Neural and genetic degeneracy underlies Caenorhabditis elegans feeding behavior

Degenerate networks, in which structurally distinct elements can perform the same function or yield the same output, are ubiquitous in biology. Degeneracy contributes to the robustness and adaptability of networks in varied environmental and evolutionary contexts. However, how degenerate neural networks regulate behavior in vivo is poorly understood, especially at the genetic level. Here, we identify degenerate neural and genetic mechanisms that underlie excitation of the pharynx (feeding organ) in the nematode Caenorhabditis elegans using cell-specific optogenetic excitation and inhibition. We show that the pharyngeal neurons MC, M2, M4, and I1 form multiple direct and indirect excitatory pathways in a robust network for control of pharyngeal pumping. I1 excites pumping via MC and M2 in a state-dependent manner. We identify nicotinic and muscarinic receptors through which the pharyngeal network regulates feeding rate. These results identify two different mechanisms by which degeneracy is manifest in a neural circuit in vivo.

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Piquiá Shells (Caryocar villosum): A Fruit by-Product with Antioxidant and Antiaging Properties in Caenorhabditis elegans

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/7590707 ◽

2020 ◽

Vol 2020 ◽

pp. 1-19 ◽

Cited By ~ 1

Author(s):

Mariana Roxo ◽

Herbenya Peixoto ◽

Pille Wetterauer ◽

Emerson Lima ◽

Michael Wink

Keyword(s):

Caenorhabditis Elegans ◽

Lethal Dose ◽

Pcr Analysis ◽

Transcriptional Level ◽

Dependent Manner ◽

Wild Type ◽

Fluorescent Reporter ◽

Triterpenoid Saponins ◽

Promising Source

In a context of rising demand for sustainable antiaging interventions, fruit processing by-products are a promising source of bioactive compounds for the production of antiaging dietary supplements. Piquiá (Caryocar villosum) is a native Amazonian fruit consisting of 65% nonedible shells. In the present study, the phytochemical profile of a hydroalcoholic extract of piquiá shells (CV) was characterized by LC-MS/MS analysis. Its antioxidant and antiaging activities were investigated using the nematode Caenorhabditis elegans as an in vivo model. CV is mainly composed by hydrolysable tannins and triterpenoid saponins. The extract enhanced stress resistance of wild-type and mutant worms by reducing the intracellular levels of reactive oxygen species (ROS) and by increasing their survival against a lethal dose of the prooxidant juglone. These effects involved the upregulation of sod-3 and downregulation of gst-4 and hsp-16.2, studied through the GFP fluorescent reporter intensity and at the transcriptional level by qRT-PCR analysis. CV extended the lifespan of wild-type worms in a DAF-16/FoxO- and SKN-1/Nrf-dependent manner. Taken together, our findings indicate piquiá shells as potential candidates for nutraceutical applications. Further studies are needed to validate the relevance of our findings to antiaging interventions in humans.

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Caenorhabditis elegans model for admixed proteinopathy of Huntington’s and Alzheimer-type

10.1101/648923 ◽

2019 ◽

Author(s):

Wadim J. Kapulkin

Keyword(s):

Caenorhabditis Elegans ◽

Clinical Symptoms ◽

Fluorescent Proteins ◽

Amyloid Formation ◽

Dependent Manner ◽

Huntington's Chorea ◽

C Elegans ◽

Pathogenic Variants ◽

Models Of Disease

ABSTRACTFormation of proteinaceous deposits composed of abnormally aggregated proteins characterizes a range of pathological conditions. Proteinaceous inclusions detected in the neurodegenerative conditions such Huntington’s chorea (HD) and Alzheimer’s disease (AD) are often referred as pathognomic and regarded as causally implicated. Despite of differences in aetiology and underlying genetics, rare cases of combined HD and AD were reported and described as admixed proteinopathies. Mixed proteopathies are characterized by the co-occurrence of at least two types of abnormal aggregation-prone variants; pathological deposition of proteinaceous inclusions might however, affect different cell populations. Here, combining plaques derived from human ß-amyloid with mutant HTT-like polyglutamine inclusions in a cell-autonomous manner, we report on the Caenorhabditis elegans model for admixed proteinopathy of Alzheimer’s and Huntington’s type. We show both types of intracellular foci are formed in vivo: non-amyloidic extended polyglutamine derived inclusions and distinguish those from the presence of mature ß- amyloid fibers. We found that polyglutamines expanded above pathogenic threshold and ß-amyloid act synergistically to promote the progression of proteotoxicity in a temperature dependent manner. We further, implicate the hsp-1 (the predominant C. elegans chaperone interacting with ER-routed Aß42) modulate the proteotoxic insults observed in combined proteopathy model. Our results demonstrate how the in vivo model of admixed proteopathy could be utilized to probe for human pathogenic variants confined to the same cellular type. In that perspective expanded aggregation-prone polyglutamines appended with fluorescent proteins could be regarded as ‘pathogenic probes’ useful in the proteotoxicity assays i.e. involving ß-amyloid and possibly other comparable models of disease-associated aggregation prone variants.We anticipate models of combined proteopathies will be informative regarding the underlying pathogenesis and provide the sensitized background for sophisticated screening. For example the combinatorial effects of multiple pathogenic aggregation-prone variants could be tested against mutant backgrounds and pharmacological compounds. Furthermore, we surmise the postulated synergistic actions might explain some of the overlaps in observed progression of clinical symptoms in HD and AD. We also formulate the conjecture regarding the polyQ containing proteins as a contributing factor in degenerative conditions associated with increased ß-amyloid formation and deposition.

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The Caenorhabditis elegans p120 catenin homologue, JAC-1, modulates cadherin–catenin function during epidermal morphogenesis

The Journal of Cell Biology ◽

10.1083/jcb.200212136 ◽

2003 ◽

Vol 162 (1) ◽

pp. 15-22 ◽

Cited By ~ 94

Author(s):

Jonathan Pettitt ◽

Elisabeth A. Cox ◽

Ian D. Broadbent ◽

Aileen Flett ◽

Jeff Hardin

Keyword(s):

Caenorhabditis Elegans ◽

Mammalian Cells ◽

Adherens Junctions ◽

Complex Function ◽

Family Members ◽

Dependent Manner ◽

P120 Catenin ◽

Epidermal Morphogenesis

The cadherin–catenin complex is essential for tissue morphogenesis during animal development. In cultured mammalian cells, p120 catenin (p120ctn) is an important regulator of cadherin–catenin complex function. However, information on the role of p120ctn family members in cadherin-dependent events in vivo is limited. We have examined the role of the single Caenorhabditis elegans p120ctn homologue JAC-1 (juxtamembrane domain [JMD]–associated catenin) during epidermal morphogenesis. Similar to other p120ctn family members, JAC-1 binds the JMD of the classical cadherin HMR-1, and GFP-tagged JAC-1 localizes to adherens junctions in an HMR-1–dependent manner. Surprisingly, depleting JAC-1 expression using RNA interference (RNAi) does not result in any obvious defects in embryonic or postembryonic development. However, jac-1(RNAi) does increase the severity and penetrance of morphogenetic defects caused by a hypomorphic mutation in the hmp-1/α-catenin gene. In these hmp-1 mutants, jac-1 depletion causes failure of the embryo to elongate into a worm-like shape, a process that involves contraction of the epidermis. Associated with failed elongation is the detachment of actin bundles from epidermal adherens junctions and failure to maintain cadherin in adherens junctions. These results suggest that JAC-1 acts as a positive modulator of cadherin function in C. elegans.

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CaMK (CMK-1) and O-GlcNAc transferase (OGT-1) modulate mechanosensory responding and habituation in an interstimulus interval-dependent manner in Caenorhabditis elegans

10.1101/115972 ◽

2017 ◽

Cited By ~ 2

Author(s):

Evan L. Ardiel ◽

Troy A. McDiarmid ◽

Tiffany A. Timbers ◽

Kirsten C. Y. Lee ◽

Javad Safaei ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Interstimulus Interval ◽

Behavioral Plasticity ◽

Neural Circuit ◽

Model Organisms ◽

Dependent Manner ◽

Mechanical Stimuli ◽

C Elegans ◽

Mutant Phenotypes ◽

Glcnac Transferase

AbstractThe ability to learn is an evolutionarily conserved adaptation that remains incompletely understood. Genetically tractable model organisms facilitate mechanistic explanations of learning that span genetic, neural circuit, and behavioural levels. Many aspects of neural physiology, including processes that underlie learning (e.g. neurotransmitter release and long-lasting changes in synaptic strength), are regulated by brief and local changes in [μm] levels of free intracellular Ca2+. On this scale, changes in [Ca2+] activate many Ca2+-sensors, including the Ca2+/calmodulin-dependent kinases (CaMKs). Here we reveal that the Caenorhabditis elegans ortholog of CaMK1/4, CMK-1, functions in primary sensory neurons to regulate responses to mechanical stimuli and behavioral plasticity, specifically habituation, a conserved form of non-associative learning. The habituation phenotypes of cmk-1 mutants were dependent on interstimulus interval (ISI), such that CMK-1 slows habituation at short ISIs, but promotes it at long ISIs. We predicted potential CaMK phosphorylation targets from catalytic site analysis of the human and C. elegans CaMKs and mutant analysis of these candidates implicated O-linked N-acetylglucosamine (O-GlcNAc) transferase, OGT-1, in mechanosensitivity and learning. Cell specific rescue and knockdown experiments showed that both CMK-1 and OGT-1 function cell autonomously in mechanosensory neurons to modulate learning. Interestingly, despite their similar mutant phenotypes, detailed behavioral analysis of double mutants demonstrated that CMK-1 and OGT-1 act in parallel genetic pathways. Our research identifies CMK-1 and OGT-1 as co-expressed yet independent regulators of mechanosensitivity and learning.

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Oscillations in the Basolateral Amygdala: Aversive Stimulation Is State Dependent and Resets the Oscillatory Phase

Journal of Neurophysiology ◽

10.1152/jn.00438.2009 ◽

2009 ◽

Vol 102 (3) ◽

pp. 1379-1387 ◽

Cited By ~ 9

Author(s):

James W. Crane ◽

Francois Windels ◽

Pankaj Sah

Keyword(s):

Cortical Neurons ◽

Basolateral Amygdala ◽

Aversive Stimulation ◽

Oscillatory Activity ◽

Resting Membrane Potential ◽

Dependent Manner ◽

Somatosensory Stimulation ◽

State Dependent ◽

Up States

Slow oscillations (<1 Hz) in neural activity occur during sleep and quiet wakefulness in both animals and humans. Here we show that in urethan-anesthetized animals, neurons in the basolateral amygdala in vivo display a slow oscillation between resting membrane potential (down-state) and depolarized potentials (up-states) occurring at a frequency of ∼0.3 Hz. This oscillation is insensitive to the holding potential and continues unabated under voltage clamp, indicating that up-states are synaptically driven. Somatosensory stimulation (footshock) delivered during the down-state evoked an all-or-none transition into an up-state. When delivered during down-states, footshocks triggered up-states and reset the phase of the neural oscillation, effectively synchronizing activity in the basolateral amygdala. This phase reset was reproduced by posterior thalamus stimulation, confirming that it was mediated by aversive sensory input. In contrast, a footshock delivered during the up-state was ineffective in stimulating BLA neurons. We conclude that oscillatory activity in the basolateral amygdala is driven by ensembles of cortical neurons. These ensembles gate the response of amygdala neurons to aversive stimulation in a state-dependent manner. Aversive stimulation is effective when the network is in the down-state but ineffective when the network is in an up-state.

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Effects of NO-Donors on Thrombus Formation and Microcirculation in Cerebral Vessels of the Rat

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650532 ◽

1996 ◽

Vol 76 (01) ◽

pp. 111-117 ◽

Cited By ~ 10

Author(s):

Yasuto Sasaki ◽

Junji Seki ◽

John C Giddings ◽

Junichiro Yamamoto

Keyword(s):

Blood Flow ◽

Thrombus Formation ◽

Dependent Manner ◽

Red Cell ◽

Cell Velocity ◽

Red Cell Velocity ◽

The Mean ◽

Wall Shear ◽

Dose Dependent

SummarySodium nitroprusside (SNP) and 3-morpholinosydnonimine (SIN-1), are known to liberate nitric oxide (NO). In this study the effects of SNP and SIN-1 on thrombus formation in rat cerebral arterioles and venules in vivo were assessed using a helium-neon (He-Ne) laser. SNP infused at doses from 10 Μg/kg/h significantly inhibited thrombus formation in a dose dependent manner. This inhibition of thrombus formation was suppressed by methylene blue. SIN-1 at a dose of 100 Μg/kg/h also demonstrated a significant antithrombotic effect. Moreover, treatment with SNP increased vessel diameter in a dose dependent manner and enhanced the mean red cell velocity measured with a fiber-optic laser-Doppler anemometer microscope (FLDAM). Blood flow, calculated from the mean red cell velocity and vessel diameters was increased significantly during infusion. In contrast, mean wall shear rates in the arterioles and venules were not changed by SNP infusion. The results indicated that SNP and SIN-1 possessed potent antithrombotic activities, whilst SNP increased cerebral blood flow without changing wall shear rate. The findings suggest that the NO released by SNP and SIN-1 may be beneficial for the treatment and protection of cerebral infarction

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The Effect of Active Site-inhibited Factor VIIa on Tissue Factor-initiated Coagulation Using Platelets before and after Aspirin Administration

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657715 ◽

1997 ◽

Vol 78 (04) ◽

pp. 1202-1208 ◽

Cited By ~ 18

Author(s):

Marianne Kjalke ◽

Julie A Oliver ◽

Dougald M Monroe ◽

Maureane Hoffman ◽

Mirella Ezban ◽

...

Keyword(s):

Tissue Factor ◽

Active Site ◽

Large Scale ◽

Thrombin Generation ◽

Factor Viia ◽

Dependent Manner ◽

Antithrombotic Agent ◽

Before And After ◽

Ic50 Values

SummaryActive site-inactivated factor VIIa has potential as an antithrombotic agent. The effects of D-Phe-L-Phe-L-Arg-chloromethyl ketone-treated factor VIla (FFR-FVIIa) were evaluated in a cell-based system mimicking in vivo initiation of coagulation. FFR-FVIIa inhibited platelet activation (as measured by expression of P-selectin) and subsequent large-scale thrombin generation in a dose-dependent manner with IC50 values of 1.4 ± 0.8 nM (n = 8) and 0.9 ± 0.7 nM (n = 7), respectively. Kd for factor VIIa binding to monocytes ki for FFR-FVIIa competing with factor VIIa were similar (11.4 ± 0.8 pM and 10.6 ± 1.1 pM, respectively), showing that FFR-FVIIa binds to tissue factor in the tenase complex with the same affinity as factor VIIa. Using platelets from volunteers before and after ingestion of aspirin (1.3 g), there were no significant differences in the IC50 values of FFR-FVIIa [after aspirin ingestion, the IC50 values were 1.7 ± 0.9 nM (n = 8) for P-selectin expression, p = 0.37, and 1.4 ± 1.3 nM (n = 7) for thrombin generation, p = 0.38]. This shows that aspirin treatment of platelets does not influence the inhibition of tissue factor-initiated coagulation by FFR-FVIIa, probably because thrombin activation of platelets is not entirely dependent upon expression of thromboxane A2.

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