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Abstract Primary (non-motile) cilia represent structurally and functionally diverse organelles whose roles as specialized cellular antenna are central to animal cell signaling pathways, sensory physiology and development. An ever-growing number of ciliary proteins, including those found in vertebrate photoreceptors, have been uncovered and linked to human disorders termed ciliopathies. Here, we demonstrate that an evolutionarily-conserved PPEF-family serine-threonine phosphatase, not functionally linked to cilia in any organism but associated with rhabdomeric (non-ciliary) photoreceptor degeneration in the Drosophila rdgC (retinal degeneration C) mutant, is a bona fide ciliary protein in C. elegans. The nematode protein, PEF-1, depends on transition zone proteins, which make up a ‘ciliary gate’ in the proximal-most region of the cilium, for its compartmentalization within cilia. Animals lacking PEF-1 protein function display structural defects to several types of cilia, including potential degeneration of microtubules. They also exhibit anomalies to cilium-dependent behaviors, including impaired responses to chemical, temperature, light, and noxious CO2 stimuli. Lastly, we demonstrate that PEF-1 function depends on conserved myristoylation and palmitoylation signals. Collectively, our findings broaden the role of PPEF proteins to include cilia, and suggest that the poorly-characterized mammalian PPEF1 and PPEF2 orthologs may also have ciliary functions and thus represent ciliopathy candidates.

Metabolic dysfunction-associated steatohepatitis (MASH) is the progressive form of liver steatosis, the most common liver disease, and substantially increases the mortality rate. However, limited therapies are currently available to prevent MASH development. Identifying potential pharmacological treatments for the condition has been hampered by its heterogeneous and complex nature. Here, we identified a hepatic nonneuronal cholinergic signaling pathway required for metabolic adaptation to caloric overload. We found that cholinergic receptor nicotinic alpha 2 subunit (CHRNA2) is highly expressed in hepatocytes of mice and humans. Further, CHRNA2 is activated by a subpopulation of local acetylcholine-producing macrophages during MASH development. The activation of CHRNA2 coordinates defensive programs against a broad spectrum of MASH-related pathogenesis, including steatosis, inflammation, and fibrosis. Hepatocyte-specific loss of CHRNA2 signaling accelerates the disease onset in different MASH mouse models. Activation of this pathway via pharmacological inhibition of acetylcholine degradation protects against MASH development. Our study uncovers a hepatic nicotinic cholinergic receptor pathway that constitutes a cell-autonomous self-defense route against prolonged metabolic stress and holds therapeutic potential for combatting human MASH.

How neural circuits drive behavior is a central question in neuroscience. Proper execution of motor behavior requires precise coordination of many neurons. Within a motor circuit, individual neurons tend to play discrete roles by promoting or suppressing motor output. How exactly neurons function in specific roles to fine tune motor output is not well understood. In C. elegans, the interneuron RIM plays important yet complex roles in locomotion behavior. Here, we show that RIM both promotes and suppresses distinct features of locomotion behavior to fine tune motor output. This dual function is achieved via the excitation and inhibition of the same motor circuit by electrical and chemical neurotransmission, respectively. Additionally, this bi-directional regulation contributes to motor adaptation in animals placed in novel environments. Our findings reveal that individual neurons within a neural circuit may act in opposing ways to regulate circuit dynamics to fine tune behavioral output.

Summary: Reducing the rate of translation promotes longevity in multiple organisms, representing a conserved mechanism for lifespan extension. Aminoacyl-tRNA synthetases (ARSs) catalyze the loading of amino acids to their cognate tRNAs, thereby playing an essential role in translation. Mutations in ARS genes are associated with various human diseases. However, little is known about the role of ARSs in aging, particularly whether and how these genes regulate lifespan. Here, using Caenorhabditis elegans as a model, we systematically characterized the role of all three types of ARS genes in lifespan regulation, including mitochondrial, cytoplasmic, and cyto-mito bifunctional ARS genes. We found that, as expected, RNAi knockdown of mitochondrial ARS genes extended lifespan. Surprisingly, knocking down cytoplasmic or cyto-mito bifunctional ARS genes shortened lifespan, though such treatment reduced the rate of translation. These results reveal opposing roles of mitochondrial and cytoplasmic ARSs in lifespan regulation, demonstrating that inhibiting translation may not always extend lifespan.

The eyeless C. elegans exhibits robust phototaxis behavior in response to short-wavelength light, particularly UV light. C. elegans senses light through LITE-1, a unique photoreceptor protein that belongs to the invertebrate taste receptor family. However, it remains unclear how LITE-1 is regulated. Here, we performed a forward genetic screen for genes that when mutated suppress LITE-1 function. One group of lite-1 suppressors are the genes required for producing the two primary antioxidants thioredoxin and glutathione, suggesting that oxidization of LITE-1 inhibits its function. Indeed, the oxidant hydrogen peroxide (H2O2) suppresses phototaxis behavior and inhibits the photoresponse in photoreceptor neurons, whereas other sensory behaviors are relatively less vulnerable to H2O2. Conversely, antioxidants can rescue the phenotype of lite-1 suppressor mutants and promote the photoresponse. As UV light illumination generates H2O2, we propose that upon light activation of LITE-1, light-produced H2O2 then deactivates LITE-1 to terminate the photoresponse, while antioxidants may promote LITE-1's recovery from its inactive state. Our studies provide a potential mechanism by which H2O2 and antioxidants act synergistically to regulate photosensation in C. elegans.

Summary: Chronic exposure to nicotine upregulates nicotinic acetylcholine receptors (nAChRs), and such upregulation is critical for the development of nicotine dependence in humans and animal models. However, how nicotine upregulates nAChRs is not well understood. Here, we identify a key role for microRNA in regulating nicotine-dependent behavior by modulating nAChR expression in C. elegans. We show that the nAChR gene acr-19 and alg-1, a key Argonaute-family member in the microRNA machinery, are specifically required for nicotine withdrawal response following chronic nicotine treatment. Chronic exposure to nicotine downregulates alg-1, leading to upregulation of acr-19. This effect is mediated by the microRNA miR-238 that recognizes the 3′ UTR of acr-19 transcript. Our results unveil a previously unrecognized role for microRNA in nicotine signaling, providing insights into how chronic nicotine administration leads to upregulation of nAChR and ultimately nicotine dependence. : Chronic exposure to nicotine upregulates nAChR, which is critical for the development of nicotine dependence. However, the underlying mechanisms are not well understood. Here, the authors identify a key role for microRNA in mediating nicotine-induced upregulation of nAChR and nicotine-dependent behavior using a C. elegans model. Keywords: neuron, tobacco, addiction

The deleterious role of reactive oxygen species has been widely reported in the nervous system. Here the authors report that surprisingly, low doses of H2O2 in fact enhances sensory neuron function and promotes sensory behaviors in C. elegans.

Temperature profoundly affects aging in both poikilotherms and homeotherms. A general belief is that lower temperatures extend lifespan, whereas higher temperatures shorten it. Although this “temperature law” is widely accepted, it has not been extensively tested. Here, we systematically evaluated the role of temperature in lifespan regulation in C. elegans. We found that, although exposure to low temperatures at the adult stage prolongs lifespan, low-temperature treatment at the larval stage surprisingly reduces lifespan. Interestingly, this differential effect of temperature on longevity in larvae and adults is mediated by the same thermosensitive TRP channel TRPA-1 that signals to the transcription factor DAF-16/FOXO. DAF-16/FOXO and TRPA-1 act in larva to shorten lifespan but extend lifespan in adulthood. DAF-16/FOXO differentially regulates gene expression in larva and adult in a temperature-dependent manner. Our results uncover complexity underlying temperature modulation of longevity, demonstrating that temperature differentially regulates lifespan at different stages of life.

Diet affects nearly every aspect of animal life such as development, metabolism, behavior, and aging, both directly by supplying nutrients and indirectly through gut microbiota. C. elegans feeds on bacteria, and like other animals, different bacterial diets induce distinct dietary responses in the worm. However, the lack of certain critical tools hampers the use of worms as a model for dietary signaling. Here, we genetically engineered the bacterial strain OP50, the standard laboratory diet for C. elegans, making it compatible for dsRNA production and delivery. Using this RNAi-compatible OP50 strain and the other bacterial strain HT115, we feed worms different diets while delivering RNAi to interrogate the genetic basis underlying diet-dependent differential modulation of development, metabolism, behavior, and aging. We show by RNAi that neuroendocrine and mTOR pathways are involved in mediating differential dietary responses. This genetic tool greatly facilitates the use of C. elegans as a model for dietary signaling.

A C. elegans model of nicotine-dependent behavior is developed, which shows that worms display behavioral responses to nicotine that parallel those observed in mammals, including acute response, tolerance, withdrawal and sensitization. The results have shown that C. elegans can be used to characterize known genes as well as to identify new genes regulating nicotine responses.

Author(s): Wei Li [1]; Zhaoyang Feng [1]; Paul W. Sternberg [3]; X. Z. Shawn Xu (corresponding author) [1, 2] The nematode Caenorhabditis elegans is commonly used as a genetic model [...]

Cocaine, a potent addictive substance, is an inhibitor of monoamine transporters, including DAT (dopamine transporter), SERT (serotonin transporter) and NET (norepinephrine transporter). Cocaine administration induces complex behavioral alterations in mammals, but the underlying mechanisms are not well understood. Here, we tested the effect of cocaine on C. elegans behavior. We show for the first time that acute cocaine treatment evokes changes in C. elegans locomotor activity. Interestingly, the neurotransmitter serotonin, rather than dopamine, is required for cocaine response in C. elegans. The C. elegans SERT MOD-5 is essential for the effect of cocaine, consistent with the role of cocaine in targeting monoamine transporters. We further show that the behavioral response to cocaine is primarily mediated by the ionotropic serotonin receptor MOD-1. Thus, cocaine modulates locomotion behavior in C. elegans primarily by impinging on its serotoninergic system.

GABA, a prominent inhibitory neurotransmitter, is best known to regulate neuronal functions in the nervous system. However, much less is known about the role of GABA signaling in other physiological processes. Interestingly, recent work showed that GABA signaling can regulate life span via a metabotropic GABAB receptor in Caenorhabditis elegans. However, the role of other types of GABA receptors in life span has not been clearly defined. It is also unclear whether GABA signaling regulates health span. Here, using C. elegans as a model, we systematically interrogated the role of various GABA receptors in both life span and health span. We find that mutations in four different GABA receptors extend health span by promoting resistance to stress and pathogen infection and that two such receptor mutants also show extended life span. Different GABA receptors engage distinct transcriptional factors to regulate life span and health span, and even the same receptor regulates life span and health span via different transcription factors. Our results uncover a novel, profound role of GABA signaling in aging in C. elegans, which is mediated by different GABA receptors coupled to distinct downstream effectors. [ABSTRACT FROM AUTHOR]

Differences in styles of learning have become important considerations at all levels of education over the last several years. Examining college students' preferred style of learning is useful for course design and effective instructional methods. Using the Felder-Silverman Index of Learning Styles (ILS), we investigate how students' styles of learning preferences differ in accounting courses delivered in traditional and online formats. We further investigate the interactions between students' learning style preferences and collaborative learning with regard to perceived learning effectiveness and satisfaction. The results indicate some differences between genders and between accounting vs. nonaccounting majors. For instance, females lean more toward a verbal and sequential learning approach than do males, who lean more toward a visual approach. Perhaps consistent with the reputation of accounting as "rule-based," accounting majors are somewhat more likely than are nonaccounting majors in general to prefer a sequential learning approach, and they are less likely to prefer a more "global" look at a problem. We also find that the dimensions of learning styles interact with the extent of collaborative learning in affecting the students learning outcomes. The findings have implications for both full-time educators and practitioners because firms also provide considerable amounts of continuing education for their professionals in either a classroom or online setting. [ABSTRACT FROM AUTHOR]

The nematode Caenorhabditis elegans is commonly used as a genetic model organism for dissecting integration of the sensory and motor systems. Despite extensive genetic and behavioural analyses that have led to the identification of many genes and neural circuits involved in regulating C. elegans locomotion behaviour, it remains unclear whether and how somatosensory feedback modulates motor output during locomotion. In particular, no stretch receptors have been identified in C. elegans, raising the issue of whether stretch-receptor-mediated proprioception is used by C. elegans to regulate its locomotion behaviour. Here we have characterized TRP-4, the C. elegans homologue of the mechanosensitive TRPN channel. We show that trp-4 mutant worms bend their body abnormally, exhibiting a body posture distinct from that of wild-type worms during locomotion, suggesting that TRP-4 is involved in stretch-receptor-mediated proprioception. We show that TRP-4 acts in a single neuron, DVA, to mediate its function in proprioception, and that the activity of DVA can be stimulated by body stretch. DVA both positively and negatively modulates locomotion, providing a unique mechanism whereby a single neuron can fine-tune motor activity. Thus, DVA represents a stretch receptor neuron that regulates sensory–motor integration during C. elegans locomotion. [ABSTRACT FROM AUTHOR]

• Using C. elegans as a model, a new study demonstrated that two TRPM channels sense pathogen colonization-induced intestinal distension. • Pathogen-induced intestinal distension triggers fast pathogen avoidance behavior, thereby limiting pathogen infection. • These findings reveal a novel role of the evolutionarily conserved TRPM channels in gut physiology and pathogen defense. Transient receptor potential (TRP) channels are expressed in many nonneural tissues where their functions are not well known. Using C. elegans as a model, a new study demonstrated that colonization of the Gram-positive pathogenic bacteria E. faecalis in the intestine causes intestinal distention. Two TRPM channels sense such intestinal distension to trigger fast pathogen avoidance behavior, thereby limiting pathogen infection. This work signifies the novel role of TRP channels in gut physiology and pathogen defense. [ABSTRACT FROM AUTHOR]

The article discusses the decline of motor system for animals and humans leading to frailty. It cites on the pharmacological interventions in slowing motor aging and extension of life span. The article also discusses the genetic ablation of SLO-1 that reduces the motor activity from age-functional deteriorations at neuromuscular junctions.