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175 Janelia Publications

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    11/28/22 | The connectome of an insect brain
    Michael Winding , Benjamin D. Pedigo , Christopher L. Barnes , Heather G. Patsolic , Youngser Park , Tom Kazimiers , Akira Fushiki , Ingrid V. Andrade , Avinash Khandelwal , Javier Valdes-Aleman , Feng Li , Nadine Randel , Elizabeth Barsotti , Ana Correia , Richard D. Fetter , Volker Hartenstein , Carey E. Priebe , Joshua T. Vogelstein , Albert Cardona , Marta Zlatic
    bioRxiv. 2022 Nov 28:. doi: 10.1101/2022.11.28.516756

    Brains contain networks of interconnected neurons, so knowing the network architecture is essential for understanding brain function. We therefore mapped the synaptic-resolution connectome of an insect brain (Drosophila larva) with rich behavior, including learning, value-computation, and action-selection, comprising 3,013 neurons and 544,000 synapses. We characterized neuron-types, hubs, feedforward and feedback pathways, and cross-hemisphere and brain-nerve cord interactions. We found pervasive multisensory and interhemispheric integration, highly recurrent architecture, abundant feedback from descending neurons, and multiple novel circuit motifs. The brain’s most recurrent circuits comprised the input and output neurons of the learning center. Some structural features, including multilayer shortcuts and nested recurrent loops, resembled powerful machine learning architectures. The identified brain architecture provides a basis for future experimental and theoretical studies of neural circuits.

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    12/22/22 | Neuronal cell types, projections, and spatial organization of the central amygdala
    O’Leary TP, Kendrick RM, Bristow BN, Sullivan KE, Wang L, Clements J, Lemire AL, Cembrowski MS
    iScience. 2022 Dec 22;25(12):105497. doi: 10.1016/j.isci.2022.105497

    The central amygdala (CEA) has been richly studied for interpreting function and behavior according to specific cell types and circuits. Such work has typically defined molecular cell types by classical inhibitory marker genes; consequently, whether marker-gene-defined cell types exhaustively cover the CEA and co-vary with connectivity remains unresolved. Here, we combined single-cell RNA sequencing, multiplexed fluorescent in situ hybridization, immunohistochemistry, and long-range projection mapping to derive a “bottom-up” understanding of CEA cell types. In doing so, we identify two major cell types, encompassing one-third of all CEA neurons, that have gone unresolved in previous studies. In spatially mapping these novel types, we identify a non-canonical CEA subdomain associated with Nr2f2 expression and uncover an Isl1-expressing medial cell type that accounts for many long-range CEA projections. Our results reveal new CEA organizational principles across cell types and spatial scales and provide a framework for future work examining cell-type-specific behavior and function.

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    12/02/22 | Hippocampal representations of foraging trajectories depend upon spatial context.
    Jiang W, Xu S, Dudman JT
    Nature Neuroscience. 2022 Dec 02;25(12):1693-1705. doi: 10.1038/s41593-022-01201-7

    Animals learn trajectories to rewards in both spatial, navigational contexts and relational, non-navigational contexts. Synchronous reactivation of hippocampal activity is thought to be critical for recall and evaluation of trajectories for learning. Do hippocampal representations differentially contribute to experience-dependent learning of trajectories across spatial and relational contexts? In this study, we trained mice to navigate to a hidden target in a physical arena or manipulate a joystick to a virtual target to collect delayed rewards. In a navigational context, calcium imaging in freely moving mice revealed that synchronous CA1 reactivation was retrospective and important for evaluation of prior navigational trajectories. In a non-navigational context, reactivation was prospective and important for initiation of joystick trajectories, even in the same animals trained in both contexts. Adaptation of trajectories to a new target was well-explained by a common learning algorithm in which hippocampal activity makes dissociable contributions to reinforcement learning computations depending upon spatial context.

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    11/29/22 | From primordial clocks to circadian oscillators
    Warintra Pitsawong , Ricardo A. P. Pádua , Timothy Grant , Marc Hoemberger , Renee Otten , Niels Bradshaw , Nikolaus Grigorieff , Dorothee Kern
    bioRxiv. 2022 Nov 29:. doi: 10.1101/2022.11.28.518275

    Circadian rhythms play an essential role in many biological processes and surprisingly only three prokaryotic proteins are required to constitute a true post-translational circadian oscillator. The evolutionary history of the three Kai proteins indicates that KaiC is the oldest member and central component of the clock, with subsequent additions of KaiB and KaiA to regulate its phosphorylation state for time synchronization. The canonical KaiABC system in cyanobacteria is well understood, but little is known about more ancient systems that possess just KaiBC, except for reports that they might exhibit a basic, hourglass-like timekeeping mechanism. Here, we investigate the primordial circadian clock in Rhodobacter sphaeroides (RS) that contains only KaiBC to elucidate its inner workings despite the missing KaiA. Using a combination X-ray crystallography and cryo-EM we find a novel dodecameric fold for KaiCRS where two hexamers are held together by a coiled-coil bundle of 12 helices. This interaction is formed by the C-terminal extension of KaiCRS and serves as an ancient regulatory moiety later superseded by KaiA. A coiled-coil register shift between daytime- and nighttime-conformations is connected to the phosphorylation sites through a long-range allosteric network that spans over 160 Å. Our kinetic data identify the difference in ATP-to-ADP ratio between day and night as the environmental cue that drives the clock and further unravels mechanistic details that shed light on the evolution of self-sustained oscillators.

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    11/29/22 | Oligodendrocyte precursor cells ingest axons in the mouse neocortex.
    Buchanan J, Elabbady L, Collman F, Jorstad NL, Bakken TE, Ott C, Glatzer J, Bleckert AA, Bodor AL, Brittain D, Bumbarger DJ, Mahalingam G, Seshamani S, Schneider-Mizell C, Takeno MM, Torres R, Yin W, Hodge RD, Castro M, Dorkenwald S, Ih D, Jordan CS, Kemnitz N, Lee K, Lu R, Macrina T, Mu S, Popovych S, Silversmith WM, Tartavull I, Turner NL, Wilson AM, Wong W, Wu J, Zlateski A, Zung J, Lippincott-Schwartz J, Lein ES, Seung HS, Bergles DE, Reid RC, da Costa NM
    Proceedings of the National Academies of Science of the U.S.A.. 2022 Nov 29;119(48):e2202580119. doi: 10.1073/pnas.2202580119

    Neurons in the developing brain undergo extensive structural refinement as nascent circuits adopt their mature form. This physical transformation of neurons is facilitated by the engulfment and degradation of axonal branches and synapses by surrounding glial cells, including microglia and astrocytes. However, the small size of phagocytic organelles and the complex, highly ramified morphology of glia have made it difficult to define the contribution of these and other glial cell types to this crucial process. Here, we used large-scale, serial section transmission electron microscopy (TEM) with computational volume segmentation to reconstruct the complete 3D morphologies of distinct glial types in the mouse visual cortex, providing unprecedented resolution of their morphology and composition. Unexpectedly, we discovered that the fine processes of oligodendrocyte precursor cells (OPCs), a population of abundant, highly dynamic glial progenitors, frequently surrounded small branches of axons. Numerous phagosomes and phagolysosomes (PLs) containing fragments of axons and vesicular structures were present inside their processes, suggesting that OPCs engage in axon pruning. Single-nucleus RNA sequencing from the developing mouse cortex revealed that OPCs express key phagocytic genes at this stage, as well as neuronal transcripts, consistent with active axon engulfment. Although microglia are thought to be responsible for the majority of synaptic pruning and structural refinement, PLs were ten times more abundant in OPCs than in microglia at this stage, and these structures were markedly less abundant in newly generated oligodendrocytes, suggesting that OPCs contribute substantially to the refinement of neuronal circuits during cortical development.

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    11/25/22 | SMP30-mediated synthesis of vitamin C activates the liver PPARα/FGF21 axis to regulate thermogenesis in mice.
    Lee B, An HJ, Kim DH, Lee M, Jeong HH, Chung KW, Go Y, Seo AY, Kim IY, Seong JK, Yu BP, Lee J, Im E, Lee I, Lee M, Yamada K, Chung HY
    Experimental and Molecular Medicine. 2022 Nov 25:. doi: 10.1038/s12276-022-00888-9

    The vitamin-C-synthesizing enzyme senescent marker protein 30 (SMP30) is a cold resistance gene in Drosophila, and vitamin C concentration increases in brown adipose tissue post-cold exposure. However, the roles of SMP30 in thermogenesis are unknown. Here, we tested the molecular mechanism of thermogenesis using wild-type (WT) and vitamin C-deficient SMP30-knockout (KO) mice. SMP30-KO mice gained more weight than WT mice without a change in food intake in response to short-term high-fat diet feeding. Indirect calorimetry and cold-challenge experiments indicated that energy expenditure is lower in SMP30-KO mice, which is associated with decreased thermogenesis in adipose tissues. Therefore, SMP30-KO mice do not lose weight during cold exposure, whereas WT mice lose weight markedly. Mechanistically, the levels of serum FGF21 were notably lower in SMP30-KO mice, and vitamin C supplementation in SMP30-KO mice recovered FGF21 expression and thermogenesis, with a marked reduction in body weight during cold exposure. Further experiments revealed that vitamin C activates PPARα to upregulate FGF21. Our findings demonstrate that SMP30-mediated synthesis of vitamin C activates the PPARα/FGF21 axis, contributing to the maintenance of thermogenesis in mice.

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    Looger Lab
    11/24/22 | Ketamine triggers a switch in excitatory neuronal activity across neocortex.
    Cichon J, Wasilczuk AZ, Looger LL, Contreras D, Kelz MB, Proekt A
    Nature Neuroscience. 2022 Nov 24:. doi: 10.1038/s41593-022-01203-5

    The brain can become transiently disconnected from the environment while maintaining vivid, internally generated experiences. This so-called 'dissociated state' can occur in pathological conditions and under the influence of psychedelics or the anesthetic ketamine (KET). The cellular and circuit mechanisms producing the dissociative state remain poorly understood. We show in mice that KET causes spontaneously active neurons to become suppressed while previously silent neurons become spontaneously activated. This switch occurs in all cortical layers and different cortical regions, is induced by both systemic and cortical application of KET and is mediated by suppression of parvalbumin and somatostatin interneuron activity and inhibition of NMDA receptors and HCN channels. Combined, our results reveal two largely non-overlapping cortical neuronal populations-one engaged in wakefulness, the other contributing to the KET-induced brain state-and may lay the foundation for understanding how the brain might become disconnected from the surrounding environment while maintaining internal subjective experiences.

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    11/23/22 | 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. 2022 Nov 23:. 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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    11/23/22 | The 3D ultrastructure of the chordotonal organs in the antenna of a microwasp remains complex although simplified.
    Diakova AV, Makarova AA, Pang S, Xu CS, Hess H, Polilov AA
    Scientific Reports. 2022 Nov 23;12(1):20172. doi: 10.1038/s41598-022-24390-4

    Insect antennae are astonishingly versatile and have multiple sensory modalities. Audition, detection of airflow, and graviception are combined in the antennal chordotonal organs. The miniaturization of these complex multisensory organs has never been investigated. Here we present a comprehensive study of the structure and scaling of the antennal chordotonal organs of the extremely miniaturized parasitoid wasp Megaphragma viggianii based on 3D electron microscopy. Johnston's organ of M. viggianii consists of 19 amphinematic scolopidia (95 cells); the central organ consists of five scolopidia (20 cells). Plesiomorphic composition includes one accessory cell per scolopidium, but in M. viggianii this ratio is only 0.3. Scolopale rods in Johnston's organ have a unique structure. Allometric analyses demonstrate the effects of scaling on the antennal chordotonal organs in insects. Our results not only shed light on the universal principles of miniaturization of sense organs, but also provide context for future interpretation of the M. viggianii connectome.

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    11/18/22 | TEMPO enables sequential genetic labeling and manipulation of vertebrate cell lineages.
    Espinosa-Medina I, Feliciano D, Belmonte-Mateos C, Linda Miyares R, Garcia-Marques J, Foster B, Lindo S, Pujades C, Koyama M, Lee T
    Neuron. 2022 Nov 18:. doi: 10.1016/j.neuron.2022.10.035

    During development, regulatory factors appear in a precise order to determine cell fates over time. Consequently, to investigate complex tissue development, it is necessary to visualize and manipulate cell lineages with temporal control. Current strategies for tracing vertebrate cell lineages lack genetic access to sequentially produced cells. Here, we present TEMPO (Temporal Encoding and Manipulation in a Predefined Order), an imaging-readable genetic tool allowing differential labeling and manipulation of consecutive cell generations in vertebrates. TEMPO is based on CRISPR and powered by a cascade of gRNAs that drive orderly activation and inactivation of reporters and/or effectors. Using TEMPO to visualize zebrafish and mouse neurogenesis, we recapitulated birth-order-dependent neuronal fates. Temporally manipulating cell-cycle regulators in mouse cortex progenitors altered the proportion and distribution of neurons and glia, revealing the effects of temporal gene perturbation on serial cell fates. Thus, TEMPO enables sequential manipulation of molecular factors, crucial to study cell-type specification.

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