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Selected Publications

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06/12/17 | Neural signatures of dynamic stimulus selection in Drosophila.
Sun Y, Nern A, Franconville R, Dana H, Schreiter ER, Looger LL, Svoboda K, Kim DS, Hermundstad AM, Jayaraman V
Nature Neuroscience. 2017 Jun 12;20(8):1104-13. doi: 10.1038/nn.4581

Many animals orient using visual cues, but how a single cue is selected from among many is poorly understood. Here we show that Drosophila ring neurons—central brain neurons implicated in navigation—display visual stimulus selection. Using in vivo two-color two-photon imaging with genetically encoded calcium indicators, we demonstrate that individual ring neurons inherit simple-cell-like receptive fields from their upstream partners. Stimuli in the contralateral visual field suppressed responses to ipsilateral stimuli in both populations. Suppression strength depended on when and where the contralateral stimulus was presented, an effect stronger in ring neurons than in their upstream inputs. This history-dependent effect on the temporal structure of visual responses, which was well modeled by a simple biphasic filter, may determine how visual references are selected for the fly's internal compass. Our approach highlights how two-color calcium imaging can help identify and localize the origins of sensory transformations across synaptically connected neural populations.

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05/22/17 | Angular velocity integration in a fly heading circuit.
Turner-Evans D, Wegener S, Rouault H, Franconville R, Wolff T, Seelig JD, Druckmann S, Jayaraman V
eLife. 2017 May 22;6:. doi: 10.7554/eLife.23496

Many animals maintain an internal representation of their heading as they move through their surroundings. Such a compass representation was recently discovered in a neural population in the Drosophila melanogaster central complex, a brain region implicated in spatial navigation. Here, we use two-photon calcium imaging and electrophysiology in head-fixed walking flies to identify a different neural population that conjunctively encodes heading and angular velocity, and is excited selectively by turns in either the clockwise or counterclockwise direction. We show how these mirror-symmetric turn responses combine with the neurons' connectivity to the compass neurons to create an elegant mechanism for updating the fly's heading representation when the animal turns in darkness. This mechanism, which employs recurrent loops with an angular shift, bears a resemblance to those proposed in theoretical models for rodent head direction cells. Our results provide a striking example of structure matching function for a broadly relevant computation.

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05/04/17 | Ring attractor dynamics in the Drosophila central brain.
Kim SS, Rouault H, Druckmann S, Jayaraman V
Science (New York, N.Y.). 2017 May 04;356(6340):849-53. doi: 10.1126/science.aal4835

Ring attractors are a class of recurrent networks hypothesized to underlie the representation of heading direction. Such network structures, schematized as a ring of neurons whose connectivity depends on their heading preferences, can sustain a bump-like activity pattern whose location can be updated by continuous shifts along either turn direction. We recently reported that a population of fly neurons represents the animal's heading via bump-like activity dynamics. We combined two-photon calcium imaging in head-fixed flying flies with optogenetics to overwrite the existing population representation with an artificial one, which was then maintained by the circuit with naturalistic dynamics. A network with local excitation and global inhibition enforces this unique and persistent heading representation. Ring attractor networks have long been invoked in theoretical work; our study provides physiological evidence of their existence and functional architecture.

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06/06/16 | The insect central complex.
Turner-Evans DB, Jayaraman V
Current Biology. 2016 Jun 06;26(11):R453-7
03/24/16 | Sensitive red protein calcium indicators for imaging neural activity.
Dana H, Mohar B, Sun Y, Narayan S, Gordus A, Hasseman JP, Tsegaye G, Holt GT, Hu A, Walpita D, Patel R, Macklin JJ, Bargmann CI, Ahrens MB, Schreiter ER, Jayaraman V, Looger LL, Svoboda K, Kim DS
eLife. 2016 Mar 24;5:. doi: 10.7554/eLife.12727

Genetically encoded calcium indicators (GECIs) allow measurement of activity in large populations of neurons and in small neuronal compartments, over times of milliseconds to months. Although GFP-based GECIs are widely used for in vivo neurophysiology, GECIs with red-shifted excitation and emission spectra have advantages for in vivo imaging because of reduced scattering and absorption in tissue, and a consequent reduction in phototoxicity. However, current red GECIs are inferior to the state-of-the-art GFP-based GCaMP6 indicators for detecting and quantifying neural activity. Here we present improved red GECIs based on mRuby (jRCaMP1a, b) and mApple (jRGECO1a), with sensitivity comparable to GCaMP6. We characterized the performance of the new red GECIs in cultured neurons and in mouse, Drosophila, zebrafish and C. elegans in vivo. Red GECIs facilitate deep-tissue imaging, dual-color imaging together with GFP-based reporters, and the use of optogenetics in combination with calcium imaging.

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01/28/16 | Studying small brains to understand the building blocks of cognition.
Haberkern H, Jayaraman V
Current Opinion in Neurobiology. 2016 Jan 28;37:59-65. doi: 10.1016/j.conb.2016.01.007

Cognition encompasses a range of higher-order mental processes, such as attention, working memory, and model-based decision-making. These processes are thought to involve the dynamic interaction of multiple central brain regions. A mechanistic understanding of such computations requires not only monitoring and manipulating specific neural populations during behavior, but also knowing the connectivity of the underlying circuitry. These goals are experimentally challenging in mammals, but are feasible in numerically simpler insect brains. In Drosophila melanogaster in particular, genetic tools enable precisely targeted physiology and optogenetics in actively behaving animals. In this article we discuss how these advantages are increasingly being leveraged to study abstract neural representations and sensorimotor computations that may be relevant for cognition in both insects and mammals.

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06/16/15 | Dynamical feature extraction at the sensory periphery guides chemotaxis.
Schulze A, Gomez-Marin A, Rajendran VG, Lott G, Musy M, Ahammad P, Deogade A, Sharpe J, Riedl J, Jarriault D, Trautman ET, Werner C, Venkadesan M, Druckmann S, Jayaraman V, Louis M
eLife. 2015 Jun 16;4:. doi: 10.7554/eLife.06694

Behavioral strategies employed for chemotaxis have been described across phyla, but the sensorimotor basis of this phenomenon has seldom been studied in naturalistic contexts. Here, we examine how signals experienced during free olfactory behaviors are processed by first-order olfactory sensory neurons (OSNs) of the Drosophila larva. We find that OSNs can act as differentiators that transiently normalize stimulus intensity-a property potentially derived from a combination of integral feedback and feed-forward regulation of olfactory transduction. In olfactory virtual reality experiments, we report that high activity levels of the OSN suppress turning, whereas low activity levels facilitate turning. Using a generalized linear model, we explain how peripheral encoding of olfactory stimuli modulates the probability of switching from a run to a turn. Our work clarifies the link between computations carried out at the sensory periphery and action selection underlying navigation in odor gradients.

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05/14/15 | Neural dynamics for landmark orientation and angular path integration.
Seelig JD, Jayaraman V
Nature. 2015 May 14;521:186-191. doi: 10.1038/nature14446

Many animals navigate using a combination of visual landmarks and path integration. In mammalian brains, head direction cells integrate these two streams of information by representing an animal's heading relative to landmarks, yet maintaining their directional tuning in darkness based on self-motion cues. Here we use two-photon calcium imaging in head-fixed Drosophila melanogaster walking on a ball in a virtual reality arena to demonstrate that landmark-based orientation and angular path integration are combined in the population responses of neurons whose dendrites tile the ellipsoid body, a toroidal structure in the centre of the fly brain. The neural population encodes the fly's azimuth relative to its environment, tracking visual landmarks when available and relying on self-motion cues in darkness. When both visual and self-motion cues are absent, a representation of the animal's orientation is maintained in this network through persistent activity, a potential substrate for short-term memory. Several features of the population dynamics of these neurons and their circular anatomical arrangement are suggestive of ring attractors, network structures that have been proposed to support the function of navigational brain circuits.

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02/13/15 | Labeling of active neural circuits in vivo with designed calcium integrators.
Fosque BF, Sun Y, Dana H, Yang CT, Ohyama T, Tadross MR, Patel R, Zlatic M, Kim DS, Ahrens MB, Jayaraman V, Looger LL, Schreiter ER
Science. 2015 Feb 13;347(6223):755-60. doi: 10.1126/science.1260922

The identification of active neurons and circuits in vivo is a fundamental challenge in understanding the neural basis of behavior. Genetically encoded calcium (Ca(2+)) indicators (GECIs) enable quantitative monitoring of cellular-resolution activity during behavior. However, such indicators require online monitoring within a limited field of view. Alternatively, post hoc staining of immediate early genes (IEGs) indicates highly active cells within the entire brain, albeit with poor temporal resolution. We designed a fluorescent sensor, CaMPARI, that combines the genetic targetability and quantitative link to neural activity of GECIs with the permanent, large-scale labeling of IEGs, allowing a temporally precise "activity snapshot" of a large tissue volume. CaMPARI undergoes efficient and irreversible green-to-red conversion only when elevated intracellular Ca(2+) and experimenter-controlled illumination coincide. We demonstrate the utility of CaMPARI in freely moving larvae of zebrafish and flies, and in head-fixed mice and adult flies.

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02/09/14 | Independent optical excitation of distinct neural populations.
Klapoetke NC, Murata Y, Kim SSoo, Pulver SR, Birdsey-Benson A, Cho YKu, Morimoto TK, Chuong AS, Carpenter EJ, Tian Z, Wang J, Xie Y, Yan Z, Zhang Y, Chow BY, Surek B, Melkonian M, Jayaraman V, Constantine-Paton M, Wong GKaShu, Boyden ES
Nature Methods. 2014 Feb 9;11:338-46. doi: 10.1038/nmeth.2836

Optogenetic tools enable examination of how specific cell types contribute to brain circuit functions. A long-standing question is whether it is possible to independently activate two distinct neural populations in mammalian brain tissue. Such a capability would enable the study of how different synapses or pathways interact to encode information in the brain. Here we describe two channelrhodopsins, Chronos and Chrimson, discovered through sequencing and physiological characterization of opsins from over 100 species of alga. Chrimson’s excitation spectrum is red shifted by 45 nm relative to previous channelrhodopsins and can enable experiments in which red light is preferred. We show minimal visual system-mediated behavioral interference when using Chrimson in neurobehavioral studies in Drosophila melanogaster. Chronos has faster kinetics than previous channelrhodopsins yet is effectively more light sensitive. Together these two reagents enable two-color activation of neural spiking and downstream synaptic transmission in independent neural populations without detectable cross-talk in mouse brain slice.

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10/01/13 | Feature detection and orientation tuning in the Drosophila central complex.
Seelig JD, Jayaraman V
Nature. 2013 Oct 9;503(7475):262-66. doi: 10.1038/nature12601

Many animals, including insects, are known to use visual landmarks to orient in their environment. In Drosophila melanogaster, behavioural genetics studies have identified a higher brain structure called the central complex as being required for the fly’s innate responses to vertical visual features and its short- and long-term memory for visual patterns. But whether and how neurons of the fly central complex represent visual features are unknown. Here we use two-photon calcium imaging in head-fixed walking and flying flies to probe visuomotor responses of ring neurons—a class of central complex neurons that have been implicated in landmark-driven spatial memory in walking flies and memory for visual patterns in tethered flying flies. We show that dendrites of ring neurons are visually responsive and arranged retinotopically. Ring neuron receptive fields comprise both excitatory and inhibitory subfields, resembling those of simple cells in the mammalian primary visual cortex. Ring neurons show strong and, in some cases, direction-selective orientation tuning, with a notable preference for vertically oriented features similar to those that evoke innate responses in flies. Visual responses were diminished during flight, but, in contrast with the hypothesized role of the central complex in the control of locomotion, not modulated during walking. Taken together, these results indicate that ring neurons represent behaviourally relevant visual features in the fly’s environment, enabling downstream central complex circuits to produce appropriate motor commands. More broadly, this study opens the door to mechanistic investigations of circuit computations underlying visually guided action selection in the Drosophila central complex.

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07/18/13 | Ultrasensitive fluorescent proteins for imaging neuronal activity.
Chen TW, Wardill TJ, Sun Y, Pulvar SR, Renninger SL, Baohan A, Schreiter ER, Kerr RA, Orger MB, Jayaraman V, Looger LL, Svoboda K, Kim DS
Nature. 2013 Jul 18;499:295-300. doi: 10.1038/nature12354

Fluorescent calcium sensors are widely used to image neural activity. Using structure-based mutagenesis and neuron-based screening, we developed a family of ultrasensitive protein calcium sensors (GCaMP6) that outperformed other sensors in cultured neurons and in zebrafish, flies and mice in vivo. In layer 2/3 pyramidal neurons of the mouse visual cortex, GCaMP6 reliably detected single action potentials in neuronal somata and orientation-tuned synaptic calcium transients in individual dendritic spines. The orientation tuning of structurally persistent spines was largely stable over timescales of weeks. Orientation tuning averaged across spine populations predicted the tuning of their parent cell. Although the somata of GABAergic neurons showed little orientation tuning, their dendrites included highly tuned dendritic segments (5–40-µm long). GCaMP6 sensors thus provide new windows into the organization and dynamics of neural circuits over multiple spatial and temporal scales.

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06/24/11 | Studying sensorimotor integration in insects.
Huston* SJ, Jayaraman V
Current Opinion in Neurobiology. 2011 Jun 24;21(4):527-34. doi: 10.1016/j.conb.2011.05.030

Sensorimotor integration is a field rich in theory backed by a large body of psychophysical evidence. Relating the underlying neural circuitry to these theories has, however, been more challenging. With a wide array of complex behaviors coordinated by their small brains, insects provide powerful model systems to study key features of sensorimotor integration at a mechanistic level. Insect neural circuits perform both hard-wired and learned sensorimotor transformations. They modulate their neural processing based on both internal variables, such as the animal’s behavioral state, and external ones, such as the time of day. Here we present some studies using insect model systems that have produced insights, at the level of individual neurons, about sensorimotor integration and the various ways in which it can be modified by context.

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08/24/10 | Walking modulates speed sensitivity in Drosophila motion vision.
Chiappe E, Seelig JD, Reiser MB, Jayaraman V
Current Biology. 2010 Aug 24;20(16):1470-5. doi: 10.1016/j.cub.2010.06.072

Changes in behavioral state modify neural activity in many systems. In some vertebrates such modulation has been observed and interpreted in the context of attention and sensorimotor coordinate transformations. Here we report state-dependent activity modulations during walking in a visual-motor pathway of Drosophila. We used two-photon imaging to monitor intracellular calcium activity in motion-sensitive lobula plate tangential cells (LPTCs) in head-fixed Drosophila walking on an air-supported ball. Cells of the horizontal system (HS)–a subgroup of LPTCs–showed stronger calcium transients in response to visual motion when flies were walking rather than resting. The amplified responses were also correlated with walking speed. Moreover, HS neurons showed a relatively higher gain in response strength at higher temporal frequencies, and their optimum temporal frequency was shifted toward higher motion speeds. Walking-dependent modulation of HS neurons in the Drosophila visual system may constitute a mechanism to facilitate processing of higher image speeds in behavioral contexts where these speeds of visual motion are relevant for course stabilization.

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07/01/10 | Two-photon calcium imaging from head-fixed Drosophila during optomotor walking behavior.
Seelig JD, Chiappe E, Lott GK, Dutta A, Osborne JE, Reiser MB, Jayaraman V
Nature Methods. 2010 Jul;7:535-40. doi: 10.1038/nmeth.1468

Drosophila melanogaster is a model organism rich in genetic tools to manipulate and identify neural circuits involved in specific behaviors. Here we present a technique for two-photon calcium imaging in the central brain of head-fixed Drosophila walking on an air-supported ball. The ball’s motion is tracked at high resolution and can be treated as a proxy for the fly’s own movements. We used the genetically encoded calcium sensor, GCaMP3.0, to record from important elements of the motion-processing pathway, the horizontal-system lobula plate tangential cells (LPTCs) in the fly optic lobe. We presented motion stimuli to the tethered fly and found that calcium transients in horizontal-system neurons correlated with robust optomotor behavior during walking. Our technique allows both behavior and physiology in identified neurons to be monitored in a genetic model organism with an extensive repertoire of walking behaviors.

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