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2434 Janelia Publications

Showing 161-170 of 2434 results
06/20/23 | The contribution of inflammatory astrocytes to BBB impairments in a brain-chip model of Parkinson's disease.
de Rus Jacquet A, Alpaugh M, Denis HL, Tancredi JL, Boutin M, Decaestecker J, Beauparlant C, Herrmann L, Saint-Pierre M, Parent M, Droit A, Breton S, Cicchetti F
Nature Communications. 2023 Jun 20;14(1):3651. doi: 10.1038/s41467-023-39038-8

Astrocyte dysfunction has previously been linked to multiple neurodegenerative disorders including Parkinson's disease (PD). Among their many roles, astrocytes are mediators of the brain immune response, and astrocyte reactivity is a pathological feature of PD. They are also involved in the formation and maintenance of the blood-brain barrier (BBB), but barrier integrity is compromised in people with PD. This study focuses on an unexplored area of PD pathogenesis by characterizing the interplay between astrocytes, inflammation and BBB integrity, and by combining patient-derived induced pluripotent stem cells with microfluidic technologies to generate a 3D human BBB chip. Here we report that astrocytes derived from female donors harboring the PD-related LRRK2 G2019S mutation are pro-inflammatory and fail to support the formation of a functional capillary in vitro. We show that inhibition of MEK1/2 signaling attenuates the inflammatory profile of mutant astrocytes and rescues BBB formation, providing insights into mechanisms regulating barrier integrity in PD. Lastly, we confirm that vascular changes are also observed in the human postmortem substantia nigra of both males and females with PD.

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06/17/23 | The Janelia Atalanta plasmids provide a simple and efficient CRISPR/Cas9-mediated homology directed repair platform for Drosophila
David L. Stern , Elizabeth Kim , Emily L. Behrman
bioRxiv. 2023 Jun 17:. doi: 10.1101/2023.06.17.545412

Homology-directed repair (HDR) is a powerful tool for modifying genomes in precise ways to address many biological questions. Use of Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR)-Cas9 induced targeted DNA double-strand breakage has substantially simplified use of homology-directed repair to introduce specific perturbations in Drosophila, but existing platforms for CRISPR-Cas9-mediated HDR in Drosophila involve multiple cloning steps and have low efficiency. To simplify cloning of HDR plasmids, we designed a new plasmid platform, the Janelia Atalanta (pJAT) series, that exploits recent advances in dsDNA synthesis to facilitate Gateway cloning of gRNA sequences and homology arms in one step. Surprisingly, the pJAT plasmids yielded considerably higher HDR efficiency (approximately 25%) than we have observed with other approaches. pJAT plasmids work in multiple Drosophila species and exhibited such high efficiency that previously impossible experiments in Drosophila, such as driving targeted chromosomal inversions, were made possible. We provide pJAT plasmids for a range of commonly performed experiments including targeted insertional mutagenesis, insertion of phiC31-mediated attP landing sites, generation of strains carrying a germ-line source of Cas9, and induction of chromosomal rearrangements. We also provide “empty” pJAT plasmids with multiple cloning sites to simplify construction of plasmids with new functionality. The pJAT platform is generic and may facilitate improved efficiency CRISPR-Cas9 HDR in a wide range of model and non-model organisms.

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06/16/23 | Architecture and dynamics of a desmosome-endoplasmic reticulum complex.
Bharathan NK, Giang W, Hoffman CL, Aaron JS, Khuon S, Chew T, Preibisch S, Trautman ET, Heinrich L, Bogovic J, Bennett D, Ackerman D, Park W, Petruncio A, Weigel AV, Saalfeld S, COSEM Project Team , Wayne Vogl A, Stahley SN, Kowalczyk AP
Nature Cell Biology. 2023 Jun 16;25(6):823-835. doi: 10.1038/s41556-023-01154-4

The endoplasmic reticulum (ER) forms a dynamic network that contacts other cellular membranes to regulate stress responses, calcium signalling and lipid transfer. Here, using high-resolution volume electron microscopy, we find that the ER forms a previously unknown association with keratin intermediate filaments and desmosomal cell-cell junctions. Peripheral ER assembles into mirror image-like arrangements at desmosomes and exhibits nanometre proximity to keratin filaments and the desmosome cytoplasmic plaque. ER tubules exhibit stable associations with desmosomes, and perturbation of desmosomes or keratin filaments alters ER organization, mobility and expression of ER stress transcripts. These findings indicate that desmosomes and the keratin cytoskeleton regulate the distribution, function and dynamics of the ER network. Overall, this study reveals a previously unknown subcellular architecture defined by the structural integration of ER tubules with an epithelial intercellular junction.

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06/15/23 | Flexible specificity of memory in Drosophila depends on a comparison between choices
Mehrab N Modi , Adithya Rajagopalan , Hervé Rouault , Yoshinori Aso , Glenn C Turner
eLife. 2023 Jun 15:. doi: 10.7554/eLife.80923

Memory guides behavior across widely varying environments and must therefore be both sufficiently specific and general. A memory too specific will be useless in even a slightly different environment, while an overly general memory may lead to suboptimal choices. Animals successfully learn to both distinguish between very similar stimuli and generalize across cues. Rather than forming memories that strike a balance between specificity and generality, Drosophila can flexibly categorize a given stimulus into different groups depending on the options available. We asked how this flexibility manifests itself in the well-characterized learning and memory pathways of the fruit fly. We show that flexible categorization in neuronal activity as well as behavior depends on the order and identity of the perceived stimuli. Our results identify the neural correlates of flexible stimulus-categorization in the fruit fly.

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06/14/23 | Tissue Morphogenesis Through Dynamic Cell and Matrix Interactions.
Wu D, Yamada KM, Wang S
Annual Reviews Cell Developmental Biology. 2023 Jun 14:. doi: 10.1146/annurev-cellbio-020223-031019

Multicellular organisms generate tissues of diverse shapes and functions from cells and extracellular matrices. Their adhesion molecules mediate cell-cell and cell-matrix interactions, which not only play crucial roles in maintaining tissue integrity but also serve as key regulators of tissue morphogenesis. Cells constantly probe their environment to make decisions: They integrate chemical and mechanical information from the environment via diffusible ligand- or adhesion-based signaling to decide whether to release specific signaling molecules or enzymes, to divide or differentiate, to move away or stay, or even whether to live or die. These decisions in turn modify their environment, including the chemical nature and mechanical properties of the extracellular matrix. Tissue morphology is the physical manifestation of the remodeling of cells and matrices by their historical biochemical and biophysical landscapes. We review our understanding of matrix and adhesion molecules in tissue morphogenesis, with an emphasis on key physical interactions that drive morphogenesis. Expected final online publication date for the , Volume 39 is October 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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06/09/23 | Not everything, not everywhere, not all at once: a study of brain-wide encoding of movement
Ziyue Aiden Wang , Susu Chen , Yi Liu , Dave Liu , Karel Svoboda , Nuo Li , Shaul Druckmann
bioRxiv. 2023 Jun 09:. doi: 10.1101/2023.06.08.544257

Activity related to movement is found throughout sensory and motor regions of the brain. However, it remains unclear how movement-related activity is distributed across the brain and whether systematic differences exist between brain areas. Here, we analyzed movement related activity in brain-wide recordings containing more than 50,000 neurons in mice performing a decision-making task. Using multiple techniques, from markers to deep neural networks, we find that movement-related signals were pervasive across the brain, but systematically differed across areas. Movement-related activity was stronger in areas closer to the motor or sensory periphery. Delineating activity in terms of sensory- and motor-related components revealed finer scale structures of their encodings within brain areas. We further identified activity modulation that correlates with decision-making and uninstructed movement. Our work charts out a largescale map of movement encoding and provides a roadmap for dissecting different forms of movement and decision-making related encoding across multi-regional neural circuits.

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06/09/23 | Organization of an Ascending Circuit that Conveys Flight Motor State
Han S. J. Cheong , Kaitlyn N. Boone , Marryn M. Bennett , Farzaan Salman , Jacob D. Ralston , Kaleb Hatch , Raven F. Allen , Alec M. Phelps , Andrew P. Cook , Jasper S. Phelps , Mert Erginkaya , Wei-Chung A. Lee , Gwyneth M. Card , Kevin C. Daly , Andrew M. Dacks
bioRxiv. 2023 Jun 09:. doi: 10.1101/2023.06.07.544074

Natural behaviors are a coordinated symphony of motor acts which drive self-induced or reafferent sensory activation. Single sensors only signal presence and magnitude of a sensory cue; they cannot disambiguate exafferent (externally-induced) from reafferent sources. Nevertheless, animals readily differentiate between these sources of sensory signals to make appropriate decisions and initiate adaptive behavioral outcomes. This is mediated by predictive motor signaling mechanisms, which emanate from motor control pathways to sensory processing pathways, but how predictive motor signaling circuits function at the cellular and synaptic level is poorly understood. We use a variety of techniques, including connectomics from both male and female electron microscopy volumes, transcriptomics, neuroanatomical, physiological and behavioral approaches to resolve the network architecture of two pairs of ascending histaminergic neurons (AHNs), which putatively provide predictive motor signals to several sensory and motor neuropil. Both AHN pairs receive input primarily from an overlapping population of descending neurons, many of which drive wing motor output. The two AHN pairs target almost exclusively non-overlapping downstream neural networks including those that process visual, auditory and mechanosensory information as well as networks coordinating wing, haltere, and leg motor output. These results support the conclusion that the AHN pairs multi-task, integrating a large amount of common input, then tile their output in the brain, providing predictive motor signals to non-overlapping sensory networks affecting motor control both directly and indirectly.

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06/08/23 | Environmental dynamics shape perceptual decision bias.
Charlton JA, Młynarski WF, Bai YH, Hermundstad AM, Goris RL
PLoS Computational Biology. 2023 Jun 08;19(6):e1011104. doi: 10.1371/journal.pcbi.1011104

To interpret the sensory environment, the brain combines ambiguous sensory measurements with knowledge that reflects context-specific prior experience. But environmental contexts can change abruptly and unpredictably, resulting in uncertainty about the current context. Here we address two questions: how should context-specific prior knowledge optimally guide the interpretation of sensory stimuli in changing environments, and do human decision-making strategies resemble this optimum? We probe these questions with a task in which subjects report the orientation of ambiguous visual stimuli that were drawn from three dynamically switching distributions, representing different environmental contexts. We derive predictions for an ideal Bayesian observer that leverages knowledge about the statistical structure of the task to maximize decision accuracy, including knowledge about the dynamics of the environment. We show that its decisions are biased by the dynamically changing task context. The magnitude of this decision bias depends on the observer's continually evolving belief about the current context. The model therefore not only predicts that decision bias will grow as the context is indicated more reliably, but also as the stability of the environment increases, and as the number of trials since the last context switch grows. Analysis of human choice data validates all three predictions, suggesting that the brain leverages knowledge of the statistical structure of environmental change when interpreting ambiguous sensory signals.

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06/07/23 | Cell type-specific contributions to a persistent aggressive internal state in female Drosophila
Hui Chiu , Alice A. Robie , Kristin M. Branson , Tanvi Vippa , Samantha Epstein , Gerald M. Rubin , David J. Anderson , Catherine E. Schretter
bioRxiv. 2023 Jun 07:. doi: 10.1101/2023.06.07.543722

Persistent internal states are important for maintaining survival-promoting behaviors, such as aggression. In female Drosophila melanogaster, we have previously shown that individually activating either aIPg or pC1d cell types can induce aggression. Here we investigate further the individual roles of these cholinergic, sexually dimorphic cell types, and the reciprocal connections between them, in generating a persistent aggressive internal state. We find that a brief 30-second optogenetic stimulation of aIPg neurons was sufficient to promote an aggressive internal state lasting at least 10 minutes, whereas similar stimulation of pC1d neurons did not. While we previously showed that stimulation of pC1e alone does not evoke aggression, persistent behavior could be promoted through simultaneous stimulation of pC1d and pC1e, suggesting an unexpected synergy of these cell types in establishing a persistent aggressive state. Neither aIPg nor pC1d show persistent neuronal activity themselves, implying that the persistent internal state is maintained by other mechanisms. Moreover, inactivation of pC1d did not significantly reduce aIPg-evoked persistent aggression arguing that the aggressive state did not depend on pC1d-aIPg recurrent connectivity. Our results suggest the need for alternative models to explain persistent female aggression.

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Card LabFlyEM
06/07/23 | Transforming descending input into behavior: The organization of premotor circuits in the Drosophila Male Adult Nerve Cord connectome
H. S. J. Cheong , K. Eichler , T. Stuerner , S. K. Asinof , A. S. Champion , E. C. Marin , T. B. Oram , M. Sumathipala , L. Venkatasubramanian , S. Namiki , I. Siwanowicz , M. Costa , S. Berg , Janelia FlyEM Project Team , G. S. X. E. Jefferis , G. M. Card
bioRxiv. 2023 Jun 07:. doi: 10.1101/2023.06.07.543976

In most animals, a relatively small number of descending neurons (DNs) connect higher brain centers in the animal’s head to motor neurons (MNs) in the nerve cord of the animal’s body that effect movement of the limbs. To understand how brain signals generate behavior, it is critical to understand how these descending pathways are organized onto the body MNs. In the fly, Drosophila melanogaster, MNs controlling muscles in the leg, wing, and other motor systems reside in a ventral nerve cord (VNC), analogous to the mammalian spinal cord. In companion papers, we introduced a densely-reconstructed connectome of the Drosophila Male Adult Nerve Cord (MANC, Takemura et al., 2023), including cell type and developmental lineage annotation (Marin et al., 2023), which provides complete VNC connectivity at synaptic resolution. Here, we present a first look at the organization of the VNC networks connecting DNs to MNs based on this new connectome information. We proofread and curated all DNs and MNs to ensure accuracy and reliability, then systematically matched DN axon terminals and MN dendrites with light microscopy data to link their VNC morphology with their brain inputs or muscle targets. We report both broad organizational patterns of the entire network and fine-scale analysis of selected circuits of interest. We discover that direct DN-MN connections are infrequent and identify communities of intrinsic neurons linked to control of different motor systems, including putative ventral circuits for walking, dorsal circuits for flight steering and power generation, and intermediate circuits in the lower tectulum for coordinated action of wings and legs. Our analysis generates hypotheses for future functional experiments and, together with the MANC connectome, empowers others to investigate these and other circuits of the Drosophila ventral nerve cord in richer mechanistic detail.

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