Light and Hydrogen Peroxide Inhibit C. elegans Feeding through Gustatory Receptor Orthologs and Pharyngeal Neurons

While gustatory sensing of the five primary flavors (sweet, salty, sour, bitter, and savory) has been extensively studied, pathways that detect non-canonical taste stimuli remain relatively unexplored. In particular, while reactive oxygen species cause generalized damage to biological systems, no gustatory mechanism to prevent ingestion of such material has been identified in any organism. We observed that light inhibits C. elegans feeding and used light as a tool to uncover molecular and neural mechanisms for gustation. Light can generate hydrogen peroxide, and we discovered that hydrogen peroxide similarly inhibits feeding. The gustatory receptor family members LITE-1 and GUR-3 are required for the inhibition of feeding by light and hydrogen peroxide. The I2 pharyngeal neurons increase calcium in response to light and hydrogen peroxide, and these responses require GUR-3 and a conserved antioxidant enzyme peroxiredoxin PRDX-2. Our results demonstrate a gustatory mechanism that mediates the detection and blocks ingestion of a noncanonical taste stimulus, hydrogen peroxide.National Science Foundation (U.S.). Graduate Research Fellowship ProgramNational Institutes of Health (U.S.) (Grant GM24663

Distinct Neural Circuits Control Rhythm Inhibition and Spitting by the Myogenic Pharynx of C. elegans

Neural circuits have long been known to modulate myogenic muscles such as the heart, yet a mechanistic understanding at the cellular and molecular levels remains limited. We studied how light inhibits pumping of the Caenorhabditis elegans pharynx, a myogenic muscular pump for feeding, and found three neural circuits that alter pumping. First, light inhibits pumping via the I2 neuron monosynaptic circuit. Our electron microscopic reconstruction of the anterior pharynx revealed evidence for synapses from I2 onto muscle that were missing from the published connectome, and we show that these “missed synapses” are likely functional. Second, light inhibits pumping through the RIP-I1-MC neuron polysynaptic circuit, in which an inhibitory signal is likely transmitted from outside the pharynx into the pharynx in a manner analogous to how the mammalian autonomic nervous system controls the heart. Third, light causes a novel pharyngeal behavior, reversal of flow or “spitting,” which is induced by the M1 neuron. These three neural circuits show that neurons can control a myogenic muscle organ not only by changing the contraction rate but also by altering the functional consequences of the contraction itself, transforming swallowing into spitting. Our observations also illustrate why connectome builders and users should be cognizant that functional synaptic connections might exist despite the absence of a declared synapse in the connectome.United States. National Institutes of Health (GM24663

Lifestyle intervention programme for Indian women with history of gestational diabetes mellitus.

Aim: To evaluate the feasibility and potential effectiveness of a lifestyle intervention (diet and physical activity) among women with history of gestational diabetes mellitus (GDM), delivered by trained facilitators. Methods: Fifty-six normoglycaemic or prediabetic women with prior GDM were recruited at mean of 17 months postpartum. Socio-demographic, medical and anthropometric data were collected. Six sessions on lifestyle modification were delivered in groups (total four groups, with 12-15 women in each group). Pre and post intervention (6 months) weight, body mass index (BMI), waist circumference, 75 g oral glucose tolerance test, blood pressure (BP) and lipid parameters were compared. Results: The intervention was feasible, with 80% of women attending four or more sessions. Post-intervention analyses showed a significant mean reduction of 1.8 kg in weight, 0.6 kg/m2 in BMI and 2 cm in waist circumference. There was also a significant drop of 0.3 mmol/L in fasting plasma glucose, 0.9 mmol/L in 2 h post glucose load value of plasma glucose, 3.6 mmHg in systolic BP, and 0.15 mmol/L in triglyceride levels. Changes in total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol and diastolic BP were non-significant. Conclusions: This study showed feasibility of the lifestyle intervention delivered in group sessions to women with prior gestational diabetes

Lifestyle intervention programme for Indian women with history of gestational diabetes mellitus.

Aim: To evaluate the feasibility and potential effectiveness of a lifestyle intervention (diet and physical activity) among women with history of gestational diabetes mellitus (GDM), delivered by trained facilitators. Methods: Fifty-six normoglycaemic or prediabetic women with prior GDM were recruited at mean of 17 months postpartum. Socio-demographic, medical and anthropometric data were collected. Six sessions on lifestyle modification were delivered in groups (total four groups, with 12-15 women in each group). Pre and post intervention (6 months) weight, body mass index (BMI), waist circumference, 75 g oral glucose tolerance test, blood pressure (BP) and lipid parameters were compared. Results: The intervention was feasible, with 80% of women attending four or more sessions. Post-intervention analyses showed a significant mean reduction of 1.8 kg in weight, 0.6 kg/m2 in BMI and 2 cm in waist circumference. There was also a significant drop of 0.3 mmol/L in fasting plasma glucose, 0.9 mmol/L in 2 h post glucose load value of plasma glucose, 3.6 mmHg in systolic BP, and 0.15 mmol/L in triglyceride levels. Changes in total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol and diastolic BP were non-significant. Conclusions: This study showed feasibility of the lifestyle intervention delivered in group sessions to women with prior gestational diabetes

Tasting light through hydrogen peroxide : molecular mechanisms and neural circuits

Thesis: Ph. D. in Neuroscience, Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2014.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Cataloged from student-submitted PDF version of thesis.Includes bibliographical references (pages 239-249).The most fascinating function of the nervous system is its ability to generate consciousness, the subjective experience or qualia that distinguishes awake life from dreamless sleep. How consciousness is generated is an ancient philosophical question which has proven resistant to scientific analysis. While the human brain is known to generate consciousness, its complexity prevents acquisition of a mechanistic understanding of consciousness. Therefore, I chose to study the much simpler nervous system of the nematode Caenorhabditis elegans. I tested worms for a specific kind of learning, called trace conditioning, which correlates with conscious awareness in humans, under the assumption that if worms were able to trace condition, they might also be capable of conscious awareness. However, I was not able to show trace conditioning in worms, so the question of whether worms exhibit consciousness remains unresolved. In the process of using light in learning experiments, I noticed that worms stop feeding immediately after being exposed to short wavelength (UV) light. Curious about whether worms might actually have a subjective experience in response to light akin to primitive vision, I investigated the molecular and neural mechanisms that control this behavioral response. I identified the I2 pharyngeal neuron as a cellular light sensor required for the speed of feeding inhibition. Hydrogen peroxide elicited behavioral and cellular responses strikingly similar to those caused by light. The sensing of both light and hydrogen peroxide were mediated by the LITE-1 and GUR-3 proteins, both putative gustatory receptors, as well as by the conserved antioxidant enzyme peroxiredoxin PRDX-2. My results suggest that the LITE-1/GUR-3 family of receptors likely detects light through its generation of hydrogen peroxide or of another redox product. This is a novel mechanism by which light can be sensed. Additionally, by studying the worm's feeding response to light, I identified a pattern of neural function in which neurons appear to act independently to control sequential phases of a behavior. In the first phase, light rapidly inhibited feeding, with the I2 neuron sensing light and releasing glutamate likely onto pharyngeal muscle, where it was received by the AVR-15 glutamate-gated chloride channel. In the second phase, the inhibition of feeding was maintained via a circuit that included the extrapharyngeal neuron RIP and pharyngeal neurons I1 and MC. Finally, in the third phase, light stimulated pharyngeal contractions via the M1 neuron. These three circuits appear to be independent. I conclude that what initially appeared to be a simple reflex is instead a sequence of behavioral responses coordinated by independent neural circuits, suggesting a motif I term "parallel temporal tiling." Although I am still uncertain about whether worms have a subjective experience of light, this research will serve as a foundation for future work aimed at this very question.by Nikhil Bhatla.Ph. D. in Neuroscienc

An hourglass circuit motif transforms a motor program via subcellularly localized muscle calcium signaling and contraction

Neural control of muscle function is fundamental to animal behavior. Many muscles can generate multiple distinct behaviors. Nonetheless, individual muscle cells are generally regarded as the smallest units of motor control. We report that muscle cells can alter behavior by contracting subcellularly. We previously discovered that noxious tastes reverse the net flow of particles through the C. elegans pharynx, a neuromuscular pump, resulting in spitting. We now show that spitting results from the subcellular contraction of the anterior region of the pm3 muscle cell. Subcellularly localized calcium increases accompany this contraction. Spitting is controlled by an ‘hourglass’ circuit motif: parallel neural pathways converge onto a single motor neuron that differentially controls multiple muscles and the critical subcellular muscle compartment. We conclude that subcellular muscle units enable modulatory motor control and propose that subcellular muscle contraction is a fundamental mechanism by which neurons can reshape behavior.</jats:p

Cytochrome P450 Drives a HIF-Regulated Behavioral Response to Reoxygenation by C. elegans

Oxygen deprivation followed by reoxygenation causes pathological responses in many disorders, including ischemic stroke, heart attacks, and reperfusion injury. Key aspects of ischemia-reperfusion can be modeled by a Caenorhabditis elegans behavior, the O2-ON response, which is suppressed by hypoxic preconditioning or inactivation of the O[subscript 2]-sensing HIF (hypoxia-inducible factor) hydroxylase EGL-9. From a genetic screen, we found that the cytochrome P450 oxygenase CYP-13A12 acts in response to the EGL-9–HIF-1 pathway to facilitate the O2-ON response. CYP-13A12 promotes oxidation of polyunsaturated fatty acids into eicosanoids, signaling molecules that can strongly affect inflammatory pain and ischemia-reperfusion injury responses in mammals. We propose that roles of the EGL-9–HIF-1 pathway and cytochrome P450 in controlling responses to reoxygenation after anoxia are evolutionarily conserved.National Institutes of Health (U.S.) (Grant GM24663)National Science Foundation (U.S.). Graduate Research Fellowship ProgramMassachusetts Institute of Technology. Undergraduate Research Opportunities ProgramHelen Hay Whitney Foundation (Postdoctoral Fellowship