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31 Publications

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    10/26/23 | Neural-circuit basis of song preference learning in fruit flies
    Keisuke Imoto , Yuki Ishikawa , Yoshinori Aso , Jan Funke , Ryoya Tanaka , Azusa Kamikouchi
    bioRxiv. 2023 Oct 26:. doi: 10.1101/2023.10.24.563693

    As observed in human language learning and song learning in birds, the fruit fly Drosophila melanogaster changes its' auditory behaviors according to prior sound experiences. Female flies that have heard male courtship songs of the same species are less responsive to courtship songs of different species. This phenomenon, known as song preference learning in flies, requires GABAergic input to pC1 neurons in the central brain, with these neurons playing a key role in mating behavior by integrating multimodal sensory and internal information. The neural circuit basis of this GABAergic input, however, has not yet been identified. Here, we find that pCd-2 neurons, totaling four cells per hemibrain and expressing the sex-determination gene doublesex, provide the GABAergic input to pC1 neurons for song preference learning. First, RNAi-mediated knockdown of GABA production in pCd-2 neurons abolished song preference learning. Second, pCd-2 neurons directly, and in many cases mutually, connect with pC1 neurons, suggesting the existence of reciprocal circuits between pC1 and pCd-2 neurons. Finally, GABAergic and dopaminergic inputs to pCd-2 neurons are necessary for song preference learning. Together, this study suggests that reciprocal circuits between pC1 and pCd-2 neurons serve as a sensory and internal state-integrated hub, allowing flexible control over female copulation. Consequently, this provides a neural circuit model that underlies experience-dependent auditory plasticity.

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    07/29/23 | Network Statistics of the Whole-Brain Connectome of Drosophila
    Albert Lin , Runzhe Yang , Sven Dorkenwald , Arie Matsliah , Amy R. Sterling , Philipp Schlegel , Szi-chieh Yu , Claire E. McKellar , Marta Costa , Katharina Eichler , Alexander Shakeel Bates , Nils Eckstein , Jan Funke , Gregory S.X.E. Jefferis , Mala Murthy
    bioRxiv. 2023 Jul 29:. doi: 10.1101/2023.07.29.551086

    Animal brains are complex organs composed of thousands of interconnected neurons. Characterizing the network properties of these brains is a requisite step towards understanding mechanisms of computation and information flow. With the completion of the Flywire project, we now have access to the connectome of a complete adult Drosophila brain, containing 130,000 neurons and millions of connections. Here, we present a statistical summary and data products of the Flywire connectome, delving into its network properties and topological features. To gain insights into local connectivity, we computed the prevalence of two- and three-node network motifs, examined their strengths and neurotransmitter compositions, and compared these topological metrics with wiring diagrams of other animals. We uncovered a population of highly connected neurons known as the “rich club” and identified subsets of neurons that may serve as integrators or broadcasters of signals. Finally, we examined subnetworks based on 78 anatomically defined brain regions. The freely available data and neuron populations presented here will serve as a foundation for models and experiments exploring the relationship between neural activity and anatomical structure.

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    07/22/23 | Towards Generalizable Organelle Segmentation in Volume Electron Microscopy.
    Heinrich L, Patton W, Bennett D, Ackerman D, Park G, Bogovic JA, Eckstein N, Petruncio A, Clements J, Pang S, Shan Xu C, Funke J, Korff W, Hess H, Lippincott-Schwartz J, Saalfeld S, Weigel A, CellMap Project Team
    Microscopy and Microanalysis. 2023 Jul 22;29(Supplement_1):975. doi: 10.1093/micmic/ozad067.487
    06/29/23 | Neuronal wiring diagram of an adult brain.
    Dorkenwald S, Matsliah A, Sterling AR, Schlegel P, Yu S, McKellar CE, Lin A, Costa M, Eichler K, Yin Y, Silversmith W, Schneider-Mizell C, Jordan CS, Brittain D, Halageri A, Kuehner K, Ogedengbe O, Morey R, Gager J, Kruk K, Perlman E, Yang R, Deutsch D, Bland D, Sorek M, Lu R, Macrina T, Lee K, Bae JA, Mu S, Nehoran B, Mitchell E, Popovych S, Wu J, Jia Z, Castro M, Kemnitz N, Ih D, Bates AS, Eckstein N, Funke J, Collman F, Bock DD, Jefferis GS, Seung HS, Murthy M, FlyWire Consortium
    bioRxiv. 2023 Jun 29:. doi: 10.1101/2023.06.27.546656

    Connections between neurons can be mapped by acquiring and analyzing electron microscopic (EM) brain images. In recent years, this approach has been applied to chunks of brains to reconstruct local connectivity maps that are highly informative, yet inadequate for understanding brain function more globally. Here, we present the first neuronal wiring diagram of a whole adult brain, containing 5×10 chemical synapses between ∼130,000 neurons reconstructed from a female . The resource also incorporates annotations of cell classes and types, nerves, hemilineages, and predictions of neurotransmitter identities. Data products are available by download, programmatic access, and interactive browsing and made interoperable with other fly data resources. We show how to derive a projectome, a map of projections between regions, from the connectome. We demonstrate the tracing of synaptic pathways and the analysis of information flow from inputs (sensory and ascending neurons) to outputs (motor, endocrine, and descending neurons), across both hemispheres, and between the central brain and the optic lobes. Tracing from a subset of photoreceptors all the way to descending motor pathways illustrates how structure can uncover putative circuit mechanisms underlying sensorimotor behaviors. The technologies and open ecosystem of the FlyWire Consortium set the stage for future large-scale connectome projects in other species.

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    06/06/23 | A Connectome of the Male Drosophila Ventral Nerve Cord
    Shin-ya Takemura , Kenneth J Hayworth , Gary B Huang , Michal Januszewski , Zhiyuan Lu , Elizabeth C Marin , Stephan Preibisch , C Shan Xu , John Bogovic , Andrew S Champion , Han S J Cheong , Marta Costa , Katharina Eichler , William Katz , Christopher Knecht , Feng Li , Billy J Morris , Christopher Ordish , Patricia K Rivlin , Philipp Schlegel , Kazunori Shinomiya , Tomke Sturner , Ting Zhao , Griffin Badalamente , Dennis Bailey , Paul Brooks , Brandon S Canino , Jody Clements , Michael Cook , Octave Duclos , Christopher R Dunne , Kelli Fairbanks , Siqi Fang , Samantha Finley-May , Audrey Francis , Reed George , Marina Gkantia , Kyle Harrington , Gary Patrick Hopkins , Joseph Hsu , Philip M Hubbard , Alexandre Javier , Dagmar Kainmueller , Wyatt Korff , Julie Kovalyak , Dominik Krzeminski , Shirley A Lauchie , Alanna Lohff , Charli Maldonado , Emily A Manley , Caroline Mooney , Erika Neace , Matthew Nichols , Omotara Ogundeyi , Nneoma Okeoma , Tyler Paterson , Elliott Phillips , Emily M Phillips , Caitlin Ribeiro , Sean M Ryan , Jon Thomson Rymer , Anne K Scott , Ashley L Scott , David Shepherd , Aya Shinomiya , Claire Smith , Alia Suleiman , Satoko Takemura , Iris Talebi , Imaan F M Tamimi , Eric T Trautman , Lowell Umayam , John J Walsh , Tansy Yang , Gerald M Rubin , Louis K Scheffer , Jan Funke , Stephan Saalfeld , Harald F Hess , Stephen M Plaza , Gwyneth M Card , Gregory S X E Jefferis , Stuart Berg
    bioRxiv. 2023 Jun 06:. doi: 10.1101/2023.06.05.543757

    Animal behavior is principally expressed through neural control of muscles. Therefore understanding how the brain controls behavior requires mapping neuronal circuits all the way to motor neurons. We have previously established technology to collect large-volume electron microscopy data sets of neural tissue and fully reconstruct the morphology of the neurons and their chemical synaptic connections throughout the volume. Using these tools we generated a dense wiring diagram, or connectome, for a large portion of the Drosophila central brain. However, in most animals, including the fly, the majority of motor neurons are located outside the brain in a neural center closer to the body, i.e. the mammalian spinal cord or insect ventral nerve cord (VNC). In this paper, we extend our effort to map full neural circuits for behavior by generating a connectome of the VNC of a male fly.

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    05/02/23 | A leaky integrate-and-fire computational model based on the connectome of the entire adult Drosophila brain reveals insights into sensorimotor processing
    Philip K. Shiu , Gabriella R. Sterne , Nico Spiller , Romain Franconville , Andrea Sandoval , Joie Zhou , Neha Simha , Chan Hyuk Kang , Seongbong Yu , Jinseop S. Kim , Sven Dorkenwald , Arie Matsliah , Philipp Schlegel , Szi-chieh Yu , Claire E. McKellar , Amy Sterling , Marta Costa , Katharina Eichler , Gregory S.X.E. Jefferis , Mala Murthy , Alexander Shakeel Bates , Nils Eckstein , Jan Funke , Salil S. Bidaye , Stefanie Hampel , Andrew M. Seeds , Kristin Scott
    bioRxiv. 2023 May 02:. doi: 10.1101/2023.05.02.539144

    The forthcoming assembly of the adult Drosophila melanogaster central brain connectome, containing over 125,000 neurons and 50 million synaptic connections, provides a template for examining sensory processing throughout the brain. Here, we create a leaky integrate-and-fire computational model of the entire Drosophila brain, based on neural connectivity and neurotransmitter identity, to study circuit properties of feeding and grooming behaviors. We show that activation of sugar-sensing or water-sensing gustatory neurons in the computational model accurately predicts neurons that respond to tastes and are required for feeding initiation. Computational activation of neurons in the feeding region of the Drosophila brain predicts those that elicit motor neuron firing, a testable hypothesis that we validate by optogenetic activation and behavioral studies. Moreover, computational activation of different classes of gustatory neurons makes accurate predictions of how multiple taste modalities interact, providing circuit-level insight into aversive and appetitive taste processing. Our computational model predicts that the sugar and water pathways form a partially shared appetitive feeding initiation pathway, which our calcium imaging and behavioral experiments confirm. Additionally, we applied this model to mechanosensory circuits and found that computational activation of mechanosensory neurons predicts activation of a small set of neurons comprising the antennal grooming circuit that do not overlap with gustatory circuits, and accurately describes the circuit response upon activation of different mechanosensory subtypes. Our results demonstrate that modeling brain circuits purely from connectivity and predicted neurotransmitter identity generates experimentally testable hypotheses and can accurately describe complete sensorimotor transformations.

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    02/01/23 | Local shape descriptors for neuron segmentation.
    Sheridan A, Nguyen TM, Deb D, Lee WA, Saalfeld S, Turaga SC, Manor U, Funke J
    Nature Methods. 2023 Feb 01;20(2):295-303. doi: 10.1038/s41592-022-01711-z

    We present an auxiliary learning task for the problem of neuron segmentation in electron microscopy volumes. The auxiliary task consists of the prediction of local shape descriptors (LSDs), which we combine with conventional voxel-wise direct neighbor affinities for neuron boundary detection. The shape descriptors capture local statistics about the neuron to be segmented, such as diameter, elongation, and direction. On a study comparing several existing methods across various specimen, imaging techniques, and resolutions, auxiliary learning of LSDs consistently increases segmentation accuracy of affinity-based methods over a range of metrics. Furthermore, the addition of LSDs promotes affinity-based segmentation methods to be on par with the current state of the art for neuron segmentation (flood-filling networks), while being two orders of magnitudes more efficient-a critical requirement for the processing of future petabyte-sized datasets.

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    01/24/23 | Hierarchical architecture of dopaminergic circuits enables second-order conditioning in Drosophila
    Daichi Yamada , Daniel Bushey , Li Feng , Karen Hibbard , Megan Sammons , Jan Funke , Ashok Litwin-Kumar , Toshihide Hige , Yoshinori Aso
    eLife. 2023 Jan 24:. doi: 10.7554/eLife.79042

    Dopaminergic neurons with distinct projection patterns and physiological properties compose memory subsystems in a brain. However, it is poorly understood whether or how they interact during complex learning. Here, we identify a feedforward circuit formed between dopamine subsystems and show that it is essential for second-order conditioning, an ethologically important form of higher-order associative learning. The Drosophila mushroom body comprises a series of dopaminergic compartments, each of which exhibits distinct memory dynamics. We find that a slow and stable memory compartment can serve as an effective “teacher” by instructing other faster and transient memory compartments via a single key interneuron, which we identify by connectome analysis and neurotransmitter prediction. This excitatory interneuron acquires enhanced response to reward-predicting odor after first-order conditioning and, upon activation, evokes dopamine release in the “student” compartments. These hierarchical connections between dopamine subsystems explain distinct properties of first- and second-order memory long known by behavioral psychologists.

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    01/01/23 | Automated reconstruction of whole-embryo cell lineages by learning from sparse annotations.
    Malin-Mayor C, Hirsch P, Guignard L, McDole K, Wan Y, Lemon WC, Kainmueller D, Keller PJ, Preibisch S, Funke J
    Nature Biotechnology. 2023 Jan 01;41(1):44-49. doi: 10.1038/s41587-022-01427-7

    We present a method to automatically identify and track nuclei in time-lapse microscopy recordings of entire developing embryos. The method combines deep learning and global optimization. On a mouse dataset, it reconstructs 75.8% of cell lineages spanning 1 h, as compared to 31.8% for the competing method. Our approach improves understanding of where and when cell fate decisions are made in developing embryos, tissues, and organs.

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    01/01/23 | Structured cerebellar connectivity supports resilient pattern separation.
    Nguyen TM, Thomas LA, Rhoades JL, Ricchi I, Yuan XC, Sheridan A, Hildebrand DG, Funke J, Regehr WG, Lee WA
    Nature. 2023 Jan 01;613(7944):543-549. doi: 10.1038/s41586-022-05471-w

    The cerebellum is thought to help detect and correct errors between intended and executed commands and is critical for social behaviours, cognition and emotion. Computations for motor control must be performed quickly to correct errors in real time and should be sensitive to small differences between patterns for fine error correction while being resilient to noise. Influential theories of cerebellar information processing have largely assumed random network connectivity, which increases the encoding capacity of the network's first layer. However, maximizing encoding capacity reduces the resilience to noise. To understand how neuronal circuits address this fundamental trade-off, we mapped the feedforward connectivity in the mouse cerebellar cortex using automated large-scale transmission electron microscopy and convolutional neural network-based image segmentation. We found that both the input and output layers of the circuit exhibit redundant and selective connectivity motifs, which contrast with prevailing models. Numerical simulations suggest that these redundant, non-random connectivity motifs increase the resilience to noise at a negligible cost to the overall encoding capacity. This work reveals how neuronal network structure can support a trade-off between encoding capacity and redundancy, unveiling principles of biological network architecture with implications for the design of artificial neural networks.

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