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31 Janelia Publications

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    Fetter LabTruman LabCardona Lab
    12/11/18 | Convergence of monosynaptic and polysynaptic sensory paths onto common motor outputs in a feeding connectome.
    Miroschnikow A, Schlegel P, Schoofs A, Hueckesfeld S, Li F, Schneider-Mizell CM, Fetter RD, Truman JW, Cardona A, Pankratz MJ
    eLife. 2018 Dec 11;7:. doi: 10.7554/eLife.40247

    We reconstructed, from a whole CNS EM volume, the synaptic map of input and output neurons that underlie food intake behavior of larvae. Input neurons originate from enteric, pharyngeal and external sensory organs and converge onto seven distinct sensory synaptic compartments within the CNS. Output neurons consist of feeding motor, serotonergic modulatory and neuroendocrine neurons. Monosynaptic connections from a set of sensory synaptic compartments cover the motor, modulatory and neuroendocrine targets in overlapping domains. Polysynaptic routes are superimposed on top of monosynaptic connections, resulting in divergent sensory paths that converge on common outputs. A completely different set of sensory compartments is connected to the mushroom body calyx. The mushroom body output neurons are connected to interneurons that directly target the feeding output neurons. Our results illustrate a circuit architecture in which monosynaptic and multisynaptic connections from sensory inputs traverse onto output neurons via a series of converging paths.

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    Cardona LabFetter Lab
    08/02/18 | MDN brain descending neurons coordinately activate backward and inhibit forward locomotion.
    Carreira-Rosario A, Zarin AA, Clark MQ, Manning L, Fetter RD, Cardona A, Doe CQ
    eLife. 2018 Aug 02;7:. doi: 10.7554/eLife.38554

    Command-like descending neurons can induce many behaviors, such as backward locomotion, escape, feeding, courtship, egg-laying, or grooming (we define 'command-like neuron' as a neuron whose activation elicits or 'commands' a specific behavior). In most animals it remains unknown how neural circuits switch between antagonistic behaviors: via top-down activation/inhibition of antagonistic circuits or via reciprocal inhibition between antagonistic circuits. Here we use genetic screens, intersectional genetics, circuit reconstruction by electron microscopy, and functional optogenetics to identify a bilateral pair of larval 'mooncrawler descending neurons' (MDNs) with command-like ability to coordinately induce backward locomotion and block forward locomotion; the former by stimulating a backward-active premotor neuron, and the latter by disynaptic inhibition of a forward-specific premotor neuron. In contrast, direct monosynaptic reciprocal inhibition between forward and backward circuits was not observed. Thus, MDNs coordinate a transition between antagonistic larval locomotor behaviors. Interestingly, larval MDNs persist into adulthood, where they can trigger backward walking. Thus, MDNs induce backward locomotion in both limbless and limbed animals.

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    07/12/18 | A complete electron microscopy volume of the brain of adult Drosophila melanogaster.
    Zheng Z, Lauritzen JS, Perlman E, Robinson CG, Nichols M, Milkie DE, Torrens O, Price J, Fisher CB, Sharifi N, Calle-Schuler SA, Kmecova L, Ali IJ, Karsh B, Trautman ET, Bogovic JA, Hanslovsky P, Jefferis GS, Kazhdan M, Khairy K
    Cell. 2018 Jul 12;174(3):730-43. doi: 10.1016/j.cell.2018.06.019

    Drosophila melanogaster has a rich repertoire of innate and learned behaviors. Its 100,000-neuron brain is a large but tractable target for comprehensive neural circuit mapping. Only electron microscopy (EM) enables complete, unbiased mapping of synaptic connectivity; however, the fly brain is too large for conventional EM. We developed a custom high-throughput EM platform and imaged the entire brain of an adult female fly at synaptic resolution. To validate the dataset, we traced brain-spanning circuitry involving the mushroom body (MB), which has been extensively studied for its role in learning. All inputs to Kenyon cells (KCs), the intrinsic neurons of the MB, were mapped, revealing a previously unknown cell type, postsynaptic partners of KC dendrites, and unexpected clustering of olfactory projection neurons. These reconstructions show that this freely available EM volume supports mapping of brain-spanning circuits, which will significantly accelerate Drosophila neuroscience..

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    02/19/18 | Single excitatory axons form clustered synapses onto CA1 pyramidal cell dendrites.
    Bloss EB, Cembrowski MS, Karsh B, Colonell J, Fetter RD, Spruston N
    Nature Neuroscience. 2018 Mar;21(3):353-63. doi: 10.1038/s41593-018-0084-6

    CA1 pyramidal neurons are a major output of the hippocampus and encode features of experience that constitute episodic memories. Feature-selective firing of these neurons results from the dendritic integration of inputs from multiple brain regions. While it is known that synchronous activation of spatially clustered inputs can contribute to firing through the generation of dendritic spikes, there is no established mechanism for spatiotemporal synaptic clustering. Here we show that single presynaptic axons form multiple, spatially clustered inputs onto the distal, but not proximal, dendrites of CA1 pyramidal neurons. These compound connections exhibit ultrastructural features indicative of strong synapses and occur much more commonly in entorhinal than in thalamic afferents. Computational simulations revealed that compound connections depolarize dendrites in a biophysically efficient manner, owing to their inherent spatiotemporal clustering. Our results suggest that distinct afferent projections use different connectivity motifs that differentially contribute to dendritic integration.

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    Fetter LabTruman LabZlatic LabCardona Lab
    12/20/17 | Divergent connectivity of homologous command-like neurons mediates segment-specific touch responses in Drosophila.
    Takagi S, Cocanougher BT, Niki S, Miyamoto D, Kohsaka H, Kazama H, Fetter RD, Truman JW, Zlatic M, Cardona A, Nose A
    Neuron. 2017 Dec 20;96(6):1373-87. doi: 10.1016/j.neuron.2017.10.030

    Animals adaptively respond to a tactile stimulus by choosing an ethologically relevant behavior depending on the location of the stimuli. Here, we investigate how somatosensory inputs on different body segments are linked to distinct motor outputs in Drosophila larvae. Larvae escape by backward locomotion when touched on the head, while they crawl forward when touched on the tail. We identify a class of segmentally repeated second-order somatosensory interneurons, that we named Wave, whose activation in anterior and posterior segments elicit backward and forward locomotion, respectively. Anterior and posterior Wave neurons extend their dendrites in opposite directions to receive somatosensory inputs from the head and tail, respectively. Downstream of anterior Wave neurons, we identify premotor circuits including the neuron A03a5, which together with Wave, is necessary for the backward locomotion touch response. Thus, Wave neurons match their receptive field to appropriate motor programs by participating in different circuits in different segments.

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    Fetter LabCardona Lab
    10/23/17 | Conserved neural circuit structure across Drosophila larva development revealed by comparative connectomics.
    Gerhard S, Andrade I, Fetter RD, Cardona A, Schneider-Mizell CM
    eLife. 2017 Oct 23;6:e29089. doi: 10.7554/eLife.29089

    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. In a previous paper (Schneider-Mizell et al., 2016), we measured the cellular neuroanatomy underlying synaptic connectivity in Drosophila. Here, we examined how neuronal morphology and connectivity change between 1st instar and 3rd 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 presynaptic 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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    Fetter LabTruman LabZlatic LabCardona Lab
    08/09/17 | The complete connectome of a learning and memory centre in an insect brain.
    Eichler K, Li F, Litwin-Kumar A, Park Y, Andrade I, Schneider-Mizell CM, Saumweber T, Huser A, Eschbach C, Gerber B, Fetter RD, Truman JW, Priebe CE, Abbott LF, Thum AS, Zlatic M, Cardona A
    Nature. 2017 Aug 09;548(7666):175-182. doi: 10.1038/nature23455

    Associating stimuli with positive or negative reinforcement is essential for survival, but a complete wiring diagram of a higher-order circuit supporting associative memory has not been previously available. Here we reconstruct one such circuit at synaptic resolution, the Drosophila larval mushroom body. We find that most Kenyon cells integrate random combinations of inputs but that a subset receives stereotyped inputs from single projection neurons. This organization maximizes performance of a model output neuron on a stimulus discrimination task. We also report a novel canonical circuit in each mushroom body compartment with previously unidentified connections: reciprocal Kenyon cell to modulatory neuron connections, modulatory neuron to output neuron connections, and a surprisingly high number of recurrent connections between Kenyon cells. Stereotyped connections found between output neurons could enhance the selection of learned behaviours. The complete circuit map of the mushroom body should guide future functional studies of this learning and memory centre.

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    Fetter LabTruman LabZlatic LabCardona Lab
    08/08/17 | Organization of the drosophila larval visual circuit.
    Larderet I, Fritsch PM, Gendre N, Neagu-Maier GL, Fetter RD, Schneider-Mizell CM, Truman JW, Zlatic M, Cardona A, Sprecher SG
    eLife. 2017 Aug 8:e28387. doi: 10.7554/eLife.28387

    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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    Fetter LabTruman LabCardona Lab
    11/15/16 | Synaptic transmission parallels neuromodulation in a central food-intake circuit.
    Schlegel P, Texada MJ, Miroschnikow A, Schoofs A, Hückesfeld S, Peters M, Schneider-Mizell CM, Lacin H, Li F, Fetter RD, Truman JW, Cardona A, Pankratz MJ
    eLife. 2016 Nov 15:. doi: 10.7554/eLife.16799

    NeuromedinU is a potent regulator of food intake and activity in mammals. In Drosophila, neurons producing the homologous neuropeptide hugin regulate feeding and locomotion in a similar manner. Here, we use EM-based reconstruction to generate the entire connectome of hugin-producing neurons in the Drosophila larval CNS. We demonstrate that hugin neurons use synaptic transmission in addition to peptidergic neuromodulation and identify acetylcholine as a key transmitter. Hugin neuropeptide and acetylcholine are both necessary for the regulatory effect on feeding. We further show that subtypes of hugin neurons connect chemosensory to endocrine system by combinations of synaptic and peptide-receptor connections. Targets include endocrine neurons producing DH44, a CRH-like peptide, and insulin-like peptides. Homologs of these peptides are likewise downstream of neuromedinU, revealing striking parallels in flies and mammals. We propose that hugin neurons are part of an ancient physiological control system that has been conserved at functional and molecular level.

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    Zlatic LabCardona LabFetter LabTruman LabScientific Computing Software
    10/05/16 | Competitive disinhibition mediates behavioral choice and sequences in Drosophila.
    Jovanic T, Schneider-Mizell CM, Shao M, Masson J, Denisov G, Fetter RD, Mensh BD, Truman JW, Cardona A, Zlatic M
    Cell. 2016 Oct 5;167(3):858-70. doi: 10.1016/j.cell.2016.09.009

    Even a simple sensory stimulus can elicit distinct innate behaviors and sequences. During sensorimotor decisions, competitive interactions among neurons that promote distinct behaviors must ensure the selection and maintenance of one behavior, while suppressing others. The circuit implementation of these competitive interactions is still an open question. By combining comprehensive electron microscopy reconstruction of inhibitory interneuron networks, modeling, electrophysiology, and behavioral studies, we determined the circuit mechanisms that contribute to the Drosophila larval sensorimotor decision to startle, explore, or perform a sequence of the two in response to a mechanosensory stimulus. Together, these studies reveal that, early in sensory processing, (1) reciprocally connected feedforward inhibitory interneurons implement behavioral choice, (2) local feedback disinhibition provides positive feedback that consolidates and maintains the chosen behavior, and (3) lateral disinhibition promotes sequence transitions. The combination of these interconnected circuit motifs can implement both behavior selection and the serial organization of behaviors into a sequence.

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