scholarly journals Novel Technological Advances in Functional Connectomics in C. elegans

2019 ◽  
Vol 7 (2) ◽  
pp. 8 ◽  
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.

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

2021 ◽  
Vol 14 ◽  
Author(s):  
Umer Saleem Bhat ◽  
Navneet Shahi ◽  
Siju Surendran ◽  
Kavita Babu
Keyword(s):  
Nervous System ◽  
Behavioral Plasticity ◽  
Environmental Changes ◽  
Sensory Information ◽  
Synaptic Activity ◽  
Small Peptides ◽  
C Elegans ◽  
Wide Range ◽  
Nervous System Function ◽  
Insight Into

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.

scholarly journals Inhibition underlies fast undulatory locomotion in C. elegans

2020 ◽  
Author(s):  
Lan Deng ◽  
Jack Denham ◽  
Charu Arya ◽  
Omer Yuval ◽  
Netta Cohen ◽  
...  
Keyword(s):  
Computational Models ◽  
Body Wall ◽  
Activity Patterns ◽  
Wild Type ◽  
C Elegans ◽  
Body Wall Muscles ◽  
Undulatory Locomotion ◽  
Gaba Transmission ◽  
Cross Inhibition

AbstractInhibition plays important roles in modulating the neural activities of sensory and motor systems at different levels from synapses to brain regions. To achieve coordinated movement, motor systems produce alternating contraction of antagonist muscles, whether along the body axis or within and among limbs. In the nematode C. elegans, a small network involving excitatory cholinergic and inhibitory GABAergic motoneurons generates the dorsoventral alternation of body-wall muscles that supports undulatory locomotion. Inhibition has been suggested to be necessary for backward undulation because mutants that are defective in GABA transmission exhibit a shrinking phenotype in response to a harsh touch to the head, whereas wild-type animals produce a backward escape response. Here, we demonstrate that the shrinking phenotype is exhibited by wild-type as well as mutant animals in response to harsh touch to the head or tail, but only GABA transmission mutants show slow locomotion after stimulation. Impairment of GABA transmission, either genetically or optogenetically, induces lower undulation frequency and lower translocation speed during crawling and swimming in both directions. The activity patterns of GABAergic motoneurons are different during low and high undulation frequencies. During low undulation frequency, GABAergic VD and DD motoneurons show similar activity patterns, while during high undulation frequency, their activity alternates. The experimental results suggest at least three non-mutually exclusive roles for inhibition that could underlie fast undulatory locomotion in C. elegans, which we tested with computational models: cross-inhibition or disinhibition of body-wall muscles, or inhibitory reset.Significance StatementInhibition serves multiple roles in the generation, maintenance, and modulation of the locomotive program and supports the alternating activation of antagonistic muscles. When the locomotor frequency increases, more inhibition is required. To better understand the role of inhibition in locomotion, we used C. elegans as an animal model, and challenged a prevalent hypothesis that cross-inhibition supports the dorsoventral alternation. We find that inhibition is related to the speed rather than the direction of locomotion and demonstrate that inhibition is unnecessary for muscle alternation during slow undulation in either direction but crucial to sustain rapid dorsoventral alternation. We combined calcium imaging of motoneurons and muscle with computational models to test hypotheses for the role of inhibition in locomotion.

scholarly journals A collective modulatory basis for multisensory integration in C. elegans

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.

scholarly journals NeuroPAL: A Neuronal Polychromatic Atlas of Landmarks for Whole-Brain Imaging in C. elegans

2019 ◽  
Author(s):  
Eviatar Yemini ◽  
Albert Lin ◽  
Amin Nejatbakhsh ◽  
Erdem Varol ◽  
Ruoxi Sun ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nervous System ◽  
Cell Fate ◽  
Activity Patterns ◽  
Expression Patterns ◽  
Yellow Emission ◽  
Metabotropic Receptors ◽  
Whole Brain ◽  
C Elegans

ABSTRACTComprehensively resolving single neurons and their cellular identities from whole-brain fluorescent images is a major challenge. We achieve this in C. elegans through the engineering and use of a multicolor transgene called NeuroPAL (a Neuronal Polychromatic Atlas of Landmarks). NeuroPAL worms share a stereotypical multicolor fluorescence map for the entire hermaphrodite nervous system that allows comprehensive determination of neuronal identities. Neurons labeled with NeuroPAL do not exhibit fluorescence in the green, cyan, or yellow emission channels, allowing the transgene to be used with numerous reporters of gene expression or neuronal dynamics. Here we showcase three studies that leverage NeuroPAL for nervous-system-wide neuronal identification. First, we determine the brainwide expression patterns of all metabotropic receptors for acetylcholine, GABA, and glutamate, completing a map of this communication network. Second, we uncover novel changes in cell fate caused by transcription factor mutations. Third, we record brainwide activity in response to attractive and repulsive chemosensory cues, characterizing multimodal coding and novel neuronal asymmetries for these stimuli. We present a software package that enables semi-automated determination of all neuronal identities based on color and positional information. The NeuroPAL framework and software provide a means to design landmark atlases for other tissues and organisms. In conclusion, we expect NeuroPAL to serve as an invaluable tool for gene expression analysis, neuronal fate studies, and for mapping whole-brain activity patterns.

scholarly journals CRISPR/Cas9-constructed pseudorabies virus mutants reveal the importance of UL13 in alphaherpesvirus escape from genome silencing

2020 ◽  
Author(s):  
Jolien Van Cleemput ◽  
Orkide O. Koyuncu ◽  
Kathlyn Laval ◽  
Esteban A. Engel ◽  
Lynn W. Enquist
Keyword(s):  
Nervous System ◽  
Peripheral Nervous System ◽  
Pseudorabies Virus ◽  
Neuronal Cell ◽  
Gene Replacement ◽  
Productive Infection ◽  
Tegument Protein ◽  
Neuronal Cultures ◽  
Tegument Proteins

Latent and recurrent productive infection of long-living cells, such as neurons, enables alphaherpesviruses to persist in their host populations. Still, the viral factors involved in these events remain largely obscure. Using a complementation assay in compartmented primary peripheral nervous system (PNS) neuronal cultures, we previously reported that productive replication of axonally-delivered genomes is facilitated by PRV tegument proteins. Here, we sought to unravel the role of tegument protein UL13 in this escape from silencing. We first constructed four new PRV mutants in the virulent Becker strain using CRISPR/Cas9-mediated gene replacement: (i) PRV Becker defective for UL13 expression (PRV ΔUL13), (ii) PRV where UL13 is fused to eGFP (PRV UL13-eGFP) and two control viruses (iii and iv) PRV where VP16 is fused with mTurquoise at either the N-terminus (PRV mTurq-VP16) or C-terminus (PRV VP16-mTurq). Live cell imaging of PRV capsids showed efficient retrograde transport after axonal infection with PRV UL13-eGFP, although we did not detect dual-color particles. Surprisingly, immunofluorescence staining of particles in mid-axons indicated that UL13 might be co-transported with PRV capsids in PNS axons. Superinfecting nerve cell bodies with UV-inactivated PRV ΔUL13 failed to efficiently promote escape from genome silencing when compared to UV-PRV wild type and UV-PRV UL13-eGFP superinfection. However, UL13 does not act directly in the escape from genome silencing, as AAV-mediated UL13 expression in neuronal cell bodies was not sufficient to provoke escape from genome silencing. Based on this, we suggest that UL13 may contribute to initiation of productive infection through phosphorylation of other tegument proteins. Importance Alphaherpesviruses have mastered various strategies to persist in an immunocompetent host, including the induction of latency and reactivation in peripheral nervous system (PNS) ganglia. We recently discovered that the molecular mechanism underlying escape from latency by the alphaherpesvirus pseudorabies virus (PRV) relies on a structural viral tegument protein. This study aimed at unravelling the role of tegument protein UL13 in PRV escape from latency. First, we confirmed the use of CRISPR/Cas9-mediated gene replacement as a versatile tool to modify the PRV genome. Next, we used our new set of viral mutants and AAV vectors to conclude on the indirect role of UL13 in PRV escape from latency in primary neurons and on its spatial localization during retrograde capsid transport in axons. Based on these findings, we speculate that UL13 phosphorylates one or more tegument proteins, thereby priming these putative proteins to induce escape from genome silencing.

Genetics of Behavior in C. elegans

2017 ◽  
pp. 150-170 ◽  
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.

scholarly journals In silico analysis of the transcriptional regulatory logic of neuronal identity specification throughout the C. elegans nervous system

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Lori Glenwinkel ◽  
Seth R Taylor ◽  
Kasper Langebeck-Jensen ◽  
Laura Pereira ◽  
Molly B Reilly ◽  
...  
Keyword(s):  
Nervous System ◽  
Transcription Factors ◽  
Single Cell ◽  
Expression Profiles ◽  
Neuronal Cell ◽  
In Silico Analysis ◽  
Specific Gene ◽  
Neuron Type ◽  
C Elegans ◽  
Neuronal Identity

The generation of the enormous diversity of neuronal cell types in a differentiating nervous system entails the activation of neuron type-specific gene batteries. To examine the regulatory logic that controls the expression of neuron type-specific gene batteries, we interrogate single cell expression profiles of all 118 neuron classes of the Caenorhabditis elegans nervous system for the presence of DNA binding motifs of 136 neuronally expressed C. elegans transcription factors. Using a phylogenetic footprinting pipeline, we identify cis-regulatory motif enrichments among neuron class-specific gene batteries and we identify cognate transcription factors for 117 of the 118 neuron classes. In addition to predicting novel regulators of neuronal identities, our nervous system-wide analysis at single cell resolution supports the hypothesis that many transcription factors directly co-regulate the cohort of effector genes that define a neuron type, thereby corroborating the concept of so-called terminal selectors of neuronal identity. Our analysis provides a blueprint for how individual components of an entire nervous system are genetically specified.

scholarly journals The Role of Microglia during West Nile Virus Infection of the Central Nervous System

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 485 ◽  
Author(s):  
Sarah Stonedahl ◽  
Penny Clarke ◽  
Kenneth L. Tyler
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
West Nile Virus ◽  
Immune Cells ◽  
Neuronal Cell ◽  
The United States ◽  
Health Concern ◽  
West Nile ◽  
The Central Nervous System

Encephalitis resulting from viral infections is a major cause of hospitalization and death worldwide. West Nile Virus (WNV) is a substantial health concern as it is one of the leading causes of viral encephalitis in the United States today. WNV infiltrates the central nervous system (CNS), where it directly infects neurons and induces neuronal cell death, in part, via activation of caspase 3-mediated apoptosis. WNV infection also induces neuroinflammation characterized by activation of innate immune cells, including microglia and astrocytes, production of inflammatory cytokines, breakdown of the blood-brain barrier, and infiltration of peripheral leukocytes. Microglia are the resident immune cells of the brain and monitor the CNS for signs of injury or pathogens. Following infection with WNV, microglia exhibit a change in morphology consistent with activation and are associated with increased expression of proinflammatory cytokines. Recent research has focused on deciphering the role of microglia during WNV encephalitis. Microglia play a protective role during infections by limiting viral growth and reducing mortality in mice. However, it also appears that activated microglia are triggered by T cells to mediate synaptic elimination at late times during infection, which may contribute to long-term neurological deficits following a neuroinvasive WNV infection. This review will discuss the important role of microglia in the pathogenesis of a neuroinvasive WNV infection. Knowledge of the precise role of microglia during a WNV infection may lead to a greater ability to treat and manage WNV encephalitis.

The evolution of complex sensory systems in mammals

1989 ◽  
Vol 146 (1) ◽  
pp. 165-176
Author(s):  
J. H. Kaas
Keyword(s):  
Nervous System ◽  
Brain Size ◽  
Activity Patterns ◽  
Sensory Information ◽  
Initial Step ◽  
Neuron Activity ◽  
Dorsal Thalamus ◽  
Extant Species ◽  
Cell Groups ◽  
Perceptual Systems

Much of the forebrain of many extant species of mammals appears to be sensory-perceptual in nature. Thus, much of the forebrain, especially the dorsal thalamus and neocortex, consists of nuclei and areas that are parts of complex systems that analyze sensory information and allow behavior to be guided by accurate inferences about the external world. Since mammals vary tremendously in brain size, they vary in the amount of tissue devoted to sensory processing. In addition, mammals vary in the sizes and numbers of processing nuclei and areas, and in how neurons and neuron groups (modules) are differentiated within such structures. Sensory-perceptual systems with more, larger and more differentiated parts may allow more stimulus parameters to be considered, experience to play a greater role, and speed calculations through increased parallel processing. The evolution of species differences in brain size, the sizes of individual parts, and internal structure of these parts are potentially understandable within a theoretical framework of gradual modifications of developmental processes. In addition to changes in the generation and specialization of neurons, alterations in the developmental timing that modify internal and external influences on neuron activity patterns seem to have a major role in the construction and maintenance of organization in the nervous system. Because similar selection pressures may arise over and over again and the mechanisms for producing changes may be few, similar changes in the nervous system are likely to occur in independent lines of evolution. It is uncertain how new cortical areas and nuclei evolve. Comparative studies suggest that: (1) all mammals have a few basic sensory areas and nuclei in common, (2) the number of areas and nuclei has increased independently in several lines of mammalian evolution, and (3) new areas have been added to the middle levels of cortical processing sequences. New areas and nuclei may have evolved as a result of sudden duplications and/or by the process of single areas or nuclei gradually differentiating into two or more areas or nuclei. The process of gradual differentiation may have involved the initial step of differentiating functionally distinct classes of cells that are mixed in a representation, followed by the local groupings of such cells into functionally distinct sets, and finally the fusion of cell groups of the same types to form separate representations.

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