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2411 Janelia Publications

Showing 81-90 of 2411 results
10/06/23 | Extracellular glutamate and GABA transients at the transition from interictal spiking to seizures.
Shimoda Y, Leite M, Graham RT, Marvin JS, Hasseman J, Kolb I, Looger LL, Magloire V, Kullmann DM
Brain. 2023 Oct 03:. doi: 10.1093/brain/awad336

Focal epilepsy is associated with intermittent brief population discharges (interictal spikes), which resemble sentinel spikes that often occur at the onset of seizures. Why interictal spikes self-terminate whilst seizures persist and propagate is incompletely understood. We used fluorescent glutamate and GABA sensors in an awake rodent model of neocortical seizures to resolve the spatiotemporal evolution of both neurotransmitters in the extracellular space. Interictal spikes were accompanied by brief glutamate transients which were maximal at the initiation site and rapidly propagated centrifugally. GABA transients lasted longer than glutamate transients and were maximal ∼1.5 mm from the focus where they propagated centripetally. Prior to seizure initiation GABA transients were attenuated, whilst glutamate transients increased, consistent with a progressive failure of local inhibitory restraint. As seizures increased in frequency, there was a gradual increase in the spatial extent of spike-associated glutamate transients associated with interictal spikes. Neurotransmitter imaging thus reveals a progressive collapse of an annulus of feed-forward GABA release, allowing seizures to escape from local inhibitory restraint.

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10/01/23 | Unsupervised Learning of Object-Centric Embeddings for Cell Instance Segmentation in Microscopy Images
Wolf S, Lalit M, McDole K, Funke J
2023 IEEE/CVF International Conference on Computer Vision (ICCV). 2023 Oct 01:. doi: 10.1109/ICCV51070.2023.01944

Segmentation of objects in microscopy images is required for many biomedical applications. We introduce object-centric embeddings (OCEs), which embed image patches such that the spatial offsets between patches cropped from the same object are preserved. Those learnt embeddings can be used to delineate individual objects and thus obtain instance segmentations. Here, we show theoretically that, under assumptions commonly found in microscopy images, OCEs can be learnt through a self-supervised task that predicts the spatial offset between image patches. Together, this forms an unsupervised cell instance segmentation method which we evaluate on nine diverse large-scale microscopy datasets. Segmentations obtained with our method lead to substantially improved results, compared to state-of-the-art baselines on six out of nine datasets, and perform on par on the remaining three datasets. If ground-truth annotations are available, our method serves as an excellent starting point for supervised training, reducing the required amount of ground-truth needed by one order of magnitude, thus substantially increasing the practical applicability of our method. Source code is available at

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09/26/23 | A rotational velocity estimate constructed through visuomotor competition updates the fly's neural compass
Brad K Hulse , Angel Stanoev , Daniel B Turner-Evans , Johannes Seelig , Vivek Jayaraman
bioRxiv. 2023 Sep 26:. doi: 10.1101/2023.09.25.559373

Navigating animals continuously integrate velocity signals to update internal representations of their directional heading and spatial location in the environment. How neural circuits combine sensory and motor information to construct these velocity estimates and how these self-motion signals, in turn, update internal representations that support navigational computations are not well understood. Recent work in Drosophila has identified a neural circuit that performs angular path integration to compute the fly's head direction, but the nature of the velocity signal is unknown. Here we identify a pair of neurons necessary for angular path integration that encode the fly's rotational velocity with high accuracy using both visual optic flow and motor information. This estimate of rotational velocity does not rely on a moment-to-moment integration of sensory and motor information. Rather, when visual and motor signals are congruent, these neurons prioritize motor information over visual information, and when the two signals are in conflict, reciprocal inhibition selects either the motor or visual signal. Together, our results suggest that flies update their head direction representation by constructing an estimate of rotational velocity that relies primarily on motor information and only incorporates optic flow signals in specific sensorimotor contexts, such as when the motor signal is absent.

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09/26/23 | Quantitative Profiling of Lysosomal pH Heterogeneity using Fluorescence Lifetime Imaging Microscopy
Dinghuan Deng , Youchen Guan , Baiping Wang , Hui Zheng , Ayse Sena Mutlu , Meng Carla Wang
bioRxiv. 2023 Sep 26:. doi: 10.1101/2023.09.25.559395

Lysosomes play crucial roles in maintaining cellular homeostasis and promoting organism fitness. The pH of lysosomes is a crucial parameter for their proper function, and it is dynamically influenced by both intracellular and environmental factors. Here, we present a method based on fluorescence lifetime imaging microscopy (FLIM) for quantitatively analyzing lysosomal pH profiles in diverse types of primary mammalian cells and in different tissues of the live organism Caenorhabditis elegans. This FLIM-based method exhibits high sensitivity in resolving subtle pH differences, thereby revealing the heterogeneity of the lysosomal population within a cell and between cell types. The method enables rapid measurement of lysosomal pH changes in response to various environmental stimuli. Furthermore, the FLIM measurement of pH-sensitive dyes circumvents the need for transgenic reporters and mitigates potential confounding factors associated with varying dye concentrations or excitation light intensity. This FLIM approach offers absolute quantification of lysosomal pH and highlights the significance of lysosomal pH heterogeneity and dynamics, providing a valuable tool for studying lysosomal functions and their regulation in various physiological and pathological contexts.

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09/26/23 | Reward expectations direct learning and drive operant matching in Drosophila
Adithya E. Rajagopalan , Ran Darshan , Karen L. Hibbard , James E. Fitzgerald , Glenn C. Turner
Proceedings of the National Academy of Sciences of the U.S.A.. 2023 Sep 26;120(39):e2221415120. doi: 10.1073/pnas.2221415120

Foraging animals must use decision-making strategies that dynamically adapt to the changing availability of rewards in the environment. A wide diversity of animals do this by distributing their choices in proportion to the rewards received from each option, Herrnstein’s operant matching law. Theoretical work suggests an elegant mechanistic explanation for this ubiquitous behavior, as operant matching follows automatically from simple synaptic plasticity rules acting within behaviorally relevant neural circuits. However, no past work has mapped operant matching onto plasticity mechanisms in the brain, leaving the biological relevance of the theory unclear. Here we discovered operant matching in Drosophila and showed that it requires synaptic plasticity that acts in the mushroom body and incorporates the expectation of reward. We began by developing a novel behavioral paradigm to measure choices from individual flies as they learn to associate odor cues with probabilistic rewards. We then built a model of the fly mushroom body to explain each fly’s sequential choice behavior using a family of biologically-realistic synaptic plasticity rules. As predicted by past theoretical work, we found that synaptic plasticity rules could explain fly matching behavior by incorporating stimulus expectations, reward expectations, or both. However, by optogenetically bypassing the representation of reward expectation, we abolished matching behavior and showed that the plasticity rule must specifically incorporate reward expectations. Altogether, these results reveal the first synaptic level mechanisms of operant matching and provide compelling evidence for the role of reward expectation signals in the fly brain.

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09/18/23 | Neural circuit mechanisms for transforming learned olfactory valences into wind-oriented movement
Yoshinori Aso , Daichi Yamada , Daniel Bushey , Karen Hibbard , Megan Sammons , Hideo Otsuna , Yichun Shuai , Toshihide Hige
eLife. 2023 Sep 18:. doi: 10.7554/eLife.85756

How memories are used by the brain to guide future action is poorly understood. In olfactory associative learning in Drosophila, multiple compartments of the mushroom body act in parallel to assign valence to a stimulus. Here, we show that appetitive memories stored in different compartments induce different levels of upwind locomotion. Using a photoactivation screen of a new collection of split-GAL4 drivers and EM connectomics, we identified a cluster of neurons postsynaptic to the mushroom body output neurons (MBONs) that can trigger robust upwind steering. These UpWind Neurons (UpWiNs) integrate inhibitory and excitatory synaptic inputs from MBONs of appetitive and aversive memory compartments, respectively. After training, disinhibition from the appetitive-memory MBONs enhances the response of UpWiNs to reward-predicting odors. Blocking UpWiNs impaired appetitive memory and reduced upwind locomotion during retrieval. Photoactivation of UpWiNs also increased the chance of returning to a location where activation was initiated, suggesting an additional role in olfactory navigation. Thus, our results provide insight into how learned abstract valences are gradually transformed into concrete memory-driven actions through divergent and convergent networks, a neuronal architecture that is commonly found in the vertebrate and invertebrate brains.

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09/16/23 | Driver lines for studying associative learning in Drosophila
Yichun Shuai , Megan Sammons , Gabriella Sterne , Karen Hibbard , He Yang , Ching-Po Yang , Claire Managan , Igor Siwanowicz , Tzumin Lee , Gerald M. Rubin , Glenn Turner , Yoshinori Aso
bioRxiv. 2023 Sep 16:. doi: 10.1101/2023.09.15.557808

The mushroom body (MB) is the center for associative learning in insects. In Drosophila, intersectional split-GAL4 drivers and electron microscopy (EM) connectomes have laid the foundation for precise interrogation of the MB neural circuits. However, many cell types upstream and downstream of the MB remained to be investigated due to lack of driver lines. Here we describe a new collection of over 800 split-GAL4 and split-LexA drivers that cover approximately 300 cell types, including sugar sensory neurons, putative nociceptive ascending neurons, olfactory and thermo-/hygro-sensory projection neurons, interneurons connected with the MB-extrinsic neurons, and various other cell types. We characterized activation phenotypes for a subset of these lines and identified the sugar sensory neuron line most suitable for reward substitution. Leveraging the thousands of confocal microscopy images associated with the collection, we analyzed neuronal morphological stereotypy and discovered that one set of mushroom body output neurons, MBON08/MBON09, exhibits striking individuality and asymmetry across animals. In conjunction with the EM connectome maps, the driver lines reported here offer a powerful resource for functional dissection of neural circuits for associative learning in adult Drosophila.

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09/15/23 | 3D architecture and a bi-cellular mechanism of touch detection in mechanosensory corpuscle
Yury A. Nikolaev , Luke H. Ziolkowski , Song Pang , Wei-Ping Li , Viktor V. Feketa , C. Shan Xu , Elena O. Gracheva , Sviatoslav N. Bagriantsev
Science Advances. 2023 Sep 15;9(37):eadi4147. doi: 10.1126/sciadv.adi4147

Mechanosensory corpuscles detect transient touch and vibratory signals in the skin of vertebrates, enabling navigation, foraging, and precise manipulation of objects1. The corpuscle core comprises a terminal neurite of a mechanoreceptor afferent, the only known touch-sensing element within corpuscles, surrounded by terminal Schwann cells called lamellar cells (LCs)24. However, the precise corpuscular ultrastructure, and the role of LCs in touch detection are unknown. Here we used enhanced focused ion beam scanning electron microscopy and electron tomography to reveal the three-dimensional architecture of avian Meissner (Grandry) corpuscle5. We show that corpuscles contain a stack of LCs innervated by two afferents, which form large-area contacts with LCs. LCs form tether-like connections with the afferent membrane and contain dense core vesicles which release their content onto the afferent. Furthermore, by performing simultaneous electrophysiological recordings from both cell types, we show that mechanosensitive LCs use calcium influx to trigger action potential firing in the afferent and thus serve as physiological touch sensors in the skin. Our findings suggest a bi-cellular mechanism of touch detection, which comprises the afferent and LCs, likely enables corpuscles to encode the nuances of tactile stimuli.

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09/15/23 | Low-latency extracellular spike assignment for high-density electrodes at single-neuron resolution
Chongxi Lai , Dohoung Kim , Brian Lustig , Shinsuke Tanaka , Brian Barbarits , Lakshmi Narayan , Jennifer Colonell , Ole Paulsen , Albert K. Lee , Timothy D. Harris
bioRxiv. 2023 Sep 15:. doi: 10.1101/2023.09.14.557854

Real-time neural signal processing is essential for brain-machine interfaces and closed-loop neuronal perturbations. However, most existing applications sacrifice cell-specific identity and temporal spiking information for speed. We developed a hybrid hardware-software system that utilizes a Field Programmable Gate Array (FPGA) chip to acquire and process data in parallel, enabling individual spikes from many simultaneously recorded neurons to be assigned single-neuron identities with 1-millisecond latency. The FPGA assigns labels, validated with ground-truth data, by comparing multichannel spike waveforms from tetrode or silicon probe recordings to a spike-sorted model generated offline in software. This platform allowed us to rapidly inactivate a region in vivo based on spikes from an upstream neuron before these spikes could excite the downstream region. Furthermore, we could decode animal location within 3 ms using data from a population of individual hippocampal neurons. These results demonstrate our system’s suitability for a broad spectrum of research and clinical applications.

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09/15/23 | Sensory neuron population expansion enhances odour tracking through relaxed projection neuron adaptation
Suguru Takagi , Liliane Abuin , S. David Stupski , J. Roman Arguello , Lucia Prieto-Godino , David L. Stern , Steeve Cruchet , Raquel Álvarez-Ocaña , Carl F. R. Wienecke , Floris van Breugel , Thomas O. Auer , Richard Benton
bioRxiv. 2023 Sep 15:. doi: 10.1101/2023.09.15.556782

From the star-nosed mole’s eponymous mechanosensory organ to the platypus’ electroreceptive bill, the expansion of sensory neuron populations detecting important environmental cues is a widespread evolutionary phenomenon in animals16. How such neuron increases contribute to improved sensory detection and behaviour remain largely unexplained. Here we address this question through comparative analysis of olfactory pathways in Drosophila melanogaster and its close relative Drosophila sechellia, which feeds and breeds exclusively on Morinda citrifolia noni fruit79. We show that D. sechellia displays selective, large expansions of noni-detecting olfactory sensory neuron (OSN) populations, and that this trait has a multigenic basis. These expansions are accompanied by an increase in synaptic connections between OSNs and their projection neuron (PN) partners that transmit information to higher brain centres. Quantification of odour-evoked responses of partner OSNs and PNs reveals that OSN population expansions do not lead to heightened PN sensitivity, beyond that due to sensory receptor tuning differences. Rather, these pathways – but not those with conserved OSN numbers – exhibit non-adapting PN activity upon odour stimulation. In noni odour plume-tracking assays, D. sechellia exhibits enhanced performance compared to D. melanogaster. Through activation and inhibition of defined proportions of a noni-sensing OSN population, we establish that increased neuron numbers contribute to this behavioural persistence. Our work reveals an unexpected functional impact of sensory neuron expansions that can synergise with peripheral receptor tuning changes to explain ecologically-relevant, species-specific behaviour.

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