The Drosophila Larval Locomotor Circuit Provides a Model to Understand Neural Circuit Development and Function.
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ABSTRACT:
SUBMITTER: Hunter I
PROVIDER: S-EPMC8282269 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:During postembryonic development, the nervous system must adapt to a growing body. How changes in neuronal structure and connectivity contribute to the maintenance of appropriate circuit function remains unclear. Previously , we measured the cellular neuroanatomy underlying synaptic connectivity in Drosophila (Schneider-Mizell et al., 2016). Here, we examined how neuronal morphology and connectivity change between first instar and third instar larval stages using serial section electron microscopy. We reconstructed nociceptive circuits in a larva of each stage and found consistent topographically arranged connectivity between identified neurons. Five-fold increases in each size, number of terminal dendritic branches, and total number of synaptic inputs were accompanied by cell type-specific connectivity changes that preserved the fraction of total synaptic input associated with each pre-synaptic partner. We propose that precise patterns of structural growth act to conserve the computational function of a circuit, for example determining the location of a dangerous stimulus.
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Project description:Individual neurons can undergo drastic structural changes, known as neuronal remodeling or structural plasticity. One example of this is in response to hormones, such as during puberty in mammals or metamorphosis in insects. However, in each of these examples, it remains unclear whether the remodeled neuron resumes prior patterns of connectivity, and if so, whether the persistent circuits drive similar behaviors. Here, we utilize a well-characterized neural circuit in the Drosophila larva: the moonwalker descending neuron (MDN) circuit. We previously showed that larval MDN induces backward crawling, and synapses onto the Pair1 interneuron to inhibit forward crawling (Carreira-Rosario et al., 2018). MDN is remodeled during metamorphosis and regulates backward walking in the adult fly. We investigated whether Pair1 is remodeled during metamorphosis and functions within the MDN circuit during adulthood. We assayed morphology and molecular markers to demonstrate that Pair1 is remodeled during metamorphosis and persists in the adult fly. MDN-Pair1 connectivity is lost during early pupal stages, when both neurons are severely pruned back, but connectivity is re-established at mid-pupal stages and persist into the adult. In the adult, optogenetic activation of Pair1 resulted in arrest of forward locomotion, similar to what is observed in larvae. Thus, the MDN-Pair1 neurons are an interneuronal circuit - a pair of synaptically connected interneurons - that is re-established during metamorphosis, yet generates similar locomotor behavior at both larval and adult stages.
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Project description:We have established a preparation in larval Drosophila to monitor fictive locomotion simultaneously across abdominal and thoracic segments of the isolated CNS with genetically encoded Ca(2+) indicators. The Ca(2+) signals closely followed spiking activity measured electrophysiologically in nerve roots. Three motor patterns are analyzed. Two comprise waves of Ca(2+) signals that progress along the longitudinal body axis in a posterior-to-anterior or anterior-to-posterior direction. These waves had statistically indistinguishable intersegmental phase delays compared with segmental contractions during forward and backward crawling behavior, despite being ∼10 times slower. During these waves, motor neurons of the dorsal longitudinal and transverse muscles were active in the same order as the muscle groups are recruited during crawling behavior. A third fictive motor pattern exhibits a left-right asymmetry across segments and bears similarities with turning behavior in intact larvae, occurring equally frequently and involving asymmetry in the same segments. Ablation of the segments in which forward and backward waves of Ca(2+) signals were normally initiated did not eliminate production of Ca(2+) waves. When the brain and subesophageal ganglion (SOG) were removed, the remaining ganglia retained the ability to produce both forward and backward waves of motor activity, although the speed and frequency of waves changed. Bilateral asymmetry of activity was reduced when the brain was removed and abolished when the SOG was removed. This work paves the way to studying the neural and genetic underpinnings of segmentally coordinated motor pattern generation in Drosophila with imaging techniques.
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Project description:Visual systems transduce, process and transmit light-dependent environmental cues. Computation of visual features depends on photoreceptor neuron types (PR) present, organization of the eye and wiring of the underlying neural circuit. Here, we describe the circuit architecture of the visual system of Drosophila larvae by mapping the synaptic wiring diagram and neurotransmitters. By contacting different targets, the two larval PR-subtypes create two converging pathways potentially underlying the computation of ambient light intensity and temporal light changes already within this first visual processing center. Locally processed visual information then signals via dedicated projection interneurons to higher brain areas including the lateral horn and mushroom body. The stratified structure of the larval optic neuropil (LON) suggests common organizational principles with the adult fly and vertebrate visual systems. The complete synaptic wiring diagram of the LON paves the way to understanding how circuits with reduced numerical complexity control wide ranges of behaviors.
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Project description:An efficient and low-cost method of examining larval movement in Drosophila melanogaster is needed to study how mutations and/or alterations in the muscular, neural, and olfactory systems affect locomotor behavior. Here, we describe the implementation of wrMTrck, a freely available ImageJ plugin originally developed for examining multiple behavioral parameters in the nematode C. elegans. Our optimized method is rapid, reproducible and does not require automated microscope setups or the purchase of proprietary software. To demonstrate the utility of this method, we analyzed the velocity and crawling paths of two Drosophila mutants that affect muscle structure and/or function. Additionally, we show that this approach is useful for tracking the behavior of adult insects, including Tribolium castaneum and Drosophila melanogaster.
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Project description:Autism spectrum disorder (ASD) is a neurologic condition characterized by alterations in social interaction and communication, and restricted and/or repetitive behaviors. The classical Type II cadherins cadherin-8 (Cdh8, CDH8) and cadherin-11 (Cdh11, CDH11) have been implicated as autism risk gene candidates. To explore the role of cadherins in the etiology of autism, we investigated their expression patterns during mouse brain development and in autism-specific human tissue. In mice, expression of cadherin-8 and cadherin-11 was developmentally regulated and enriched in the cortex, hippocampus, and thalamus/striatum during the peak of dendrite formation and synaptogenesis. Both cadherins were expressed in synaptic compartments but only cadherin-8 associated with the excitatory synaptic marker neuroligin-1. Induced pluripotent stem cell (iPSC)-derived cortical neural precursor cells (NPCs) and cortical organoids generated from individuals with autism showed upregulated CDH8 expression levels, but downregulated CDH11. We used Cdh11 knock-out (KO) mice of both sexes to analyze the function of cadherin-11, which could help explain phenotypes observed in autism. Cdh11-/- hippocampal neurons exhibited increased dendritic complexity along with altered neuronal and synaptic activity. Similar to the expression profiles in human tissue, levels of cadherin-8 were significantly elevated in Cdh11 KO brains. Additionally, excitatory synaptic markers neuroligin-1 and postsynaptic density (PSD)-95 were both increased. Together, these results strongly suggest that cadherin-11 is involved in regulating the development of neuronal circuitry and that alterations in the expression levels of cadherin-11 may contribute to the etiology of autism.
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Project description:Animals use sensory information to move toward more favorable conditions. Drosophila larvae can move up or down gradients of odors (chemotax), light (phototax), and temperature (thermotax) by modulating the probability, direction, and size of turns based on sensory input. Whether larvae can anemotax in gradients of mechanosensory cues is unknown. Further, although many of the sensory neurons that mediate taxis have been described, the central circuits are not well understood. Here, we used high-throughput, quantitative behavioral assays to demonstrate Drosophila larvae anemotax in gradients of wind speeds and to characterize the behavioral strategies involved. We found that larvae modulate the probability, direction, and size of turns to move away from higher wind speeds. This suggests that similar central decision-making mechanisms underlie taxis in somatosensory and other sensory modalities. By silencing the activity of single or very few neuron types in a behavioral screen, we found two sensory (chordotonal and multidendritic class III) and six nerve cord neuron types involved in anemotaxis. We reconstructed the identified neurons in an electron microscopy volume that spans the entire larval nervous system and found they received direct input from the mechanosensory neurons or from each other. In this way, we identified local interneurons and first- and second-order subesophageal zone (SEZ) and brain projection neurons. Finally, silencing a dopaminergic brain neuron type impairs anemotaxis. These findings suggest that anemotaxis involves both nerve cord and brain circuits. The candidate neurons and circuitry identified in our study provide a basis for future detailed mechanistic understanding of the circuit principles of anemotaxis.
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Project description:The neural mechanisms determining the timing of even simple actions, such as when to walk or rest, are largely mysterious. One intriguing, but untested, hypothesis posits a role for ongoing activity fluctuations in neurons of central action selection circuits that drive animal behavior from moment to moment. To examine how fluctuating activity can contribute to action timing, we paired high-resolution measurements of freely walking Drosophila melanogaster with data-driven neural network modeling and dynamical systems analysis. We generated fluctuation-driven network models whose outputs-locomotor bouts-matched those measured from sensory-deprived Drosophila. From these models, we identified those that could also reproduce a second, unrelated dataset: the complex time-course of odor-evoked walking for genetically diverse Drosophila strains. Dynamical models that best reproduced both Drosophila basal and odor-evoked locomotor patterns exhibited specific characteristics. First, ongoing fluctuations were required. In a stochastic resonance-like manner, these fluctuations allowed neural activity to escape stable equilibria and to exceed a threshold for locomotion. Second, odor-induced shifts of equilibria in these models caused a depression in locomotor frequency following olfactory stimulation. Our models predict that activity fluctuations in action selection circuits cause behavioral output to more closely match sensory drive and may therefore enhance navigation in complex sensory environments. Together these data reveal how simple neural dynamics, when coupled with activity fluctuations, can give rise to complex patterns of animal behavior.
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Project description:BackgroundTwo key questions in understanding the genetic control of behaviors are: what genes are involved and how these genes interact. To answer these questions at a systems level, we conducted high-content profiling of Drosophila larval locomotor behaviors for over 100 genotypes.ResultsWe studied 69 genes whose C. elegans orthologs were neuronal signalling genes with significant locomotor phenotypes, and conducted RNAi with ubiquitous, pan-neuronal, or motor-neuronal Gal4 drivers. Inactivation of 42 genes, including the nicotinic acetylcholine receptors nAChRα1 and nAChRα3, in the neurons caused significant movement defects. Bioinformatic analysis suggested 81 interactions among these genes based on phenotypic pattern similarities. Comparing the worm and fly data sets, we found that these genes were highly conserved in having neuronal expressions and locomotor phenotypes. However, the genetic interactions were not conserved for ubiquitous profiles, and may be mildly conserved for the neuronal profiles. Unexpectedly, our data also revealed a possible motor-neuronal control of body size, because inactivation of Rdl and Gαo in the motor neurons reduced the larval body size. Overall, these data established a framework for further exploring the genetic control of Drosophila larval locomotion.ConclusionsHigh content, quantitative phenotyping of larval locomotor behaviours provides a framework for system-level understanding of the gene networks underlying such behaviours.
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Project description:Animals generate diverse motor behaviors, yet how the same motor neurons (MNs) generate two distinct or antagonistic behaviors remains an open question. Here, we characterize Drosophila larval muscle activity patterns and premotor/motor circuits to understand how they generate forward and backward locomotion. We show that all body wall MNs are activated during both behaviors, but a subset of MNs change recruitment timing for each behavior. We used TEM to reconstruct a full segment of all 60 MNs and 236 premotor neurons (PMNs), including differentially-recruited MNs. Analysis of this comprehensive connectome identified PMN-MN 'labeled line' connectivity; PMN-MN combinatorial connectivity; asymmetric neuronal morphology; and PMN-MN circuit motifs that could all contribute to generating distinct behaviors. We generated a recurrent network model that reproduced the observed behaviors, and used functional optogenetics to validate selected model predictions. This PMN-MN connectome will provide a foundation for analyzing the full suite of larval behaviors.
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