◽  
Hannes E. Bülow ◽  
Scott W. Emmons
Keyword(s):  
Nervous System ◽  
Cell Adhesion ◽  
Neural Cell ◽  
Male Mating ◽  
Synaptic Connections ◽  
Adhesion Protein ◽  
C Elegans ◽  
Neural Cell Adhesion ◽  
Heparan Sulfates ◽  
And Function

AbstractThe nervous system regulates complex behaviors through a network of neurons interconnected by synapses. How specific synaptic connections are genetically determined is still unclear. Male mating is the most complex behavior in C. elegans. It is composed of sequential steps that are governed by more than 3,000 chemical connections. Here we show that heparan sulfates (HS) play a role in the formation and function of the male neural network. Cell-autonomous and non-autonomous 3-O sulfation by the HS modification enzyme HST-3.1/HS 3-O-sulfotransferase, localized to the HSPG glypicans LON-2/glypican and GPN-1/glypican, was specifically required for response to hermaphrodite contact during mating. Loss of 3-O sulfation resulted in the presynaptic accumulation of RAB-3, a molecule that localizes to synaptic vesicles, disrupting the formation of synapses in a component of the mating circuits. We also show that neural cell adhesion protein neurexin promotes and neural cell adhesion protein neuroligin inhibits formation of the same set of synapses in a parallel pathway. Thus, neural cell adhesion proteins and extracellular matrix components act together in the formation of synaptic connections.Author SummaryThe formation of the nervous system requires the function of several genetically-encoded proteins to form complex networks. Enzymatically-generated modifications of these proteins play a crucial role during this process. These authors analyzed the role of heparan sulfates in the process of synaptogenesis in the male tail of C. elegans. A modification of heparan sulfate is required for the formation of specific synapses between neurons by acting cell-autonomously and non-autonomously. Could it be that heparan sulfates and their diverse modifications are a component of the specification factor that neurons use to make such large numbers of connections unique?

scholarly journals Global accumulation of circRNAs during aging in Caenorhabditis elegans

2017 ◽  
Author(s):  
Mariela Cortés-López ◽  
Matthew Gruner ◽  
Daphne A. Cooper ◽  
Hannah N. Gruner ◽  
Alexandru-Ioan Voda ◽  
...  
Keyword(s):  
Global Scale ◽  
Circular Rnas ◽  
Rna Seq ◽  
Aging Research ◽  
C Elegans ◽  
Fourth Larval Stage ◽  
Functional Consequences ◽  
Exceptional Stability ◽  
Massive Accumulation

SummaryCircular RNAs (CircRNAs) are a newly appreciated class of RNAs that lack free 5´ and 3´ ends, are expressed by the thousands in diverse forms of life, and are mostly of enigmatic function. Ostensibly due to their resistance to exonucleases, circRNAs are known to be exceptionally stable. Here, we examined the global profile of circRNAs in C. elegans during aging by performing ribo-depleted total RNA-seq from the fourth larval stage (L4) through 10-day old adults. Using stringent bioinformatic criteria and experimental validation, we annotated 1,166 circRNAs, including 575 newly discovered circRNAs. These circRNAs were derived from 797 genes with diverse functions, including genes involved in the determination of lifespan. A massive accumulation of circRNAs during aging was uncovered. Many hundreds of circRNAs were significantly increased among the aging time-points and increases of select circRNAs by over 40-fold during aging were quantified by qRT-PCR. The age-accumulation of circRNAs was not accompanied by increased expression of linear RNAs from the same host genes. We attribute the global scale of circRNA age-accumulation to the high composition of postmitotic cells in adult C. elegans, coupled with the high resistance of circRNAs to decay. These findings suggest that the exceptional stability of circRNAs might explain age-accumulation trends observed from neural tissues of other organisms, which also have a high composition of post-mitotic cells. Given the suitability of C. elegans for aging research, it is now poised as an excellent model system to determine if there are functional consequences of circRNA accumulation during aging.

scholarly journals Multicellular rosettes organize neuropil formation

2020 ◽  
Author(s):  
Christopher A. Brittin ◽  
Anthony Santella ◽  
Kristopher Barnes ◽  
Mark W. Moyle ◽  
Li Fan ◽  
...  
Keyword(s):  
Functional Organization ◽  
Critical Role ◽  
Ring Structure ◽  
Nerve Ring ◽  
Cell Behaviors ◽  
Dense Networks ◽  
C Elegans ◽  
Single Axon ◽  
Organizational Features

SummaryNeuropils are compartments in the nervous system containing dense networks of neurites and synapses which function as information processing centers. Neuropil formation requires structural and functional organization at and across different scales, achieving single-axon precision for circuits that carry out the core functions while simultaneously accommodating variability among individuals [1; 2; 3; 4]. How these organizational features emerge over development is poorly understood. The nerve ring is the primary neuropil in C. elegans, and its structure is thoroughly mapped [5; 6]. We show that prior to axon outgrowth, nerve ring neurons form a ring of multicellular rosettes with surrounding cells to organize the stratified nerve ring structure [7; 8]. Axon bundles which correspond to future nerve ring strata grow from rosette centers, travel along the ring on “bridge” cells that are simultaneously engaged in adjacent rosettes, and assemble into a topographic scaffold of the nerve ring. SAX-3/Robo is required for proper rosette formation and outgrowth from the center. Furthermore, axon contact sites that form early in development are more conserved than the later ones, indicating a temporal component in neuropil structural variability. Our results reveal an unexpected and critical role of collective cell behaviors prior to innervation to pattern a complex neuropil and orchestrate its formation across scales.

scholarly journals Neuropeptides and Behaviors: How Small Peptides Regulate Nervous System Function and Behavioral Outputs

2021 ◽  
Vol 14 ◽  
Author(s):  
Umer Saleem Bhat ◽  
Navneet Shahi ◽  
Siju Surendran ◽  
Kavita Babu
Keyword(s):  
Nervous System ◽  
Behavioral Plasticity ◽  
Environmental Changes ◽  
Sensory Information ◽  
Synaptic Activity ◽  
Small Peptides ◽  
C Elegans ◽  
Wide Range ◽  
Nervous System Function ◽  
Insight Into

One of the reasons that most multicellular animals survive and thrive is because of the adaptable and plastic nature of their nervous systems. For an organism to survive, it is essential for the animal to respond and adapt to environmental changes. This is achieved by sensing external cues and translating them into behaviors through changes in synaptic activity. The nervous system plays a crucial role in constantly evaluating environmental cues and allowing for behavioral plasticity in the organism. Multiple neurotransmitters and neuropeptides have been implicated as key players for integrating sensory information to produce the desired output. Because of its simple nervous system and well-established neuronal connectome, C. elegans acts as an excellent model to understand the mechanisms underlying behavioral plasticity. Here, we critically review how neuropeptides modulate a wide range of behaviors by allowing for changes in neuronal and synaptic signaling. This review will have a specific focus on feeding, mating, sleep, addiction, learning and locomotory behaviors in C. elegans. With a view to understand evolutionary relationships, we explore the functions and associated pathophysiology of C. elegans neuropeptides that are conserved across different phyla. Further, we discuss the mechanisms of neuropeptidergic signaling and how these signals are regulated in different behaviors. Finally, we attempt to provide insight into developing potential therapeutics for neuropeptide-related disorders.

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