Neuromodulation and Behavioral Flexibility in Larval Zebrafish: From Neurotransmitters to Circuits

Animals adapt their behaviors to their ever-changing needs. Internal states, such as hunger, fear, stress, and arousal are important behavioral modulators controlling the way an organism perceives sensory stimuli and reacts to them. The translucent zebrafish larva is an ideal model organism for studying neuronal circuits regulating brain states, owning to the possibility of easy imaging and manipulating activity of genetically identified neurons while the animal performs stereotyped and well-characterized behaviors. The main neuromodulatory circuits present in mammals can also be found in the larval zebrafish brain, with the advantage that they contain small numbers of neurons. Importantly, imaging and behavioral techniques can be combined with methods for generating targeted genetic modifications to reveal the molecular underpinnings mediating the functions of such circuits. In this review we discuss how studying the larval zebrafish brain has contributed to advance our understanding of circuits and molecular mechanisms regulating neuromodulation and behavioral flexibility.

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The Mechanisms Behind the Biological Activity of Flavonoids

Current Medicinal Chemistry ◽

10.2174/0929867325666180706104829 ◽

2019 ◽

Vol 26 (39) ◽

pp. 6976-6990 ◽

Cited By ~ 12

Author(s):

Ana María González-Paramás ◽

Begoña Ayuda-Durán ◽

Sofía Martínez ◽

Susana González-Manzano ◽

Celestino Santos-Buelga

Keyword(s):

Gene Expression ◽

Biological Activity ◽

Phenolic Compounds ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Radical Scavenging ◽

Model Organism ◽

Stress Theory ◽

Radical Scavenging Properties

: Flavonoids are phenolic compounds widely distributed in the human diet. Their intake has been associated with a decreased risk of different diseases such as cancer, immune dysfunction or coronary heart disease. However, the knowledge about the mechanisms behind their in vivo activity is limited and still under discussion. For years, their bioactivity was associated with the direct antioxidant and radical scavenging properties of phenolic compounds, but nowadays this assumption is unlikely to explain their putative health effects, or at least to be the only explanation for them. New hypotheses about possible mechanisms have been postulated, including the influence of the interaction of polyphenols and gut microbiota and also the possibility that flavonoids or their metabolites could modify gene expression or act as potential modulators of intracellular signaling cascades. This paper reviews all these topics, from the classical view as antioxidants in the context of the Oxidative Stress theory to the most recent tendencies related with the modulation of redox signaling pathways, modification of gene expression or interactions with the intestinal microbiota. The use of C. elegans as a model organism for the study of the molecular mechanisms involved in biological activity of flavonoids is also discussed.

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Xyloglucan processing machinery in Xanthomonas pathogens and its role in the transcriptional activation of virulence factors

Nature Communications ◽

10.1038/s41467-021-24277-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Plinio S. Vieira ◽

Isabela M. Bonfim ◽

Evandro A. Araujo ◽

Ricardo R. Melo ◽

Augusto R. Lima ◽

...

Keyword(s):

Virulence Factors ◽

Transcriptional Activation ◽

Molecular Mechanisms ◽

Model Organism ◽

Citrus Canker ◽

Effector Proteins ◽

Glycoside Hydrolases ◽

Host Cells ◽

System A ◽

Enzymatic Machinery

AbstractXyloglucans are highly substituted and recalcitrant polysaccharides found in the primary cell walls of vascular plants, acting as a barrier against pathogens. Here, we reveal that the diverse and economically relevant Xanthomonas bacteria are endowed with a xyloglucan depolymerization machinery that is linked to pathogenesis. Using the citrus canker pathogen as a model organism, we show that this system encompasses distinctive glycoside hydrolases, a modular xyloglucan acetylesterase and specific membrane transporters, demonstrating that plant-associated bacteria employ distinct molecular strategies from commensal gut bacteria to cope with xyloglucans. Notably, the sugars released by this system elicit the expression of several key virulence factors, including the type III secretion system, a membrane-embedded apparatus to deliver effector proteins into the host cells. Together, these findings shed light on the molecular mechanisms underpinning the intricate enzymatic machinery of Xanthomonas to depolymerize xyloglucans and uncover a role for this system in signaling pathways driving pathogenesis.

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Abstract 3407: The Transcriptional Mediator Complex Is Essential For Cardiac Valve Formation

Circulation ◽

10.1161/circ.118.suppl_18.s_418-d ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Steffen Just ◽

Ina Berger ◽

Benjamin Meder ◽

David Hassel ◽

Alexander Hess ◽

...

Keyword(s):

Molecular Mechanisms ◽

Model Organism ◽

Mutant Phenotype ◽

Cardiac Valve ◽

Mediator Complex ◽

Zebrafish Embryos ◽

Sequence Alignments ◽

Human Cardiomyocytes ◽

Ping Pong ◽

Valve Formation

The genetic causes of congenital heart diseases especially cardiac valve disorders are mostly unknown. During the last decade, the zebrafish became an excellent and established model organism (1) to uncover these genetic defects and (2) to elucidate the underlying molecular pathomechanisms. We recently isolated the zebrafish mutation ping pong ( png m683 ) in a large-scale ENU-mutagenesis screen for recessive lethal mutations that perturb cardiac function. png mutant zebrafish embryos show pathologically developed cardiac valves. Due to malformation of the cardiac AV valves, png mutant zebrafish embryos exhibit vigorous regurgitation of blood between the atrium and the ventricle. Furthermore, as a result of the cardiac valve malformation and cardiac dysfunction png mutants die at day 6 post fertilization. Expression of several factors known to be crucial for the proper development and formation of the atrio-ventricluar canal (e.g. notch1b, bmp4 or versican) is significantly altered in png mutant zebrafish hearts. By a positional cloning approach we demonstrate that the ping pong phenotype is caused by a promotor mutation in a zebrafish gene encoding for a novel component of the “transcriptional mediator complex”. This mediator complex is a multi-protein complex that acts as a transcriptional coactivator and transduces informations from transcription factors to the RNA polymerase II. png is strongly expressed in zebrafish as well as human cardiomyocytes. Furthermore, sequence alignments demonstrate the evolutionary conservation of the ping pong gene product. Gene specific knock-down studies by means of modified antisense oligonucleotides reveal a phenocopy of the png mutant phenotype whereas injection of the gene-specific mRNA in png mutant embryos restores the mutant phenotype indicating that png is indeed responsible for the observed phenotype. The zebrafish evolved as an excellent model organism to study the molecular signalling pathways involved in cardiac valve formation. By detailed characterization of the zebrafish line ping pong we will obtain new insights into these molecular mechanisms especially the transcriptional control of valve formation and therefore the pathomechanisms of human cardiac valve disorders.

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Stochastic left–right neuronal asymmetry in Caenorhabditis elegans

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2015.0407 ◽

2016 ◽

Vol 371 (1710) ◽

pp. 20150407 ◽

Cited By ~ 16

Author(s):

Amel Alqadah ◽

Yi-Wen Hsieh ◽

Rui Xiong ◽

Chiou-Fen Chuang

Keyword(s):

Caenorhabditis Elegans ◽

Molecular Mechanisms ◽

Neurological Diseases ◽

Calcium Signalling ◽

Model Organism ◽

Brain Asymmetry ◽

C Elegans ◽

Left And Right ◽

Left Right Asymmetry ◽

Neuronal Asymmetry

Left–right asymmetry in the nervous system is observed across species. Defects in left–right cerebral asymmetry are linked to several neurological diseases, but the molecular mechanisms underlying brain asymmetry in vertebrates are still not very well understood. The Caenorhabditis elegans left and right amphid wing ‘C’ (AWC) olfactory neurons communicate through intercellular calcium signalling in a transient embryonic gap junction neural network to specify two asymmetric subtypes, AWC OFF (default) and AWC ON (induced), in a stochastic manner. Here, we highlight the molecular mechanisms that establish and maintain stochastic AWC asymmetry. As the components of the AWC asymmetry pathway are highly conserved, insights from the model organism C. elegans may provide a window onto how brain asymmetry develops in humans. This article is part of the themed issue ‘Provocative questions in left–right asymmetry’.

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Transgenic Epigenetics: Using Transgenic Organisms to Examine Epigenetic Phenomena

Genetics Research International ◽

10.1155/2012/689819 ◽

2012 ◽

Vol 2012 ◽

pp. 1-14 ◽

Cited By ~ 2

Author(s):

Lori A. McEachern

Keyword(s):

Molecular Mechanisms ◽

Model Organism ◽

Evolutionary Conservation ◽

Model Organisms ◽

Valuable Insight ◽

Epigenetic Control ◽

Transgenic Organisms ◽

Epigenetic Analysis ◽

Insight Into ◽

Epigenetic Processes

Non-model organisms are generally more difficult and/or time consuming to work with than model organisms. In addition, epigenetic analysis of model organisms is facilitated by well-established protocols, and commercially-available reagents and kits that may not be available for, or previously tested on, non-model organisms. Given the evolutionary conservation and widespread nature of many epigenetic mechanisms, a powerful method to analyze epigenetic phenomena from non-model organisms would be to use transgenic model organisms containing an epigenetic region of interest from the non-model. Interestingly, while transgenic Drosophila and mice have provided significant insight into the molecular mechanisms and evolutionary conservation of the epigenetic processes that target epigenetic control regions in other model organisms, this method has so far been under-exploited for non-model organism epigenetic analysis. This paper details several experiments that have examined the epigenetic processes of genomic imprinting and paramutation, by transferring an epigenetic control region from one model organism to another. These cross-species experiments demonstrate that valuable insight into both the molecular mechanisms and evolutionary conservation of epigenetic processes may be obtained via transgenic experiments, which can then be used to guide further investigations and experiments in the species of interest.

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Regeneration, Plasticity, and Induced Molecular Programs in Adult Zebrafish Brain

BioMed Research International ◽

10.1155/2015/769763 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 17

Author(s):

Mehmet Ilyas Cosacak ◽

Christos Papadimitriou ◽

Caghan Kizil

Keyword(s):

Neural Plasticity ◽

Molecular Mechanisms ◽

Clinical Settings ◽

Regenerative Capacity ◽

Zebrafish Brain ◽

Aquatic Vertebrates ◽

Neural Stem Progenitor Cells ◽

Set Up ◽

Regenerative Therapies ◽

The Brain

Regenerative capacity of the brain is a variable trait within animals. Aquatic vertebrates such as zebrafish have widespread ability to renew their brains upon damage, while mammals have—if not none—very limited overall regenerative competence. Underlying cause of such a disparity is not fully evident; however, one of the reasons could be activation of peculiar molecular programs, which might have specific roles after injury or damage, by the organisms that regenerate. If this hypothesis is correct, then there must be genes and pathways that (a) are expressed only after injury or damage in tissues, (b) are biologically and functionally relevant to restoration of neural tissue, and (c) are not detected in regenerating organisms. Presence of such programs might circumvent the initial detrimental effects of the damage and subsequently set up the stage for tissue redevelopment to take place by modulating the plasticity of the neural stem/progenitor cells. Additionally, if transferable, those “molecular mechanisms of regeneration” could open up new avenues for regenerative therapies of humans in clinical settings. This review focuses on the recent studies addressing injury/damage-induced molecular programs in zebrafish brain, underscoring the possibility of the presence of genes that could be used as biomarkers of neural plasticity and regeneration.

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Epigenetic Effects Induced by Methamphetamine and Methamphetamine-Dependent Oxidative Stress

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/4982453 ◽

2018 ◽

Vol 2018 ◽

pp. 1-28 ◽

Cited By ~ 18

Author(s):

Fiona Limanaqi ◽

Stefano Gambardella ◽

Francesca Biagioni ◽

Carla L. Busceti ◽

Francesco Fornai

Keyword(s):

Molecular Mechanisms ◽

Neuropsychiatric Disorders ◽

Behavioral Alterations ◽

Neuronal Phenotype ◽

Cellular Events ◽

Epigenetic Effects ◽

Molecular Events ◽

Epigenetic Events ◽

Genetic Modifications ◽

Altered Gene

Methamphetamine is a widely abused drug, which possesses neurotoxic activity and powerful addictive effects. Understanding methamphetamine toxicity is key beyond the field of drug abuse since it allows getting an insight into the molecular mechanisms which operate in a variety of neuropsychiatric disorders. In fact, key alterations produced by methamphetamine involve dopamine neurotransmission in a way, which is reminiscent of spontaneous neurodegeneration and psychiatric schizophrenia. Thus, understanding the molecular mechanisms operated by methamphetamine represents a wide window to understand both the addicted brain and a variety of neuropsychiatric disorders. This overlapping, which is already present when looking at the molecular and cellular events promoted immediately after methamphetamine intake, becomes impressive when plastic changes induced in the brain of methamphetamine-addicted patients are considered. Thus, the present manuscript is an attempt to encompass all the molecular events starting at the presynaptic dopamine terminals to reach the nucleus of postsynaptic neurons to explain how specific neurotransmitters and signaling cascades produce persistent genetic modifications, which shift neuronal phenotype and induce behavioral alterations. A special emphasis is posed on disclosing those early and delayed molecular events, which translate an altered neurotransmitter function into epigenetic events, which are derived from the translation of postsynaptic noncanonical signaling into altered gene regulation. All epigenetic effects are considered in light of their persistent changes induced in the postsynaptic neurons including sensitization and desensitization, priming, and shift of neuronal phenotype.

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A novel calcium-concentrating compartment drives biofilm formation and persistent infections

10.1101/2020.01.08.898569 ◽

2020 ◽

Author(s):

Alona Keren-Paz ◽

Malena Cohen-Cymberknoh ◽

Dror Kolodkin-Gal ◽

Iris Karunker ◽

Simon Dersch ◽

...

Keyword(s):

Biofilm Formation ◽

Calcium Uptake ◽

Molecular Mechanisms ◽

Model Organism ◽

Bacterial Cells ◽

Mineral Layer ◽

Cellular Compartment ◽

Persistent Infections ◽

Cellular Metal

AbstractBacterial biofilms produce a robust internal mineral layer, composed of calcite, which strengthens the colony and protects the residing bacteria from antibiotics. In this work, we provide evidence that the assembly of a functional mineralized macro-structure begins with mineral precipitation within a defined cellular compartment in a differentiated subpopulation of cells. Transcriptomic analysis of a model organism, Bacillus subtilis, revealed that calcium was essential for activation of the biofilm state, and highlighted the role of cellular metal homeostasis and carbon metabolism in biomineralization. The molecular mechanisms promoting calcite formation were conserved in pathogenic Pseudomonas aeruginosa biofilms, resulting in formation of calcite crystals tightly associated with bacterial cells in sputum samples collected from cystic fibrosis patients. Biomineralization inhibitors targeting calcium uptake and carbonate accumulation significantly reduced the damage inflicted by P. aeruginosa biofilms to lung tissues. Therefore, better understanding of the conserved molecular mechanisms promoting biofilm calcification can path the way to the development of novel classes of antibiotics to combat otherwise untreatable biofilm infections.

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The C. elegans Hypertonic Stress Response: Big Insights from Shrinking Worms

Cellular Physiology and Biochemistry ◽

10.33594/000000332 ◽

2020 ◽

Vol 55 (S1) ◽

pp. 89-105

Keyword(s):

Stress Response ◽

Cell Volume ◽

Molecular Mechanisms ◽

Model Organism ◽

Future Research ◽

Transcriptional Level ◽

Molecular Signaling ◽

Hypertonic Stress ◽

Macromolecular Assemblies ◽

C Elegans

Cell volume is one of the most aggressively defended physiological set points in biology. Changes in intracellular ion and water concentrations, which are induced by changes in metabolism or environmental exposures, disrupt protein folding, enzymatic activity, and macromolecular assemblies. To counter these challenges, cells and organisms have evolved multifaceted, evolutionarily conserved molecular mechanisms to restore cell volume and repair stress induced damage. However, many unanswered questions remain regarding the nature of cell volume 'sensing' as well as the molecular signaling pathways involved in activating physiological response mechanisms. Unbiased genetic screening in the model organism C. elegans is providing new and unexpected insights into these questions, particularly questions relating to the hypertonic stress response (HTSR) pathway. One surprising characteristic of the HTSR pathway in C. elegans is that it is under strong negative regulation by proteins involved in protein homeostasis and the extracellular matrix (ECM). The role of the ECM in particular highlights the importance of studying the HTSR in the context of a live organism where native ECM-tissue associations are preserved. A second novel and recently discovered characteristic is that the HTSR is regulated at the post-transcriptional level. The goal of this review is to describe these discoveries, to provide context for their implications, and to raise outstanding questions to guide future research.

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Colourfulness as a possible measure of object proximity in the larval zebrafish brain

10.1101/2020.12.03.410241 ◽

2020 ◽

Author(s):

Philipp Bartel ◽

Filip K Janiak ◽

Daniel Osorio ◽

Tom Baden

Keyword(s):

Dynamic Range ◽

Red Light ◽

Visible Spectrum ◽

Visual Ecology ◽

Neural Representation ◽

Spectral Tuning ◽

Fish Brain ◽

Visual Neurons ◽

Zebrafish Brain ◽

Larval Zebrafish

The encoding of light increments and decrements by separate On- and Off- systems is a fundamental ingredient of vision, which supports the detection of edges in space and time and makes efficient use of limited dynamic range of visual neurons [1]. Theory predicts that the neural representation of On- and Off-signals should be approximately balanced, including across an animals’ full visible spectrum. Here we find that larval zebrafish violate this textbook expectation: in the fish brain, UV-stimulation near exclusively gives On-responses, blue/green-stimulation mostly Off- responses, and red-light alone elicits approximately balanced On- and Off-responses (see also [2–4]). We link these findings to zebrafish visual ecology, and suggest that the observed spectral tuning boosts the encoding of object “colourfulness”, which correlates with object proximity in their underwater world [5].

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