Neuropeptides and Behaviors: How Small Peptides Regulate Nervous System Function and Behavioral Outputs

One of the reasons that most multicellular animals survive and thrive is because of the adaptable and plastic nature of their nervous systems. For an organism to survive, it is essential for the animal to respond and adapt to environmental changes. This is achieved by sensing external cues and translating them into behaviors through changes in synaptic activity. The nervous system plays a crucial role in constantly evaluating environmental cues and allowing for behavioral plasticity in the organism. Multiple neurotransmitters and neuropeptides have been implicated as key players for integrating sensory information to produce the desired output. Because of its simple nervous system and well-established neuronal connectome, C. elegans acts as an excellent model to understand the mechanisms underlying behavioral plasticity. Here, we critically review how neuropeptides modulate a wide range of behaviors by allowing for changes in neuronal and synaptic signaling. This review will have a specific focus on feeding, mating, sleep, addiction, learning and locomotory behaviors in C. elegans. With a view to understand evolutionary relationships, we explore the functions and associated pathophysiology of C. elegans neuropeptides that are conserved across different phyla. Further, we discuss the mechanisms of neuropeptidergic signaling and how these signals are regulated in different behaviors. Finally, we attempt to provide insight into developing potential therapeutics for neuropeptide-related disorders.

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Epigenetic bookmarking of H2S exposure in Caenorhabditis elegans

10.1101/619734 ◽

2019 ◽

Cited By ~ 1

Author(s):

Emily M. Fawcett ◽

Jenna K. Johnson ◽

Chris Braden ◽

Esteli M. Garcia ◽

Dana L. Miller

Keyword(s):

Environmental Stress ◽

Environmental Changes ◽

Low Doses ◽

Epigenetic Landscape ◽

Protective Mechanisms ◽

C Elegans ◽

Mechanistic Insight ◽

Wide Range ◽

Subsequent Exposure ◽

Insight Into

AbstractPhysiological memories of environmental stress can serve to predict future environmental changes, allowing the organism to initiate protective mechanisms and survive. Although physiological memories, or bookmarks, of environmental stress have been described in a wide range of organisms, from bacteria to plants to humans, the mechanism by which these memories persist in the absence of stress is still largely unknown. We have discovered that C. elegans transiently exposed to low doses of hydrogen sulfide (H2S) survive subsequent exposure to otherwise lethal H2S concentrations and induce H2S-responsive transcripts more robustly than naïve controls. H2S bookmarking can occur at any developmental stage and persists through cell divisions and development but is erased by fasting. We show that maintenance of the H2S bookmark requires the SET-2 histone methyltransferase and the CoREST-like demethylase complex. We propose a model in which exposure to low doses of H2S generates a long-lasting, epigenetic memory by modulating H3K4me2 modifications at specific promoters. Understanding the fundamental aspects of H2S bookmarking in this tractable system can provide mechanistic insight into how environmental exposures are translated into the epigenetic landscape in animals.

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Novel Technological Advances in Functional Connectomics in C. elegans

Journal of Developmental Biology ◽

10.3390/jdb7020008 ◽

2019 ◽

Vol 7 (2) ◽

pp. 8 ◽

Cited By ~ 6

Author(s):

DiLoreto ◽

Chute ◽

Bryce ◽

Srinivasan

Keyword(s):

Nervous System ◽

Computational Modeling ◽

Activity Patterns ◽

Sensory Information ◽

Neuronal Cell ◽

Network Models ◽

Connectivity Matrix ◽

C Elegans ◽

Technological Advances

The complete structure and connectivity of the Caenorhabditis elegans nervous system (“mind of a worm”) was first published in 1986, representing a critical milestone in the field of connectomics. The reconstruction of the nervous system (connectome) at the level of synapses provided a unique perspective of understanding how behavior can be coded within the nervous system. The following decades have seen the development of technologies that help understand how neural activity patterns are connected to behavior and modulated by sensory input. Investigations on the developmental origins of the connectome highlight the importance of role of neuronal cell lineages in the final connectivity matrix of the nervous system. Computational modeling of neuronal dynamics not only helps reconstruct the biophysical properties of individual neurons but also allows for subsequent reconstruction of whole-organism neuronal network models. Hence, combining experimental datasets with theoretical modeling of neurons generates a better understanding of organismal behavior. This review discusses some recent technological advances used to analyze and perturb whole-organism neuronal function along with developments in computational modeling, which allows for interrogation of both local and global neural circuits, leading to different behaviors. Combining these approaches will shed light into how neural networks process sensory information to generate the appropriate behavioral output, providing a complete understanding of the worm nervous system.

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Drosophila CAKI/CMG Protein, a Homolog of Human CASK, Is Essential for Regulation of Neurotransmitter Vesicle Release

Journal of Neurophysiology ◽

10.1152/jn.00954.2004 ◽

2005 ◽

Vol 94 (2) ◽

pp. 1074-1083 ◽

Cited By ~ 29

Author(s):

Mauro A. Zordan ◽

Michele Massironi ◽

Maria Giovanna Ducato ◽

Geertruy te Kronnie ◽

Rodolfo Costa ◽

...

Keyword(s):

Nervous System ◽

Neurotransmitter Release ◽

Transmembrane Protein ◽

Protein A ◽

Model Organism ◽

Brain Regions ◽

Synaptic Activity ◽

Giant Fiber ◽

Nervous System Function

Vertebrate CASK is a member of the membrane-associated guanylate kinase (MAGUK) family of proteins. CASK is present in the nervous system where it binds to neurexin, a transmembrane protein localized in the presynaptic membrane. The Drosophila homologue of CASK is CAKI or CAMGUK. CAKI is expressed in the nervous system of larvae and adult flies. In adult flies, the expression of caki is particularly evident in the visual brain regions. To elucidate the functional role of CASK, we employed a caki null mutant in the model organism Drosophila melanogaster. By means of electrophysiological methods, we analyzed, in adult flies, the spontaneous and evoked neurotransmitter release at the neuromuscular junction (NMJ) as well as the functional status of the giant fiber pathway and of the visual system. We found that in caki mutants, when synaptic activity is modified, the spontaneous neurotransmitter release of the indirect flight muscle NMJ was increased, the response of the giant fiber pathway to continuous stimulation was impaired, and electroretinographic responses to single and continuous repetitive stimuli were altered and optomotor behavior was abnormal. These results support the involvement of CAKI in neurotransmitter release and nervous system function.

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Memory of recent oxygen experience switches pheromone valence in Caenorhabditis elegans

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1618934114 ◽

2017 ◽

Vol 114 (16) ◽

pp. 4195-4200 ◽

Cited By ~ 24

Author(s):

Lorenz A. Fenk ◽

Mario de Bono

Keyword(s):

Caenorhabditis Elegans ◽

Behavioral Plasticity ◽

Prior Experience ◽

Sensory Information ◽

Dependent Manner ◽

Oxygen Environment ◽

C Elegans ◽

Sustained Change ◽

Context Dependent ◽

Physiological Correlate

Animals adjust their behavioral priorities according to momentary needs and prior experience. We show that Caenorhabditis elegans changes how it processes sensory information according to the oxygen environment it experienced recently. C. elegans acclimated to 7% O2 are aroused by CO2 and repelled by pheromones that attract animals acclimated to 21% O2. This behavioral plasticity arises from prolonged activity differences in a circuit that continuously signals O2 levels. A sustained change in the activity of O2-sensing neurons reprograms the properties of their postsynaptic partners, the RMG hub interneurons. RMG is gap-junctionally coupled to the ASK and ADL pheromone sensors that respectively drive pheromone attraction and repulsion. Prior O2 experience has opposite effects on the pheromone responsiveness of these neurons. These circuit changes provide a physiological correlate of altered pheromone valence. Our results suggest C. elegans stores a memory of recent O2 experience in the RMG circuit and illustrate how a circuit is flexibly sculpted to guide behavioral decisions in a context-dependent manner.

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A collective modulatory basis for multisensory integration in C. elegans

10.1101/424135 ◽

2018 ◽

Author(s):

Gareth Harris ◽

Taihong Wu ◽

Gaia Linfield ◽

Myung-Kyu Choi ◽

He Liu ◽

...

Keyword(s):

Decision Making ◽

Nervous System ◽

Multisensory Integration ◽

Multisensory Processing ◽

Neurological Diseases ◽

Sensory Information ◽

Sensory Cues ◽

C Elegans ◽

Behavioral Decision ◽

Integrated Response

AbstractIn the natural environment, animals often encounter multiple sensory cues that are simultaneously present. The nervous system integrates the relevant sensory information to generate behavioral responses that have adaptive values. However, the signal transduction pathways and the molecules that regulate integrated behavioral response to multiple sensory cues are not well defined. Here, we characterize a collective modulatory basis for a behavioral decision in C. elegans when the animal is presented with an attractive food source together with a repulsive odorant. We show that distributed neuronal components in the worm nervous system and several neuromodulators orchestrate the decision-making process, suggesting that various states and contexts may modulate the multisensory integration. Among these modulators, we identify a new function of a conserved TGF-β pathway that regulates the integrated decision by inhibiting the signaling from a set of central neurons. Interestingly, we find that a common set of modulators, including the TGF-β pathway, regulate the integrated response to the pairing of different foods and repellents. Together, our results provide insights into the modulatory signals regulating multisensory integration and reveal potential mechanistic basis for the complex pathology underlying defects in multisensory processing shared by common neurological diseases.Author SummaryThe present study characterizes the modulation of a behavioral decision in C. elegans when the worm is presented with a food lawn that is paired with a repulsive smell. We show that multiple sensory neurons and interneurons play roles in making the decision. We also identify several modulatory molecules that are essential for the integrated decision when the animal faces a choice between the cues of opposing valence. We further show that many of these factors, which often represent different states and contexts, are common for behavioral decisions that integrate sensory information from different types of foods and repellents. Overall, our results reveal a collective molecular and cellular basis for integration of simultaneously present attractive and repulsive cues to fine-tune decision-making.

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Neuroscience Needs Ethology: The Marked Example of the Moth Pheromone System

10.20944/preprints202007.0357.v1 ◽

2020 ◽

Author(s):

Herve Thevenon

Keyword(s):

Animal Species ◽

Intrinsic Value ◽

Sensory Information ◽

Systemic Review ◽

Auditory Stimuli ◽

C Elegans ◽

Pheromone System ◽

Translational Studies ◽

Insight Into ◽

Genetic Toolkit

The key premise of translational studies is that knowledge gained in one animal species can be transposed to other animals. So far translational bridges have mainly relied on genetic and physiological similarities, in experimental setups where behaviours and environment are often oversimplified. These simplifications were recently criticised for decreasing the intrinsic value of the published results. The inclusion of wild behaviour and rich environments in neuroscience experimental designs is difficult to achieve because no animal model has it all. As an example, the genetic toolkit of moths species is virtually non-existent when compared to C. elegans, rats, mice, or zebrafish, however the balance is reversed for wild behaviours. The ethological knowledge gathered about the moth was instrumental for designing natural-like auditory stimuli, that were used in association with electrophysiology in order to understand how moths use these variable sounds produced by their predators in order to trump death. Conversely, we are still stuck with understanding how male moths make sense of their complex and diffuse olfactory landscape in order to locate conspecific females up to several hundred meters away, and precisely identify a conspecific in a sympatric swarm in order to reproduce. This systemic review articulates the ethological knowledge pertaining to this unresolved problem and leverages the paradigm to gain insight into how male moths process sparse and uncertain environmental sensory information.

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Genetics of Behavior in C. elegans

The Oxford Handbook of Invertebrate Neurobiology ◽

10.1093/oxfordhb/9780190456757.013.5 ◽

2017 ◽

pp. 150-170 ◽

Cited By ~ 2

Author(s):

Denise S. Walker ◽

Yee Lian Chew ◽

William R. Schafer

Keyword(s):

Nervous System ◽

Caenorhabditis Elegans ◽

Molecular Genetics ◽

Sensory Information ◽

Macro Level ◽

Gene Products ◽

Individual Gene ◽

C Elegans ◽

Behavioral States ◽

Motor Outputs

The nematode Caenorhabditis elegans is among the most intensely studied animals in modern experimental biology. In particular, because of its amenability to classical and molecular genetics, its simple and compact nervous system, and its transparency to optogenetic recording and manipulation, C. elegans has been widely used to investigate how individual gene products act in the context of neuronal circuits to generate behavior. C. elegans is the first and at present the only animal whose neuronal connectome has been characterized at the level of individual neurons and synapses, and the wiring of this connectome shows surprising parallels with the micro- and macro-level structures of larger brains. This chapter reviews our current molecular- and circuit-level understanding of behavior in C. elegans. In particular, we discuss mechanisms underlying the processing of sensory information, the generation of specific motor outputs, and the control of behavioral states.

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A cellular and regulatory map of the GABAergic nervous system of C. elegans

eLife ◽

10.7554/elife.17686 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 79

Author(s):

Marie Gendrel ◽

Emily G Atlas ◽

Oliver Hobert

Keyword(s):

Nervous System ◽

Gaba Receptors ◽

Cholinergic Neurons ◽

Transcriptional Regulators ◽

Comprehensive Analysis ◽

Gaba Uptake ◽

C Elegans ◽

Positive Neuron ◽

Nervous System Function ◽

Extracellular Environment

Neurotransmitter maps are important complements to anatomical maps and represent an invaluable resource to understand nervous system function and development. We report here a comprehensive map of neurons in the C. elegans nervous system that contain the neurotransmitter GABA, revealing twice as many GABA-positive neuron classes as previously reported. We define previously unknown glia-like cells that take up GABA, as well as 'GABA uptake neurons' which do not synthesize GABA but take it up from the extracellular environment, and we map the expression of previously uncharacterized ionotropic GABA receptors. We use the map of GABA-positive neurons for a comprehensive analysis of transcriptional regulators that define the GABA phenotype. We synthesize our findings of specification of GABAergic neurons with previous reports on the specification of glutamatergic and cholinergic neurons into a nervous system-wide regulatory map which defines neurotransmitter specification mechanisms for more than half of all neuron classes in C. elegans.

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The Emergent Connectome in Caenorhabditis elegans Embryogenesis

10.1101/146035 ◽

2017 ◽

Cited By ~ 1

Author(s):

◽

Bradly Alicea

Keyword(s):

Nervous System ◽

Caenorhabditis Elegans ◽

Cell Lineage ◽

Model Organism ◽

Secondary Data ◽

Building Blocks ◽

C Elegans ◽

Differentiated Cells ◽

Adult Hermaphrodite ◽

Nervous System Function

ABSTRACTThe relatively new field of connectomics provides us with a unique window into nervous system function. In the model organism Caenorhabditis elegans, this promise is even greater due to the relatively small number of cells (302) in its nervous system. While the adult C. elegans connectome has been characterized, the emergence of these networks in development has yet to be established. In this paper, we approach this problem using secondary data describing the birth times of terminally-differentiated cells as they appear in the embryo and a connectomics model for nervous system cells in the adult hermaphrodite. By combining these two sources of data, we can better understand patterns that emerge in an incipient connectome. This includes identifying at what point in embryogenesis the cells of a connectome first comes into being, potentially observing some of the earliest neuron-neuron interactions, and making comparisons between the formally-defined connectome and developmental cell lineages. An analysis is also conducted to root terminally-differentiated cells in their developmental cell lineage precursors. This reveals subnetworks with different properties at 300 minutes of embryogenesis. Additional investigations reveal the spatial position of neuronal cells born during pre-hatch development, both within and outside the connectome model, in the context of all developmental cells in the embryo. Overall, these analyses reveal important information about the birth order of specific cells in the connectome, key building blocks of global connectivity, and how these structures correspond to key events in early development.

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Rictor/TORC2 mediates gut-to-brain signaling in the regulation of phenotypic plasticity in C. elegans

10.1101/189613 ◽

2017 ◽

Author(s):

Michael P. O’Donnell ◽

Pin-Hao Chao ◽

Jan E. Kammenga ◽

Piali Sengupta

Keyword(s):

Nervous System ◽

Internal State ◽

Environmental Signals ◽

C Elegans ◽

Signaling Complex ◽

External Cues ◽

Nervous System Function ◽

Sensory Nervous System ◽

Neuronal Functions ◽

Available Information

ABSTRACTAnimals integrate external cues with information about internal conditions such as metabolic state to execute the appropriate behavioral and developmental decisions. Information about food quality and quantity is assessed by the intestine and transmitted to modulate neuronal functions via mechanisms that are not fully understood. The conserved Target of Rapamycin complex 2 (TORC2) controls multiple processes in response to cellular stressors and growth factors. Here we show that TORC2 coordinates larval development and adult behaviors in response to environmental cues and feeding state in the bacterivorous nematode C. elegans. During development, pheromone, bacterial food, and temperature regulate expression of the daf-7 TGF-β and daf-28 insulin-like peptide in sensory neurons to promote a binary decision between reproductive growth and entry into the alternate dauer larval stage. We find that TORC2 acts in the intestine to regulate neuronal expression of both daf-7 and daf-28, which together reflect bacterial-diet dependent feeding status, thus providing a mechanism for integration of food signals with external cues in the regulation of neuroendocrine gene expression. In the adult, TORC2 similarly acts in the intestine to modulate food-regulated foraging behaviors via the PDFR-1 neuropeptide receptor. We also demonstrate that genetic variation affects food-dependent larval and adult phenotypes, and identify quantitative trait loci (QTL) associated with these traits.Together, these results suggest that TORC2 acts as a hub for communication of feeding state information from the gut to the brain, thereby contributing to modulation of neuronal function by internal state.AUTHOR SUMMARYDecision-making in all animals, including humans, involves weighing available information about the external environment as well as the animals’ internal conditions. Information about the environment is obtained via the sensory nervous system, whereas internal state can be assessed via cues such as levels of hormones or nutrients. How multiple external and internal inputs are processed in the nervous system to drive behavior or development is not fully understood. In this study, we examine how the nematode C. elegans integrates dietary information received by the gut with environmental signals to alter nervous system function. We have found that a signaling complex, called TORC2, acts in the gut to relay nutrition signals to alter hormonal signaling by the nervous system in C. elegans. Altered neuronal signaling in turn affects a food-dependent binary developmental decision in larvae, as well as food-dependent foraging behaviors in adults. Our results provide a mechanism by which animals prioritize specific signals such as feeding status to appropriately alter their development and/or behavior.

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