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179 Publications

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    12/29/23 | Ketamine modulates a norepinephrine-astroglial circuit to persistently suppress futility-induced passivity.
    Marc Duque , Alex B. Chen , Eric Hsu , Sujatha Narayan , Altyn Rymbek , Shahinoor Begum , Gesine Saher , Adam E. Cohen , David E. Olson , David A. Prober , Dwight E. Bergles , Mark C. Fishman , Florian Engert , Misha B. Ahrens
    bioRxiv. 2023 Dec 29:. doi: 10.1101/2022.12.29.522099

    Mood-altering compounds hold promise for the treatment of many psychiatric disorders, such as depression, but connecting their molecular, circuit, and behavioral effects has been challenging. Here we find that, analogous to effects in rodent learned helplessness models, ketamine pre-exposure persistently suppresses futility-induced passivity in larval zebrafish. While antidepressants are thought to primarily act on neurons, brain-wide imaging in behaving zebrafish showed that ketamine elevates intracellular calcium in astroglia for many minutes, followed by persistent calcium downregulation post-washout. Calcium elevation depends on astroglial α1-adrenergic receptors and is required for suppression of passivity. Chemo-/optogenetic perturbations of noradrenergic neurons and astroglia demonstrate that the aftereffects of glial calcium elevation are sufficient to suppress passivity by inhibiting neuronal-astroglial integration of behavioral futility. Imaging in mouse cortex reveals that ketamine elevates astroglial calcium through conserved pathways, suggesting that ketamine exerts its behavioral effects by persistently modulating evolutionarily ancient neuromodulatory systems spanning neurons and astroglia.

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    12/22/23 | Phase diversity-based wavefront sensing for fluorescence microscopy.
    Johnson C, Guo M, Schneider MC, Su Y, Khuon S, Reiser N, Wu Y, Riviere PL, Shroff H
    bioRxiv. 2023 Dec 22:. doi: 10.1101/2023.12.19.572369

    Fluorescence microscopy is an invaluable tool in biology, yet its performance is compromised when the wavefront of light is distorted due to optical imperfections or the refractile nature of the sample. Such optical aberrations can dramatically lower the information content of images by degrading image contrast, resolution, and signal. Adaptive optics (AO) methods can sense and subsequently cancel the aberrated wavefront, but are too complex, inefficient, slow, or expensive for routine adoption by most labs. Here we introduce a rapid, sensitive, and robust wavefront sensing scheme based on phase diversity, a method successfully deployed in astronomy but underused in microscopy. Our method enables accurate wavefront sensing to less than λ/35 root mean square (RMS) error with few measurements, and AO with no additional hardware besides a corrective element. After validating the method with simulations, we demonstrate calibration of a deformable mirror > 100-fold faster than comparable methods (corresponding to wavefront sensing on the ~100 ms scale), and sensing and subsequent correction of severe aberrations (RMS wavefront distortion exceeding λ/2), restoring diffraction-limited imaging on extended biological samples.

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    12/22/23 | Spatiotemporal-social association predicts immunological similarity in rewilded mice.
    Downie AE, Oyesola O, Barre RS, Caudron Q, Chen Y, Dennis EJ, Garnier R, Kiwanuka K, Menezes A, Navarrete DJ, Mondragón-Palomino O, Saunders JB, Tokita CK, Zaldana K, Cadwell K, Loke P, Graham AL
    Science Advances. 2023 Dec 22;9(51):eadh8310. doi: 10.1126/sciadv.adh8310

    Environmental influences on immune phenotypes are well-documented, but our understanding of which elements of the environment affect immune systems, and how, remains vague. Behaviors, including socializing with others, are central to an individual's interaction with its environment. We therefore tracked behavior of rewilded laboratory mice of three inbred strains in outdoor enclosures and examined contributions of behavior, including associations measured from spatiotemporal co-occurrences, to immune phenotypes. We found extensive variation in individual and social behavior among and within mouse strains upon rewilding. In addition, we found that the more associated two individuals were, the more similar their immune phenotypes were. Spatiotemporal association was particularly predictive of similar memory T and B cell profiles and was more influential than sibling relationships or shared infection status. These results highlight the importance of shared spatiotemporal activity patterns and/or social networks for immune phenotype and suggest potential immunological correlates of social life.

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    12/12/23 | Model-Based Inference of Synaptic Plasticity Rules
    Yash Mehta , Danil Tyulmankov , Adithya E. Rajagopalan , Glenn C. Turner , James E. Fitzgerald , Jan Funke
    bioRxiv. 2023 Dec 12:. doi: 10.1101/2023.12.11.571103

    Understanding learning through synaptic plasticity rules in the brain is a grand challenge for neuroscience. Here we introduce a novel computational framework for inferring plasticity rules from experimental data on neural activity trajectories and behavioral learning dynamics. Our methodology parameterizes the plasticity function to provide theoretical interpretability and facilitate gradient-based optimization. For instance, we use Taylor series expansions or multilayer perceptrons to approximate plasticity rules, and we adjust their parameters via gradient descent over entire trajectories to closely match observed neural activity and behavioral data. Notably, our approach can learn intricate rules that induce long nonlinear time-dependencies, such as those incorporating postsynaptic activity and current synaptic weights. We validate our method through simulations, accurately recovering established rules, like Oja’s, as well as more complex hypothetical rules incorporating reward-modulated terms. We assess the resilience of our technique to noise and, as a tangible application, apply it to behavioral data from Drosophila during a probabilistic reward-learning experiment. Remarkably, we identify an active forgetting component of reward learning in flies that enhances the predictive accuracy of previous models. Overall, our modeling framework provides an exciting new avenue to elucidate the computational principles governing synaptic plasticity and learning in the brain.

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    12/08/23 | Permanent deconstruction of intracellular primary cilia in differentiating granule cell neurons.
    Ott CM, Constable S, Nguyen TM, White K, Lee WA, Lippincott-Schwartz J, Mukhopadhyay S
    bioRxiv. 2023 Dec 08:. doi: 10.1101/2023.12.07.565988

    Primary cilia on granule cell neuron progenitors in the developing cerebellum detect sonic hedgehog to facilitate proliferation. Following differentiation, cerebellar granule cells become the most abundant neuronal cell type in the brain. While essential during early developmental stages, the fate of granule cell cilia is unknown. Here, we provide nanoscopic resolution of ciliary dynamics by studying developmental changes in granule cell cilia using large-scale electron microscopy volumes and immunostaining of mouse cerebella. We found that many granule cell primary cilia were intracellular and concealed from the external environment. Cilia were disassembed in differentiating granule cell neurons in a process we call cilia deconstruction that was distinct from pre-mitotic cilia resorption in proliferating progenitors. In differentiating granule cells, ciliary loss involved unique disassembly intermediates, and, as maturation progressed, mother centriolar docking at the plasma membrane. Cilia did not reform from the docked centrioles, rather, in adult mice granule cell neurons remained unciliated. Many neurons in other brain regions require cilia to regulate function and connectivity. In contrast, our results show that granule cell progenitors had concealed cilia that underwent deconstruction potentially to prevent mitogenic hedgehog responsiveness. The ciliary deconstruction mechanism we describe could be paradigmatic of cilia removal during differentiation in other tissues.

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    12/07/23 | Anatomically distributed neural representations of instincts in the hypothalamus.
    Stagkourakis S, Spigolon G, Marks M, Feyder M, Kim J, Perona P, Pachitariu M, Anderson DJ
    bioRxiv. 2023 Dec 07:. doi: 10.1101/2023.11.21.568163

    Artificial activation of anatomically localized, genetically defined hypothalamic neuron populations is known to trigger distinct innate behaviors, suggesting a hypothalamic nucleus-centered organization of behavior control. To assess whether the encoding of behavior is similarly anatomically confined, we performed simultaneous neuron recordings across twenty hypothalamic regions in freely moving animals. Here we show that distinct but anatomically distributed neuron ensembles encode the social and fear behavior classes, primarily through mixed selectivity. While behavior class-encoding ensembles were spatially distributed, individual ensembles exhibited strong localization bias. Encoding models identified that behavior actions, but not motion-related variables, explained a large fraction of hypothalamic neuron activity variance. These results identify unexpected complexity in the hypothalamic encoding of instincts and provide a foundation for understanding the role of distributed neural representations in the expression of behaviors driven by hardwired circuits.

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    12/05/23 | Imaging neuronal voltage beyond the scattering limit
    Tsai-Wen Chen , Xian-Bin Huang , Sarah E. Plutkis , Katie L. Holland , Luke D. Lavis , Bei-Jung Lin
    bioRxiv. 2023 Dec 05:. doi: 10.1101/2023.12.03.568403

    Voltage imaging is a promising technique for high-speed recording of neuronal population activity. However, tissue scattering severely limits its application in dense neuronal populations. Here, we adopted the principle of localization microscopy, a technique that enables super-resolution imaging of single-molecules, to resolve dense neuronal activities in vivo. Leveraging the sparse activation of neurons during action potentials (APs), we precisely localize the fluorescence change associated with each AP, creating a super-resolution image of neuronal activities. This approach, termed Activity Localization Imaging (ALI), identifies overlapping neurons and separates their activities with over 10-fold greater precision than what tissue scattering permits. Using ALI, we simultaneously recorded over a hundred densely-labeled CA1 neurons, creating a map of hippocampal theta oscillation at single-cell and single-cycle resolution.

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    12/04/23 | Mitochondrial GTP metabolism controls reproductive aging in C. elegans.
    Lee Y, Savini M, Chen T, Yang J, Zhao Q, Ding L, Gao SM, Senturk M, Sowa JN, Wang JD, Wang MC
    Developmental Cell. 2023 Dec 04;58(23):2718-2731.e7. doi: 10.1016/j.devcel.2023.08.019

    Healthy mitochondria are critical for reproduction. During aging, both reproductive fitness and mitochondrial homeostasis decline. Mitochondrial metabolism and dynamics are key factors in supporting mitochondrial homeostasis. However, how they are coupled to control reproductive health remains unclear. We report that mitochondrial GTP (mtGTP) metabolism acts through mitochondrial dynamics factors to regulate reproductive aging. We discovered that germline-only inactivation of GTP- but not ATP-specific succinyl-CoA synthetase (SCS) promotes reproductive longevity in Caenorhabditis elegans. We further identified an age-associated increase in mitochondrial clustering surrounding oocyte nuclei, which is attenuated by GTP-specific SCS inactivation. Germline-only induction of mitochondrial fission factors sufficiently promotes mitochondrial dispersion and reproductive longevity. Moreover, we discovered that bacterial inputs affect mtGTP levels and dynamics factors to modulate reproductive aging. These results demonstrate the significance of mtGTP metabolism in regulating oocyte mitochondrial homeostasis and reproductive longevity and identify mitochondrial fission induction as an effective strategy to improve reproductive health.

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    12/01/23 | Structure, interaction, and nervous connectivity of beta cell primary cilia
    Andreas Müller , Nikolai Klena , Song Pang , Leticia Elizabeth Galicia Garcia , Davud Sulaymankhil , Oleksandra Topcheva , Monika Seliskar , Hassan Mziaut , Eyke Schöniger , Daniela Friedland , Nicole Kipke , Susanne Kretschmar , Carla Münster , Jürgen Weitz , Marius Distler , Thomas Kurth , Deborah Schmidt , Harald F. Hess , C. Shan Xu , Gaia Pigino , Michele Solimena
    bioRxiv. 2023 Dec 01:. doi: 10.1101/2023.12.01.568979

    Primary cilia are sensory organelles present in many cell types. Based on an array of microtubules termed axoneme they form a specialized membrane compartment partaking in various signaling processes. Primary cilia of pancreatic islet beta cells play a role in autocrine and paracrine signaling and are linked to diabetes. Yet, the structural basis for their functions is unclear. We present three-dimensional reconstructions of complete mouse and human beta cell cilia, revealing a disorganized 9+0 axoneme structure. Within the islet cilia are spatially confined within deep ciliary pockets or squeezed into narrow extracellular spaces between adjacent cells. Beta and alpha cell cilia physically interact with neighboring islet cells pushing and strongly bending their plasma membranes. Furthermore, beta cells can contain multiple cilia that can meet with other islet cell cilia in the extracellular space. Additionally, beta cell cilia establish connections with islet-projecting nerves. These findings highlight the pivotal role of beta cell primary cilia in islet cell connectivity, pointing at their potential functional role in integrating islet intrinsic and extrinsic signals. These novel insights contribute to understanding their significance in health and diabetes.

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    11/30/23 | Connectomic reconstruction predicts the functional organization of visual inputs to the navigation center of the brain.
    Garner D, Kind E, Nern A, Houghton L, Zhao A, Sancer G, Rubin GM, Wernet MF, Kim SS
    bioRxiv. 2023 Nov 30:. doi: 10.1101/2023.11.29.569241

    Many animals, including humans, navigate their surroundings by visual input, yet we understand little about how visual information is transformed and integrated by the navigation system. In , compass neurons in the donut-shaped ellipsoid body of the central complex generate a sense of direction by integrating visual input from ring neurons, a part of the anterior visual pathway (AVP). Here, we densely reconstruct all neurons in the AVP using FlyWire, an AI-assisted tool for analyzing electron-microscopy data. The AVP comprises four neuropils, sequentially linked by three major classes of neurons: MeTu neurons, which connect the medulla in the optic lobe to the small unit of anterior optic tubercle (AOTUsu) in the central brain; TuBu neurons, which connect the anterior optic tubercle to the bulb neuropil; and ring neurons, which connect the bulb to the ellipsoid body. Based on neuronal morphologies, connectivity between different neural classes, and the locations of synapses, we identified non-overlapping channels originating from four types of MeTu neurons, which we further divided into ten subtypes based on the presynaptic connections in medulla and postsynaptic connections in AOTUsu. To gain an objective measure of the natural variation within the pathway, we quantified the differences between anterior visual pathways from both hemispheres and between two electron-microscopy datasets. Furthermore, we infer potential visual features and the visual area from which any given ring neuron receives input by combining the connectivity of the entire AVP, the MeTu neurons' dendritic fields, and presynaptic connectivity in the optic lobes. These results provide a strong foundation for understanding how distinct visual features are extracted and transformed across multiple processing stages to provide critical information for computing the fly's sense of direction.

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