scholarly journals Long-term activity drives dendritic branch elaboration of a C. elegans sensory neuron

2019 ◽  
Author(s):  
Jesse A Cohn ◽  
Elizabeth R Cebul ◽  
Giulio Valperga ◽  
Mario de Bono ◽  
Maxwell G Heiman ◽  
...  
Keyword(s):  
Sensory Neuron ◽  
Neuronal Activity ◽  
Morphological Changes ◽  
Model Organism ◽  
Neuronal Morphology ◽  
Sensory Transduction ◽  
Central Component ◽  
C Elegans ◽  
Activity Dependent

ABSTRACTNeuronal activity often leads to alterations in gene expression and cellular architecture. The nematode Caenorhabditis elegans, owing to its compact translucent nervous system, is a powerful system in which to study conserved aspects of the development and plasticity of neuronal morphology. Here we focus on one sensory neuron in the worm, termed URX, which senses oxygen and signals tonically proportional to environmental oxygen. Previous studies have reported that URX has variable branched endings at its dendritic sensory tip. By controlling oxygen levels and analyzing mutants, we found that these branched endings grow over time as a consequence of neuronal activity. Furthermore, we observed that the branches contain microtubules, but do not appear to harbor the guanylyl cyclase GCY-35, a central component of the oxygen sensory transduction pathway. Interestingly, we found that although URX dendritic tips grow branches in response to long-term activity, the degree of branch elaboration does not correlate with oxygen sensitivity at the cellular or the behavioral level. Given the strengths of C. elegans as a model organism, URX may serve as a potent system for uncovering genes and mechanisms involved in activity-dependent morphological changes in neurons.

scholarly journals Systematic identification of 3′-UTR regulatory elements in activity-dependent mRNA stability in hippocampal neurons

2014 ◽  
Vol 369 (1652) ◽  
pp. 20130509 ◽  
Author(s):  
Jonathan E. Cohen ◽  
Philip R. Lee ◽  
R. Douglas Fields
Keyword(s):  
Neuronal Activity ◽  
Mrna Stability ◽  
Hippocampal Neurons ◽  
Transcriptional Control ◽  
Regulatory Elements ◽  
Memory Storage ◽  
Long Term Memory ◽  
Synaptic Connections ◽  
Activity Dependent

Ongoing neuronal activity during development and plasticity acts to refine synaptic connections and contributes to the induction of plasticity and ultimately long-term memory storage. Activity-dependent, post-transcriptional control of mRNAs occurs through transport to axonal and dendritic compartments, local translation and mRNA stability. We have identified a mechanism that contributes to activity-dependent regulation of mRNA stability during synaptic plasticity in rat hippocampal neurons. In this study, we demonstrate rapid, post-transcriptional control over process-enriched mRNAs by neuronal activity. Systematic analysis of the 3′-UTRs of destabilized transcripts, identifies enrichment in sequence motifs corresponding to microRNA (miRNA)-binding sites. The miRNAs that were identified, miR-326-3p/miR-330-5p, miR-485-5p, miR-666-3p and miR-761 are predicted to regulate networks of genes important in plasticity and development. We find that these miRNAs are developmentally regulated in the hippocampus, many increasing by postnatal day 14. We further find that miR-485-5p controls NGF-induced neurite outgrowth in PC12 cells, tau expression and axonal development in hippocampal neurons. miRNAs can function at the synapse to rapidly control and affect short- and long-term changes at the synapse. These processes likely occur during refinement of synaptic connections and contribute to the induction of plasticity and learning and memory.

scholarly journals Repression of an activity-dependent autocrine insulin signal is required for sensory neuron development in C. elegans

Development ◽  
2019 ◽  
Vol 146 (22) ◽  
pp. dev182873 ◽  
Author(s):  
Lauren Bayer Horowitz ◽  
Julia P. Brandt ◽  
Niels Ringstad
Keyword(s):  
Sensory Neuron ◽  
Neuron Development ◽  
Insulin Signal ◽  
C Elegans ◽  
Activity Dependent

scholarly journals Tauopathy-associated tau modifications selectively impact neurodegeneration and mitophagy in a novel C. elegans single-copy transgenic model

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Sanjib Guha ◽  
Sarah Fischer ◽  
Gail V. W. Johnson ◽  
Keith Nehrke
Keyword(s):  
Genetic Model ◽  
Neurodegenerative Disorder ◽  
Model Organism ◽  
Single Copy ◽  
Neuronal Morphology ◽  
Mitochondrial Morphology ◽  
Mitochondrial Stress ◽  
C Elegans ◽  
Touch Receptor Neurons ◽  
New Perspective

Abstract Background A defining pathological hallmark of the progressive neurodegenerative disorder Alzheimer’s disease (AD) is the accumulation of misfolded tau with abnormal post-translational modifications (PTMs). These include phosphorylation at Threonine 231 (T231) and acetylation at Lysine 274 (K274) and at Lysine 281 (K281). Although tau is recognized to play a central role in pathogenesis of AD, the precise mechanisms by which these abnormal PTMs contribute to the neural toxicity of tau is unclear. Methods Human 0N4R tau (wild type) was expressed in touch receptor neurons of the genetic model organism C. elegans through single-copy gene insertion. Defined mutations were then introduced into the single-copy tau transgene through CRISPR-Cas9 genome editing. These mutations included T231E, to mimic phosphorylation of a commonly observed pathological epitope, and K274/281Q, to mimic disease-associated lysine acetylation – collectively referred as “PTM-mimetics” – as well as a T231A phosphoablation mutant. Stereotypical touch response assays were used to assess behavioral defects in the transgenic strains as a function of age. Genetically-encoded fluorescent biosensors were expressed in touch neurons and used to measure neuronal morphology, mitochondrial morphology, mitophagy, and macro autophagy. Results Unlike existing tau overexpression models, C. elegans single-copy expression of tau did not elicit overt pathological phenotypes at baseline. However, strains expressing disease associated PTM-mimetics (T231E and K274/281Q) exhibited reduced touch sensation and neuronal morphological abnormalities that increased with age. In addition, the PTM-mimetic mutants lacked the ability to engage neuronal mitophagy in response to mitochondrial stress. Conclusions Limiting the expression of tau results in a genetic model where modifications that mimic pathologic tauopathy-associated PTMs contribute to cryptic, stress-inducible phenotypes that evolve with age. These findings and their relationship to mitochondrial stress provides a new perspective into the pathogenic mechanisms underlying AD.

scholarly journals Actin Cytoskeleton Role in the Maintenance of Neuronal Morphology and Long-Term Memory

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1795
Author(s):  
Raphael Lamprecht
Keyword(s):  
Actin Cytoskeleton ◽  
Neuronal Network ◽  
Morphological Changes ◽  
Neuronal Morphology ◽  
Regulatory Proteins ◽  
Long Term Memory ◽  
Term Memory ◽  
Actin Regulatory Proteins ◽  
Spine Structure

Evidence indicates that long-term memory formation creates long-lasting changes in neuronal morphology within a specific neuronal network that forms the memory trace. Dendritic spines, which include most of the excitatory synapses in excitatory neurons, are formed or eliminated by learning. These changes may be long-lasting and correlate with memory strength. Moreover, learning-induced changes in the morphology of existing spines can also contribute to the formation of the neuronal network that underlies memory. Altering spines morphology after memory consolidation can erase memory. These observations strongly suggest that learning-induced spines modifications can constitute the changes in synaptic connectivity within the neuronal network that form memory and that stabilization of this network maintains long-term memory. The formation and elimination of spines and other finer morphological changes in spines are mediated by the actin cytoskeleton. The actin cytoskeleton forms networks within the spine that support its structure. Therefore, it is believed that the actin cytoskeleton mediates spine morphogenesis induced by learning. Any long-lasting changes in the spine morphology induced by learning require the preservation of the spine actin cytoskeleton network to support and stabilize the spine new structure. However, the actin cytoskeleton is highly dynamic, and the turnover of actin and its regulatory proteins that determine and support the actin cytoskeleton network structure is relatively fast. Molecular models, suggested here, describe ways to overcome the dynamic nature of the actin cytoskeleton and the fast protein turnover and to support an enduring actin cytoskeleton network within the spines, spines stability and long-term memory. These models are based on long-lasting changes in actin regulatory proteins concentrations within the spine or the formation of a long-lasting scaffold and the ability for its recurring rebuilding within the spine. The persistence of the actin cytoskeleton network within the spine is suggested to support long-lasting spine structure and the maintenance of long-term memory.

scholarly journals Alcohol Co-Administration Changes Mephedrone-Induced Alterations of Neuronal Activity

2021 ◽  
Vol 12 ◽  
Author(s):  
Milo Grotell ◽  
Bjørnar den Hollander ◽  
Aaro Jalkanen ◽  
Essi Törrönen ◽  
Jouni Ihalainen ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Morphological Changes ◽  
Brain Regions ◽  
Long Term Effects ◽  
Brain Scans ◽  
Ambient Temperatures ◽  
Delayed Effects ◽  
Golgi Staining ◽  
Adolescent Rats

Mephedrone (4-MMC), despite its illegal status, is still a widely used psychoactive substance. Its effects closely mimic those of the classical stimulant drug methamphetamine (METH). Recent research suggests that unlike METH, 4-MMC is not neurotoxic on its own. However, the neurotoxic effects of 4-MMC may be precipitated under certain circumstances, such as administration at high ambient temperatures. Common use of 4-MMC in conjunction with alcohol raises the question whether this co-consumption could also precipitate neurotoxicity. A total of six groups of adolescent rats were treated twice daily for four consecutive days with vehicle, METH (5 mg/kg) or 4-MMC (30 mg/kg), with or without ethanol (1.5 g/kg). To investigate persistent delayed effects of the administrations at two weeks after the final treatments, manganese-enhanced magnetic resonance imaging brain scans were performed. Following the scans, brains were collected for Golgi staining and spine analysis. 4-MMC alone had only subtle effects on neuronal activity. When administered with ethanol, it produced a widespread pattern of deactivation, similar to what was seen with METH-treated rats. These effects were most profound in brain regions which are known to have high dopamine and serotonin activities including hippocampus, nucleus accumbens and caudate-putamen. In the regions showing the strongest activation changes, no morphological changes were observed in spine analysis. By itself 4-MMC showed few long-term effects. However, when co-administered with ethanol, the apparent functional adaptations were profound and comparable to those of neurotoxic METH.

scholarly journals Long-term activity drives dendritic branch elaboration of a C. elegans sensory neuron

2020 ◽  
Vol 461 (1) ◽  
pp. 66-74 ◽  
Author(s):  
Jesse A. Cohn ◽  
Elizabeth R. Cebul ◽  
Giulio Valperga ◽  
Lotti Brose ◽  
Mario de Bono ◽  
...  
Keyword(s):  
Sensory Neuron ◽  
Dendritic Branch ◽  
C Elegans

scholarly journals Automated Platform for Long-Term Culture and High-Content Phenotyping of Single C. elegans Worms

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
H. B. Atakan ◽  
R. Xiang ◽  
M. Cornaglia ◽  
L. Mouchiroud ◽  
E. Katsyuba ◽  
...  
Keyword(s):  
High Throughput ◽  
Agar Plate ◽  
Model Organism ◽  
Suitable Model ◽  
Microfluidic Chips ◽  
Long Term Culture ◽  
C Elegans ◽  
Bleaching Procedure ◽  
Automated Platform

Abstract The nematode Caenorhabditis elegans is a suitable model organism in drug screening. Traditionally worms are grown on agar plates, posing many challenges for long-term culture and phenotyping of animals under identical conditions. Microfluidics allows for ‘personalized’ phenotyping, as microfluidic chips permit collecting individual responses over worms’ full life. Here, we present a multiplexed, high-throughput, high-resolution microfluidic approach to culture C. elegans from embryo to the adult stage at single animal resolution. We allocated single embryos to growth chambers, for observing the main embryonic and post-embryonic development stages and phenotypes, while exposing worms to up to 8 different well-controlled chemical conditions. Our approach allowed eliminating bacteria aggregation and biofilm formation-related clogging issues, which enabled us performing up to 80 hours of automated single worm culture studies. Our microfluidic platform is linked with an automated phenotyping code that registers organism-associated phenotypes at high-throughput. We validated our platform with a dose-response study of the anthelmintic drug tetramisole by studying its influence through the life cycle of the nematodes. In parallel, we could observe development effects and variations in single embryo and worm viability due to the bleaching procedure that is standardly used for harvesting the embryos from a worm culture agar plate.

scholarly journals HeALTH: An Automated Platform for Long-term Longitudinal Studies of Whole Organisms under Precise Environmental Control

2019 ◽  
Author(s):  
Kim N. Le ◽  
Mei Zhan ◽  
Yongmin Cho ◽  
Jason Wan ◽  
Dhaval S. Patel ◽  
...  
Keyword(s):  
Aging Process ◽  
Large Scale ◽  
Environmental Control ◽  
Model Organism ◽  
Model Systems ◽  
Aging Research ◽  
C Elegans ◽  
Environmental Perturbations ◽  
Automated Platform

ABSTRACTHealth and longevity in all organisms are strongly influenced by the environment. To fully understand how environmental factors interact with genetic and stochastic factors to modulate the aging process, it is crucial to precisely control environmental conditions for long-term studies. In the commonly used model organism Caenorhabditis elegans, existing assays for healthspan and lifespan have inherent limitations, making it difficult to perform large-scale, longitudinal aging studies under precise environmental control. To address this constraint, we developed the Health and Lifespan Testing Hub (HeALTH), an automated, microfluidic-based system for robust, long-term, longitudinal behavioral monitoring. Our system provides spatiotemporal environmental control. We demonstrate health and lifespan studies under a variety of genetic and environmental perturbations while observing how individuality plays a role in the aging process. This system is generalizable beyond aging research for C. elegans, particularly for short- or long-term behavioral assays, and is also possible to be adapted for other model systems.

Comparative assessment of morphological mechanisms of maintaining structural liver homeostasis in the dynamics of exposure to coal-rock dust and sodium fluoride on the body

2020 ◽  
pp. 189-194
Author(s):  
M. S. Bugaeva ◽  
O. I. Bondarev ◽  
N. N. Mikhailova ◽  
L. G. Gorokhova
Keyword(s):  
Sodium Fluoride ◽  
Morphological Changes ◽  
The Body ◽  
System Level ◽  
Production Factor ◽  
Coal Rock ◽  
The Impact ◽  
Structural Homeostasis ◽  
Rock Dust

Introduction. The impact on the body of such factors of the production environment as coal-rock dust and fluorine compounds leads to certain shift s in strict indicators of homeostasis at the system level. Maintaining the relative constancy of the internal environment of the body is provided by the functional consistency of all organs and systems, the leading of which is the liver. Organ repair plays a crucial role in restoring the structure of genetic material and maintaining normal cell viability. When this mechanism is damaged, the compensatory capabilities of the organ are disrupted, homeostasis is disrupted at the cellular and organizational levels, and the development of the main pathological processes is noted.The aim of the study is to compare the morphological mechanisms of maintaining structural homeostasis of the liver in the dynamics of the impact on the body of coal-rock dust and sodium fluoride.Materials and methods. Experimental studies were conducted on adult white male laboratory rats. Features of morphological mechanisms for maintaining structural homeostasis of the liver in the dynamics of exposure to coal-rock dust and sodium fluoride were studied on experimental models of pneumoconiosis and fluoride intoxication. For histological examination in experimental animals, liver sampling was performed after 1, 3, 6, 9, 12 weeks of the experiment.Results. The specificity of morphological changes in the liver depending on the harmful production factor was revealed. It is shown that chronic exposure to coal-rock dust and sodium fluoride is characterized by the development of similar morphological changes in the liver and its vessels from the predominance of the initial compensatory-adaptive to pronounced violations of the stromal and parenchymal components. Long-term inhalation of coal-rock dust at 1–3 weeks of seeding triggers adaptive mechanisms in the liver in the form of increased functional activity of cells, formation of double-core hepatocytes, activation of immunocompetent cells and endotheliocytes, ensuring the preservation of the parenchyma and the general morphostructure of the organ until the 12th week of the experiment. Exposure to sodium fluoride leads to early disruption of liver compensatory mechanisms and the development of dystrophic changes in the parenchyma with the formation of necrosis foci as early as the 6th week of the experiment.Conclusions. The study of mechanisms for compensating the liver structure in conditions of long-term exposure to coal-rock dust and sodium fluoride, as well as processes that indicate their failure, and the timing of their occurrence, is of theoretical and practical importance for developing recommendations for the timely prevention and correction of pathological conditions developing in employees of the aluminum and coal industry.The authors declare no conflict of interests.

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