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27 Janelia Publications

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    05/28/22 | An essential experimental control for functional connectivity mapping with optogenetics.
    David Tadres , Hiroshi M. Shiozaki , Ibrahim Tastekin , David L. Stern , Matthieu Louis
    bioRxiv. 2022 May 28:. doi: 10.1101/2022.05.26.493610

    To establish functional connectivity between two candidate neurons that might form a circuit element, a common approach is to activate an optogenetic tool such as Chrimson in the candidate pre-synaptic neuron and monitor fluorescence of the calcium-sensitive indicator GCaMP in a candidate post-synaptic neuron. While performing such experiments, we found that low levels of leaky Chrimson expression can lead to strong artifactual GCaMP signals in presumptive postsynaptic neurons even when Chrimson is not intentionally expressed in any particular neurons. Withholding all-trans retinal, the chromophore required as a co-factor for Chrimson response to light, eliminates GCaMP signal but does not provide an experimental control for leaky Chrimson expression. Leaky Chrimson expression appears to be an inherent feature of current Chrimson transgenes, since artifactual connectivity was detected with Chrimson transgenes integrated into three different genomic locations (two insertions tested in larvae; a third insertion tested in the adult fly). These false-positive signals may complicate the interpretation of functional connectivity experiments. We illustrate how a no-Gal4 negative control improves interpretability of functional connectivity assays. We also propose a simple but effective procedure to identify experimental conditions that minimize potentially incorrect interpretations caused by leaky Chrimson expression.

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    05/26/22 | One engram two readouts: stimulus dynamics switch a learned behavior in Drosophila
    Mehrab N Modi , Adithya Rajagopalan , Hervé Rouault , Yoshinori Aso , Glenn C Turner
    bioRxiv. 2022 May 26:. doi: 10.1101/2022.05.24.492551

    Memory guides the choices an animal makes across widely varying conditions in dynamic environments. Consequently, the most adaptive choice depends on the options available. How can a single memory support optimal behavior across different sets of choice options? We address this using olfactory learning in Drosophila. Even when we restrict an odor-punishment association to a single set of synapses using optogenetics, we find that flies still show choice behavior that depends on the options it encounters. Here we show that how the odor choices are presented to the animal influences memory recall itself. Presenting two similar odors in sequence enabled flies to not only discriminate them behaviorally but also at the level of neural activity. However, when the same odors were encountered as solitary stimuli, no such differences were detectable. These results show that memory recall is not simply a comparison to a static learned template, but can be adaptively modulated by stimulus dynamics.

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    05/25/22 | Expectation-based learning rules underlie dynamic foraging in Drosophila
    Adithya E. Rajagopalan , Ran Darshan , James E. Fitzgerald , Glenn C. Turner
    bioRxiv. 2022 May 25:. doi: 10.1101/2022.05.24.493252

    Foraging animals must use decision-making strategies that dynamically account for uncertainty in the world. To cope with this uncertainty, animals have developed strikingly convergent strategies that use information about multiple past choices and reward to learn representations of the current state of the world. However, the underlying learning rules that drive the required learning have remained unclear. Here, working in the relatively simple nervous system of Drosophila, we combine behavioral measurements, mathematical modeling, and neural circuit perturbations to show that dynamic foraging depends on a learning rule incorporating reward expectation. Using a novel olfactory dynamic foraging task, we characterize the behavioral strategies used by individual flies when faced with unpredictable rewards and show, for the first time, that they perform operant matching. We build on past theoretical work and demonstrate that this strategy requires the existence of a covariance-based learning rule in the mushroom body - a hub for learning in the fly. In particular, the behavioral consequences of optogenetic perturbation experiments suggest that this learning rule incorporates reward expectation. Our results identify a key element of the algorithm underlying dynamic foraging in flies and suggest a comprehensive mechanism that could be fundamental to these behaviors across species.

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    04/02/22 | 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
    bioRxiv. 2022 Apr 02:. doi: 10.1101/2022.03.30.486484

    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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    03/14/22 | A population of descending neurons that regulates the flight motor of Drosophila.
    Namiki S, Ros IG, Morrow C, Rowell WJ, Card GM, Korff W, Dickinson MH
    Current Biology. 2022 Mar 14;32(5):1189-1196. doi: 10.1016/j.cub.2022.01.008

    Similar to many insect species, Drosophila melanogaster is capable of maintaining a stable flight trajectory for periods lasting up to several hours. Because aerodynamic torque is roughly proportional to the fifth power of wing length, even small asymmetries in wing size require the maintenance of subtle bilateral differences in flapping motion to maintain a stable path. Flies can even fly straight after losing half of a wing, a feat they accomplish via very large, sustained kinematic changes to both the damaged and intact wings. Thus, the neural network responsible for stable flight must be capable of sustaining fine-scaled control over wing motion across a large dynamic range. In this study, we describe an unusual type of descending neuron (DNg02) that projects directly from visual output regions of the brain to the dorsal flight neuropil of the ventral nerve cord. Unlike many descending neurons, which exist as single bilateral pairs with unique morphology, there is a population of at least 15 DNg02 cell pairs with nearly identical shape. By optogenetically activating different numbers of DNg02 cells, we demonstrate that these neurons regulate wingbeat amplitude over a wide dynamic range via a population code. Using two-photon functional imaging, we show that DNg02 cells are responsive to visual motion during flight in a manner that would make them well suited to continuously regulate bilateral changes in wing kinematics. Collectively, we have identified a critical set of descending neurons that provides the sensitivity and dynamic range required for flight control.

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    12/16/21 | Synaptic targets of photoreceptors specialized to detect color and skylight polarization in .
    Kind E, Longden KD, Nern A, Zhao A, Sancer G, Flynn MA, Laughland CW, Gezahegn B, Ludwig HD, Thomson AG, Obrusnik T, Alarcón PG, Dionne H, Bock DD, Rubin GM, Reiser MB, Wernet MF
    eLife. 2021 Dec 16;10:. doi: 10.7554/eLife.71858

    Color and polarization provide complementary information about the world and are detected by specialized photoreceptors. However, the downstream neural circuits that process these distinct modalities are incompletely understood in any animal. Using electron microscopy, we have systematically reconstructed the synaptic targets of the photoreceptors specialized to detect color and skylight polarization in Drosophila, and we have used light microscopy to confirm many of our findings. We identified known and novel downstream targets that are selective for different wavelengths or polarized light, and followed their projections to other areas in the optic lobes and the central brain. Our results revealed many synapses along the photoreceptor axons between brain regions, new pathways in the optic lobes, and spatially segregated projections to central brain regions. Strikingly, photoreceptors in the polarization-sensitive dorsal rim area target fewer cell types, and lack strong connections to the lobula, a neuropil involved in color processing. Our reconstruction identifies shared wiring and modality-specific specializations for color and polarization vision, and provides a comprehensive view of the first steps of the pathways processing color and polarized light inputs.

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    12/06/21 | Functional architecture of neural circuits for leg proprioception in Drosophila.
    Chen C, Agrawal S, Mark B, Mamiya A, Sustar A, Phelps JS, Lee WA, Dickson BJ, Card GM, Tuthill JC
    Current Biology. 2021 Dec 06;31(23):5163. doi: 10.1016/j.cub.2021.09.035

    To effectively control their bodies, animals rely on feedback from proprioceptive mechanosensory neurons. In the Drosophila leg, different proprioceptor subtypes monitor joint position, movement direction, and vibration. Here, we investigate how these diverse sensory signals are integrated by central proprioceptive circuits. We find that signals for leg joint position and directional movement converge in second-order neurons, revealing pathways for local feedback control of leg posture. Distinct populations of second-order neurons integrate tibia vibration signals across pairs of legs, suggesting a role in detecting external substrate vibration. In each pathway, the flow of sensory information is dynamically gated and sculpted by inhibition. Overall, our results reveal parallel pathways for processing of internal and external mechanosensory signals, which we propose mediate feedback control of leg movement and vibration sensing, respectively. The existence of a functional connectivity map also provides a resource for interpreting connectomic reconstruction of neural circuits for leg proprioception.

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    01/01/21 | Neural circuit mechanisms of sexual receptivity in Drosophila females.
    Wang K, Wang F, Forknall N, Yang T, Patrick C, Parekh R, Dickson BJ
    Nature. 2021 Jan 01;589(7843):577-81. doi: 10.1038/s41586-020-2972-7

    Choosing a mate is one of the most consequential decisions a female will make during her lifetime. A female fly signals her willingness to mate by opening her vaginal plates, allowing a courting male to copulate. Vaginal plate opening (VPO) occurs in response to the male courtship song and is dependent on the mating status of the female. How these exteroceptive (song) and interoceptive (mating status) inputs are integrated to regulate VPO remains unknown. Here we characterize the neural circuitry that implements mating decisions in the brain of female Drosophila melanogaster. We show that VPO is controlled by a pair of female-specific descending neurons (vpoDNs). The vpoDNs receive excitatory input from auditory neurons (vpoENs), which are tuned to specific features of the D. melanogaster song, and from pC1 neurons, which encode the mating status of the female. The song responses of vpoDNs, but not vpoENs, are attenuated upon mating, accounting for the reduced receptivity of mated females. This modulation is mediated by pC1 neurons. The vpoDNs thus directly integrate the external and internal signals that control the mating decisions of Drosophila females.

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    12/01/20 | A programmable sequence of reporters for lineage analysis.
    Garcia-Marques J, Espinosa-Medina I, Ku K, Yang C, Koyama M, Yu H, Lee T
    Nature Neuroscience. 2020 Dec 01;23(12):1618-28. doi: 10.1038/s41593-020-0676-9

    We present CLADES (cell lineage access driven by an edition sequence), a technology for cell lineage studies based on CRISPR-Cas9 techniques. CLADES relies on a system of genetic switches to activate and inactivate reporter genes in a predetermined order. Targeting CLADES to progenitor cells allows the progeny to inherit a sequential cascade of reporters, thereby coupling birth order to reporter expression. This system, which can also be temporally induced by heat shock, enables the temporal resolution of lineage development and can therefore be used to deconstruct an extended cell lineage by tracking the reporters expressed in the progeny. When targeted to the germ line, the same cascade progresses across animal generations, predominantly marking each generation with the corresponding combination of reporters. CLADES therefore offers an innovative strategy for making programmable cascades of genes that can be used for genetic manipulation or to record serial biological events.

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    10/05/20 | Circuit and behavioral mechanisms of sexual rejection by drosophila females.
    Wang F, Wang K, Forknall N, Parekh R, Dickson BJ
    Current Biology. 2020 Oct 05;30(19):. doi: 10.1016/j.cub.2020.07.083

    The mating decisions of Drosophila melanogaster females are primarily revealed through either of two discrete actions: opening of the vaginal plates to allow copulation, or extrusion of the ovipositor to reject the male. Both actions are triggered by the male courtship song, and both are dependent upon the female's mating status. Virgin females are more likely to open their vaginal plates in response to song; mated females are more likely to extrude their ovipositor. Here, we examine the neural cause and behavioral consequence of ovipositor extrusion. We show that the DNp13 descending neurons act as command-type neurons for ovipositor extrusion, and that ovipositor extrusion is an effective deterrent only when performed by females that have previously mated. The DNp13 neurons respond to male song via direct synaptic input from the pC2l auditory neurons. Mating status does not modulate the song responses of DNp13 neurons, but rather how effectively they can engage the motor circuits for ovipositor extrusion. We present evidence that mating status information is mediated by ppk sensory neurons in the uterus, which are activated upon ovulation. Vaginal plate opening and ovipositor extrusion are thus controlled by anatomically and functionally distinct circuits, highlighting the diversity of neural decision-making circuits even in the context of closely related behaviors with shared exteroceptive and interoceptive inputs.

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