Publications by authors named "Hiromu Tanimoto"

62 Publications

acquires seconds-scale rhythmic behavior.

J Exp Biol 2021 Apr 1. Epub 2021 Apr 1.

Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-Ku, Sendai, 980-8577, Japan

Detection of the temporal structure of stimuli is crucial for prediction. While perception of interval timing is relevant for immediate behavioral adaptations, it has been scarcely investigated, especially in invertebrates. Here we examined if the fruit fly, , can acquire rhythmic behavior in the range of seconds. To this end, we developed a novel temporal conditioning paradigm utilizing repeated electric shocks. Combined automatic behavioral annotation and time-frequency analysis revealed that behavioral rhythms continued after cessation of the shocks. Furthermore, we found that aging impaired interval timing. This study thus not only demonstrated the ability of insects to acquire behavioral rhythms of a few seconds, but highlighted a life-course decline of temporal coordination, that is common also in mammals.
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http://dx.doi.org/10.1242/jeb.242443DOI Listing
April 2021

Voluntary intake of psychoactive substances is regulated by the dopamine receptor Dop1R1 in Drosophila.

Sci Rep 2021 Feb 9;11(1):3432. Epub 2021 Feb 9.

Graduate School of Life Sciences, Tohoku University, Sendai, 980-8577, Japan.

Dysregulated motivation to consume psychoactive substances leads to addictive behaviors that often result in serious health consequences. Understanding the neuronal mechanisms that drive drug consumption is crucial for developing new therapeutic strategies. The fruit fly Drosophila melanogaster offers a unique opportunity to approach this problem with a battery of sophisticated neurogenetic tools available, but how they consume these drugs remains largely unknown. Here, we examined drug self-administration behavior of Drosophila and the underlying neuronal mechanisms. We measured the preference of flies for five different psychoactive substances using a two-choice feeding assay and monitored its long-term changes. We found that flies show acute preference for ethanol and methamphetamine, but not for cocaine, caffeine or morphine. Repeated intake of ethanol, but not methamphetamine, increased over time. Preference for methamphetamine and the long-term escalation of ethanol preference required the dopamine receptor Dop1R1 in the mushroom body. The protein level of Dop1R1 increased after repeated intake of ethanol, but not methamphetamine, which correlates with the acquired preference. Genetic overexpression of Dop1R1 enhanced ethanol preference. These results reveal a striking diversity of response to individual drugs in the fly and the role of dopamine signaling and its plastic changes in controlling voluntary intake of drugs.
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http://dx.doi.org/10.1038/s41598-021-82813-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873259PMC
February 2021

Mushroom body output differentiates memory processes and distinct memory-guided behaviors.

Curr Biol 2021 Mar 20;31(6):1294-1302.e4. Epub 2021 Jan 20.

Graduate School of Life Sciences, Tohoku University, Sendai 980-8577, Japan. Electronic address:

The mushroom body (MB) of Drosophila melanogaster has multiple functions in controlling memory and behavior. However, circuit mechanisms that generate this functional diversity are largely unclear. Here, we systematically probed the behavioral contribution of each type of MB output neuron (MBON) by blocking during acquisition, retention, or retrieval of reward or punishment memories. We evaluated the contribution using two conditioned responses: memory-guided odor choice and odor source attraction. Quantitative analysis revealed that these conditioned odor responses are controlled by different sets of MBONs. We found that the valence of memory, rather than the transition of memory steps, has a larger impact on the patterns of required MBONs. Moreover, we found that the glutamatergic MBONs forming recurrent circuits commonly contribute to appetitive memory acquisition, suggesting a pivotal role of this circuit motif for reward processing. Our results provide principles how the MB output circuit processes associative memories of different valence and controls distinct memory-guided behaviors.
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http://dx.doi.org/10.1016/j.cub.2020.12.032DOI Listing
March 2021

Neuronal octopamine signaling regulates mating-induced germline stem cell increase in female .

Elife 2020 10 20;9. Epub 2020 Oct 20.

Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Japan.

Stem cells fuel the development and maintenance of tissues. Many studies have addressed how local signals from neighboring niche cells regulate stem cell identity and their proliferative potential. However, the regulation of stem cells by tissue-extrinsic signals in response to environmental cues remains poorly understood. Here we report that efferent octopaminergic neurons projecting to the ovary are essential for germline stem cell (GSC) increase in response to mating in female . The neuronal activity of the octopaminergic neurons is required for mating-induced GSC increase as they relay the mating signal from sex peptide receptor-positive cholinergic neurons. Octopamine and its receptor Oamb are also required for mating-induced GSC increase via intracellular Ca signaling. Moreover, we identified Matrix metalloproteinase-2 as a downstream component of the octopamine-Ca signaling to induce GSC increase. Our study provides a mechanism describing how neuronal system couples stem cell behavior to environmental cues through stem cell niche signaling.
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http://dx.doi.org/10.7554/eLife.57101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591258PMC
October 2020

Cofactor-enabled functional expression of fruit fly, honeybee, and bumblebee nicotinic receptors reveals picomolar neonicotinoid actions.

Proc Natl Acad Sci U S A 2020 07 1;117(28):16283-16291. Epub 2020 Jul 1.

Department of Applied Biological Chemistry, Faculty of Agriculture, Kindai University, Nara 631-8505, Japan;

The difficulty of achieving robust functional expression of insect nicotinic acetylcholine receptors (nAChRs) has hampered our understanding of these important molecular targets of globally deployed neonicotinoid insecticides at a time when concerns have grown regarding the toxicity of this chemotype to insect pollinators. We show that thioredoxin-related transmembrane protein 3 (TMX3) is essential to enable robust expression in oocytes of honeybee () and bumblebee () as well as fruit fly () nAChR heteromers targeted by neonicotinoids and not hitherto robustly expressed. This has enabled the characterization of picomolar target site actions of neonicotinoids, findings important in understanding their toxicity.
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http://dx.doi.org/10.1073/pnas.2003667117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368294PMC
July 2020

The Corazonin-PTTH Neuronal Axis Controls Systemic Body Growth by Regulating Basal Ecdysteroid Biosynthesis in Drosophila melanogaster.

Curr Biol 2020 06 7;30(11):2156-2165.e5. Epub 2020 May 7.

Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, 305-8577 Tsukuba, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan.

Steroid hormones play key roles in development, growth, and reproduction in various animal phyla [1]. The insect steroid hormone, ecdysteroid, coordinates growth and maturation, represented by molting and metamorphosis [2]. In Drosophila melanogaster, the prothoracicotropic hormone (PTTH)-producing neurons stimulate peak levels of ecdysteroid biosynthesis for maturation [3]. Additionally, recent studies on PTTH signaling indicated that basal levels of ecdysteroid negatively affect systemic growth prior to maturation [4-8]. However, it remains unclear how PTTH signaling is regulated for basal ecdysteroid biosynthesis. Here, we report that Corazonin (Crz)-producing neurons regulate basal ecdysteroid biosynthesis by affecting PTTH neurons. Crz belongs to gonadotropin-releasing hormone (GnRH) superfamily, implying an analogous role in growth and maturation [9]. Inhibition of Crz neuronal activity increased pupal size, whereas it hardly affected pupariation timing. This phenotype resulted from enhanced growth rate and a delay in ecdysteroid elevation during the mid-third instar larval (L3) stage. Interestingly, Crz receptor (CrzR) expression in PTTH neurons was higher during the mid- than the late-L3 stage. Silencing of CrzR in PTTH neurons increased pupal size, phenocopying the inhibition of Crz neuronal activity. When Crz neurons were optogenetically activated, a strong calcium response was observed in PTTH neurons during the mid-L3, but not the late-L3, stage. Furthermore, we found that octopamine neurons contact Crz neurons in the subesophageal zone (SEZ), transmitting signals for systemic growth. Together, our results suggest that the Crz-PTTH neuronal axis modulates ecdysteroid biosynthesis in response to octopamine, uncovering a regulatory neuroendocrine system in the developmental transition from growth to maturation.
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http://dx.doi.org/10.1016/j.cub.2020.03.050DOI Listing
June 2020

Future perspectives of neurogenetics - in honor of Troy D. Zars (1967-2018).

J Neurogenet 2020 03;34(1)

Editor-in-Chief Department of Biology, University of Iowa, Iowa City, IA, USA.

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http://dx.doi.org/10.1080/01677063.2020.1715975DOI Listing
March 2020

Dopamine Receptor Dop1R2 Stabilizes Appetitive Olfactory Memory through the Raf/MAPK Pathway in .

J Neurosci 2020 04 26;40(14):2935-2942. Epub 2020 Feb 26.

Graduate School of Life Sciences, Tohoku University, Aoba-Ku, Sendai 980-8577, Japan,

In , dopamine signaling to the mushroom body intrinsic neurons, Kenyon cells (KCs), is critical to stabilize olfactory memory. Little is known about the downstream intracellular molecular signaling underlying memory stabilization. Here we address this question in the context of sugar-rewarded olfactory long-term memory (LTM). We show that associative training increases the phosphorylation of MAPK in KCs, via Dop1R2 signaling. Consistently, the attenuation of , , or expression in KCs selectively impairs LTM, but not short-term memory. Moreover, we show that the LTM deficit caused by the knockdown of can be rescued by expressing active Raf in KCs. Thus, the Dop1R2/Raf/MAPK pathway is a pivotal downstream effector of dopamine signaling for stabilizing appetitive olfactory memory. Dopaminergic input to the Kenyon cells (KCs) is pivotal to stabilize memory in This process is mediated by dopamine receptors like Dop1R2. Nevertheless, little is known for its underlying molecular mechanism. Here we show that the Raf/MAPK pathway is specifically engaged in appetitive long-term memory in KCs. With combined biochemical and behavioral experiments, we reveal that activation of the Raf/MAPK pathway is regulated through Dop1R2, shedding light on how dopamine modulates intracellular signaling for memory stabilization.
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http://dx.doi.org/10.1523/JNEUROSCI.1572-19.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7117890PMC
April 2020

Environmental Light Is Required for Maintenance of Long-Term Memory in .

J Neurosci 2020 02 13;40(7):1427-1439. Epub 2020 Jan 13.

Department of Biological Sciences, Tokyo Metropolitan University, Tokyo 192-0397, Japan,

Long-term memory (LTM) is stored as functional modifications of relevant neural circuits in the brain. A large body of evidence indicates that the initial establishment of such modifications through the process known as memory consolidation requires learning-dependent transcriptional activation and protein synthesis. However, it remains poorly understood how the consolidated memory is maintained for a long period in the brain, despite constant turnover of molecular substrates. Using the courtship conditioning assay of adult males as a memory paradigm, here, we show that in , environmental light plays a critical role in LTM maintenance. LTM is impaired when flies are kept in constant darkness (DD) during the memory maintenance phase. Because light activates the brain neurons expressing the neuropeptide pigment-dispersing factor (Pdf), we examined the possible involvement of Pdf neurons in LTM maintenance. Temporal activation of Pdf neurons compensated for the DD-dependent LTM impairment, whereas temporal knockdown of Pdf during the memory maintenance phase impaired LTM in light/dark cycles. Furthermore, we demonstrated that the transcription factor cAMP response element-binding protein (CREB) is required in the memory center, namely, the mushroom bodies (MBs), for LTM maintenance, and Pdf signaling regulates light-dependent transcription via CREB. Our results demonstrate for the first time that universally available environmental light plays a critical role in LTM maintenance by activating the evolutionarily conserved memory modulator CREB in MBs via the Pdf signaling pathway. Temporary memory can be consolidated into long-term memory (LTM) through protein synthesis and functional modifications of neuronal circuits in the brain. Once established, LTM requires continual maintenance so that it is kept for an extended period against molecular turnover and cellular reorganization that may disrupt memory traces. How is LTM maintained mechanistically? Despite the critical importance of LTM maintenance, its molecular and cellular underpinnings remain elusive. This study using is significant because it revealed for the first time in any organism that universally available environmental light plays an essential role in LTM maintenance. Interestingly, light does so by activating the evolutionarily conserved transcription factor cAMP response element-binding protein via peptidergic signaling.
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http://dx.doi.org/10.1523/JNEUROSCI.1282-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044726PMC
February 2020

Neurochemical Organization of the Drosophila Brain Visualized by Endogenously Tagged Neurotransmitter Receptors.

Cell Rep 2020 01;30(1):284-297.e5

Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi 980-8577, Japan. Electronic address:

Neurotransmitters often have multiple receptors that induce distinct responses in receiving cells. Expression and localization of neurotransmitter receptors in individual neurons are therefore critical for understanding the operation of neural circuits. Here we describe a comprehensive library of reporter strains in which a convertible T2A-GAL4 cassette is inserted into endogenous neurotransmitter receptor genes of Drosophila. Using this library, we profile the expression of 75 neurotransmitter receptors in the brain. Cluster analysis reveals neurochemical segmentation of the brain, distinguishing higher brain centers from the rest. By recombinase-mediated cassette exchange, we convert T2A-GAL4 into split-GFP and Tango to visualize subcellular localization and activation of dopamine receptors in specific cell types. This reveals striking differences in their subcellular localization, which may underlie the distinct cellular responses to dopamine in different behavioral contexts. Our resources thus provide a versatile toolkit for dissecting the cellular organization and function of neurotransmitter systems in the fly brain.
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http://dx.doi.org/10.1016/j.celrep.2019.12.018DOI Listing
January 2020

Bodily Awareness: How Flies Learn Their Own Body Size.

Authors:
Hiromu Tanimoto

Curr Biol 2019 06;29(12):R572-R574

Graduate School of Life Sciences, Tohoku University, Katahira 2-1-1, 980-8577 Sendai, Japan. Electronic address:

Animals need to perceive their own body size to apprehend their relationship to the environment. A new study shows that the fruit fly Drosophila acquires the requisite information on its body size from visual feedback during walking, and has further identified a subset of neurons responsible for maintenance of body-size memory.
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http://dx.doi.org/10.1016/j.cub.2019.05.007DOI Listing
June 2019

Photo gallery for the Yamamoto special issue.

Authors:
Hiromu Tanimoto

J Neurogenet 2019 Mar - Jun;33(2):152-156. Epub 2019 Jun 7.

a Graduate School of Life Sciences , Tohoku University , Sendai , Japan.

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http://dx.doi.org/10.1080/01677063.2019.1619719DOI Listing
July 2020

Comparative behavioral genetics: the Yamamoto approach.

J Neurogenet 2019 Mar - Jun;33(2):41-43. Epub 2019 May 30.

b Department of Biology , University of Iowa , Iowa City , IA , USA.

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http://dx.doi.org/10.1080/01677063.2019.1616720DOI Listing
July 2020

Tango knock-ins visualize endogenous activity of G protein-coupled receptors in Drosophila.

J Neurogenet 2019 Mar - Jun;33(2):44-51. Epub 2019 May 14.

a Genetic Strains Research Center , National Institute of Genetics , Mishima , Japan.

G protein-coupled receptors (GPCRs) represent a family of seven-pass transmembrane protein receptors whose ligands include neuropeptides and small-molecule neuromodulators such as dopamine and serotonin. These neurotransmitters act at long distances and are proposed to define the ground state of the nervous system. The genome encodes approximately 50 neuropeptides and their functions in physiology and behavior are now under intensive studies. Key information currently lacking in the field is the spatiotemporal activation patterns of endogenous GPCRs. Here we report application of the Tango system, a reporter assay to detect GPCR activity, to endogenous GPCRs in the fly genome. We developed a method to integrate the sensor component of the Tango system to the C-terminus of endogenous genes by using genome editing techniques. We demonstrate that Tango sensors in the () locus allow sensitive detection of mating-dependent SPR activity in the female reproductive organ. The method is easily applicable to any GPCR and will provide a way to systematically characterize GPCRs in the fly brain.
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http://dx.doi.org/10.1080/01677063.2019.1611806DOI Listing
July 2020

Courtship behavior induced by appetitive olfactory memory.

J Neurogenet 2019 Mar - Jun;33(2):143-151. Epub 2019 Apr 8.

a Graduate School of Life Sciences , Tohoku University , Sendai 980-8577 , Japan.

Reinforcement signals such as food reward and noxious punishment can change diverse behaviors. This holds true in fruit flies, , which can be conditioned by an odor and sugar reward or electric shock punishment. Despite a wide variety of behavior modulated by learning, conditioned responses have been traditionally measured by altered odor preference in a choice, and other memory-guided behaviors have been only scarcely investigated. Here, we analyzed detailed conditioned odor responses of flies after sugar associative learning by employing a video recording and semi-automated processing pipeline. Trajectory analyses revealed that multiple behavioral components were altered along with conditioned approach to the rewarded odor. Notably, we found that lateral wing extension, a hallmark of courtship behavior of , was robustly increased specifically in the presence of the rewarded odor. Strikingly, genetic disruption of the mushroom body output did not impair conditioned courtship increase, while markedly weakening conditioned odor approach. Our results highlight the complexity of conditioned responses and their distinct regulatory mechanisms that may underlie coordinated yet complex memory-guided behaviors in flies.
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http://dx.doi.org/10.1080/01677063.2019.1593978DOI Listing
July 2020

Data-driven analysis of motor activity implicates 5-HT2A neurons in backward locomotion of larval Drosophila.

Sci Rep 2018 07 9;8(1):10307. Epub 2018 Jul 9.

Department of Physics, Graduate School of Science, University of Tokyo, Tokyo, 113-0033, Japan.

Rhythmic animal behaviors are regulated in part by neural circuits called the central pattern generators (CPGs). Classifying neural population activities correlated with body movements and identifying the associated component neurons are critical steps in understanding CPGs. Previous methods that classify neural dynamics obtained by dimension reduction algorithms often require manual optimization which could be laborious and preparation-specific. Here, we present a simpler and more flexible method that is based on the pre-trained convolutional neural network model VGG-16 and unsupervised learning, and successfully classifies the fictive motor patterns in Drosophila larvae under various imaging conditions. We also used voxel-wise correlation mapping to identify neurons associated with motor patterns. By applying these methods to neurons targeted by 5-HT2A-GAL4, which we generated by the CRISPR/Cas9-system, we identified two classes of interneurons, termed Seta and Leta, which are specifically active during backward but not forward fictive locomotion. Optogenetic activation of Seta and Leta neurons increased backward locomotion. Conversely, thermogenetic inhibition of 5-HT2A-GAL4 neurons or application of a 5-HT2 antagonist decreased backward locomotion induced by noxious light stimuli. This study establishes an accelerated pipeline for activity profiling and cell identification in larval Drosophila and implicates the serotonergic system in the modulation of backward locomotion.
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http://dx.doi.org/10.1038/s41598-018-28680-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037780PMC
July 2018

Behavioral Modulation by Spontaneous Activity of Dopamine Neurons.

Front Syst Neurosci 2017 11;11:88. Epub 2017 Dec 11.

Graduate School of Life Sciences, Tohoku University, Sendai, Japan.

Dopamine modulates a variety of animal behaviors that range from sleep and learning to courtship and aggression. Besides its well-known phasic firing to natural reward, a substantial number of dopamine neurons (DANs) are known to exhibit ongoing intrinsic activity in the absence of an external stimulus. While accumulating evidence points at functional implications for these intrinsic "spontaneous activities" of DANs in cognitive processes, a causal link to behavior and its underlying mechanisms has yet to be elucidated. Recent physiological studies in the model organism have uncovered that DANs in the fly brain are also spontaneously active, and that this activity reflects the behavioral/internal states of the animal. Strikingly, genetic manipulation of basal DAN activity resulted in behavioral alterations in the fly, providing critical evidence that links spontaneous DAN activity to behavioral states. Furthermore, circuit-level analyses have started to reveal cellular and molecular mechanisms that mediate or regulate spontaneous DAN activity. Through reviewing recent findings in different animals with the major focus on flies, we will discuss potential roles of this physiological phenomenon in directing animal behaviors.
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http://dx.doi.org/10.3389/fnsys.2017.00088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732226PMC
December 2017

The Role of the Gustatory System in the Coordination of Feeding.

eNeuro 2017 Nov-Dec;4(6). Epub 2017 Nov 20.

Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi 980-8577, Japan.

To survive, all animals must find, inspect, and ingest food. Behavioral coordination and control of feeding is therefore a challenge that animals must face. Here, we focus on how the gustatory system guides the precise execution of behavioral sequences that promote ingestion and suppresses competing behaviors. We summarize principles learnt from , where underlying sensory neuronal mechanisms are illustrated in great detail. Moreover, we compare these principles with findings in other animals, where such coordination plays prominent roles. These examples suggest that the use of gustatory information for feeding coordination has an ancient origin and is prevalent throughout the animal kingdom.
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http://dx.doi.org/10.1523/ENEURO.0324-17.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5694965PMC
July 2018

Suppression of Dopamine Neurons Mediates Reward.

PLoS Biol 2016 Dec 20;14(12):e1002586. Epub 2016 Dec 20.

Tohoku University Graduate School of Life Sciences, Sendai, Japan.

Massive activation of dopamine neurons is critical for natural reward and drug abuse. In contrast, the significance of their spontaneous activity remains elusive. In Drosophila melanogaster, depolarization of the protocerebral anterior medial (PAM) cluster dopamine neurons en masse signals reward to the mushroom body (MB) and drives appetitive memory. Focusing on the functional heterogeneity of PAM cluster neurons, we identified that a single class of PAM neurons, PAM-γ3, mediates sugar reward by suppressing their own activity. PAM-γ3 is selectively required for appetitive olfactory learning, while activation of these neurons in turn induces aversive memory. Ongoing activity of PAM-γ3 gets suppressed upon sugar ingestion. Strikingly, transient inactivation of basal PAM-γ3 activity can substitute for reward and induces appetitive memory. Furthermore, we identified the satiety-signaling neuropeptide Allatostatin A (AstA) as a key mediator that conveys inhibitory input onto PAM-γ3. Our results suggest the significance of basal dopamine release in reward signaling and reveal a circuit mechanism for negative regulation.
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http://dx.doi.org/10.1371/journal.pbio.1002586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5172549PMC
December 2016

Dynamics of memory-guided choice behavior in Drosophila.

Proc Jpn Acad Ser B Phys Biol Sci 2016 ;92(8):346-357

Tohoku University Graduate School of Life Sciences.

Memory retrieval requires both accuracy and speed. Olfactory learning of the fruit fly Drosophila melanogaster serves as a powerful model system to identify molecular and neuronal substrates of memory and memory-guided behavior. The behavioral expression of olfactory memory has traditionally been tested as a conditioned odor response in a simple T-maze, which measures the result, but not the speed, of odor choice. Here, we developed multiplexed T-mazes that allow video recording of the choice behavior. Automatic fly counting in each arm of the maze visualizes choice dynamics. Using this setup, we show that the transient blockade of serotonergic neurons slows down the choice, while leaving the eventual choice intact. In contrast, activation of the same neurons impairs the eventual performance leaving the choice speed unchanged. Our new apparatus contributes to elucidating how the speed and the accuracy of memory retrieval are implemented in the fly brain.
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http://dx.doi.org/10.2183/pjab.92.346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5243950PMC
March 2017

Direct neural pathways convey distinct visual information to Drosophila mushroom bodies.

Elife 2016 04 15;5. Epub 2016 Apr 15.

Max-Planck Institut für Neurobiologie, Martinsried, Germany.

Previously, we demonstrated that visual and olfactory associative memories of Drosophila share mushroom body (MB) circuits (Vogt et al., 2014). Unlike for odor representation, the MB circuit for visual information has not been characterized. Here, we show that a small subset of MB Kenyon cells (KCs) selectively responds to visual but not olfactory stimulation. The dendrites of these atypical KCs form a ventral accessory calyx (vAC), distinct from the main calyx that receives olfactory input. We identified two types of visual projection neurons (VPNs) directly connecting the optic lobes and the vAC. Strikingly, these VPNs are differentially required for visual memories of color and brightness. The segregation of visual and olfactory domains in the MB allows independent processing of distinct sensory memories and may be a conserved form of sensory representations among insects.
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http://dx.doi.org/10.7554/eLife.14009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884080PMC
April 2016

Functional dissociation in sweet taste receptor neurons between and within taste organs of Drosophila.

Nat Commun 2016 Feb 19;7:10678. Epub 2016 Feb 19.

Graduate School of Life Sciences, Tohoku University, Katahira 2-1-1, Miyagi, Sendai 980-8577, Japan.

Finding food sources is essential for survival. Insects detect nutrients with external taste receptor neurons. Drosophila possesses multiple taste organs that are distributed throughout its body. However, the role of different taste organs in feeding remains poorly understood. By blocking subsets of sweet taste receptor neurons, we show that receptor neurons in the legs are required for immediate sugar choice. Furthermore, we identify two anatomically distinct classes of sweet taste receptor neurons in the leg. The axonal projections of one class terminate in the thoracic ganglia, whereas the other projects directly to the brain. These two classes are functionally distinct: the brain-projecting neurons are involved in feeding initiation, whereas the thoracic ganglia-projecting neurons play a role in sugar-dependent suppression of locomotion. Distinct receptor neurons for the same taste quality may coordinate early appetitive responses, taking advantage of the legs as the first appendages to contact food.
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http://dx.doi.org/10.1038/ncomms10678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4762887PMC
February 2016

Four Individually Identified Paired Dopamine Neurons Signal Reward in Larval Drosophila.

Curr Biol 2016 Mar 11;26(5):661-9. Epub 2016 Feb 11.

Department of Biology, University of Fribourg, 1600 Fribourg, Switzerland; Department of Biology, University of Konstanz, 78464 Konstanz, Germany; Zukunftskolleg, University of Konstanz, 78464 Konstanz, Germany. Electronic address:

Dopaminergic neurons serve multiple functions, including reinforcement processing during associative learning [1-12]. It is thus warranted to understand which dopaminergic neurons mediate which function. We study larval Drosophila, in which only approximately 120 of a total of 10,000 neurons are dopaminergic, as judged by the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme of dopamine biosynthesis [5, 13]. Dopaminergic neurons mediating reinforcement in insect olfactory learning target the mushroom bodies, a higher-order "cortical" brain region [1-5, 11, 12, 14, 15]. We discover four previously undescribed paired neurons, the primary protocerebral anterior medial (pPAM) neurons. These neurons are TH positive and subdivide the medial lobe of the mushroom body into four distinct subunits. These pPAM neurons are acutely necessary for odor-sugar reward learning and require intact TH function in this process. However, they are dispensable for aversive learning and innate behavior toward the odors and sugars employed. Optogenetical activation of pPAM neurons is sufficient as a reward. Thus, the pPAM neurons convey a likely dopaminergic reward signal. In contrast, DL1 cluster neurons convey a corresponding punishment signal [5], suggesting a cellular division of labor to convey dopaminergic reward and punishment signals. On the level of individually identified neurons, this uncovers an organizational principle shared with adult Drosophila and mammals [1-4, 7, 9, 10] (but see [6]). The numerical simplicity and connectomic tractability of the larval nervous system [16-19] now offers a prospect for studying circuit principles of dopamine function at unprecedented resolution.
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http://dx.doi.org/10.1016/j.cub.2016.01.012DOI Listing
March 2016

Reward signal in a recurrent circuit drives appetitive long-term memory formation.

Elife 2015 Nov 17;4:e10719. Epub 2015 Nov 17.

Graduate School of Life Sciences, Tohoku University, Sendai, Japan.

Dopamine signals reward in animal brains. A single presentation of a sugar reward to Drosophila activates distinct subsets of dopamine neurons that independently induce short- and long-term olfactory memories (STM and LTM, respectively). In this study, we show that a recurrent reward circuit underlies the formation and consolidation of LTM. This feedback circuit is composed of a single class of reward-signaling dopamine neurons (PAM-α1) projecting to a restricted region of the mushroom body (MB), and a specific MB output cell type, MBON-α1, whose dendrites arborize that same MB compartment. Both MBON-α1 and PAM-α1 neurons are required during the acquisition and consolidation of appetitive LTM. MBON-α1 additionally mediates the retrieval of LTM, which is dependent on the dopamine receptor signaling in the MB α/β neurons. Our results suggest that a reward signal transforms a nascent memory trace into a stable LTM using a feedback circuit at the cost of memory specificity.
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http://dx.doi.org/10.7554/eLife.10719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643015PMC
November 2015

Reversing Stimulus Timing in Visual Conditioning Leads to Memories with Opposite Valence in Drosophila.

PLoS One 2015 2;10(10):e0139797. Epub 2015 Oct 2.

Max Planck Institute of Neurobiology, 82152, Martinsried, Germany; Tohoku University Graduate School of Life Sciences, 980-8577, Sendai, Japan.

Animals need to associate different environmental stimuli with each other regardless of whether they temporally overlap or not. Drosophila melanogaster displays olfactory trace conditioning, where an odor is followed by electric shock reinforcement after a temporal gap, leading to conditioned odor avoidance. Reversing the stimulus timing in olfactory conditioning results in the reversal of memory valence such that an odor that follows shock is later on approached (i.e. relief conditioning). Here, we explored the effects of stimulus timing on memory in another sensory modality, using a visual conditioning paradigm. We found that flies form visual memories of opposite valence depending on stimulus timing and can associate a visual stimulus with reinforcement despite being presented with a temporal gap. These results suggest that associative memories with non-overlapping stimuli and the effect of stimulus timing on memory valence are shared across sensory modalities.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0139797PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4592196PMC
June 2016

A model for non-monotonic intensity coding.

R Soc Open Sci 2015 May 6;2(5):150120. Epub 2015 May 6.

Max Planck Institute of Neurobiology , Martinsried 82152, Germany ; Research Group Molecular Systems Biology of Learning , Leibniz Institute for Neurobiology , Magdeburg 39118, Germany ; Center for Brain and Behavioural Sciences , Magdeburg, Germany.

Peripheral neurons of most sensory systems increase their response with increasing stimulus intensity. Behavioural responses, however, can be specific to some intermediate intensity level whose particular value might be innate or associatively learned. Learning such a preference requires an adjustable trans- formation from a monotonic stimulus representation at the sensory periphery to a non-monotonic representation for the motor command. How do neural systems accomplish this task? We tackle this general question focusing on odour-intensity learning in the fruit fly, whose first- and second-order olfactory neurons show monotonic stimulus-response curves. Nevertheless, flies form associative memories specific to particular trained odour intensities. Thus, downstream of the first two olfactory processing layers, odour intensity must be re-coded to enable intensity-specific associative learning. We present a minimal, feed-forward, three-layer circuit, which implements the required transformation by combining excitation, inhibition, and, as a decisive third element, homeostatic plasticity. Key features of this circuit motif are consistent with the known architecture and physiology of the fly olfactory system, whereas alternative mechanisms are either not composed of simple, scalable building blocks or not compatible with physiological observations. The simplicity of the circuit and the robustness of its function under parameter changes make this computational motif an attractive candidate for tuneable non-monotonic intensity coding.
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http://dx.doi.org/10.1098/rsos.150120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453257PMC
May 2015

Genome-Wide Association Analyses Point to Candidate Genes for Electric Shock Avoidance in Drosophila melanogaster.

PLoS One 2015 18;10(5):e0126986. Epub 2015 May 18.

Research Group Molecular Systems Biology of Learning, Leibniz Institute of Neurobiology, Magdeburg, Germany; Max Planck Institute of Neurobiology, Martinsried, Germany; Center for Behavioral Brain Sciences, Magdeburg, Germany.

Electric shock is a common stimulus for nociception-research and the most widely used reinforcement in aversive associative learning experiments. Yet, nothing is known about the mechanisms it recruits at the periphery. To help fill this gap, we undertook a genome-wide association analysis using 38 inbred Drosophila melanogaster strains, which avoided shock to varying extents. We identified 514 genes whose expression levels and/ or sequences co-varied with shock avoidance scores. We independently scrutinized 14 of these genes using mutants, validating the effect of 7 of them on shock avoidance. This emphasizes the value of our candidate gene list as a guide for follow-up research. In addition, by integrating our association results with external protein-protein interaction data we obtained a shock avoidance-associated network of 38 genes. Both this network and the original candidate list contained a substantial number of genes that affect mechanosensory bristles, which are hair-like organs distributed across the fly's body. These results may point to a potential role for mechanosensory bristles in shock sensation. Thus, we not only provide a first list of candidate genes for shock avoidance, but also point to an interesting new hypothesis on nociceptive mechanisms.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0126986PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4436303PMC
April 2016

Distinct dopamine neurons mediate reward signals for short- and long-term memories.

Proc Natl Acad Sci U S A 2015 Jan 29;112(2):578-83. Epub 2014 Dec 29.

Tohoku University Graduate School of Life Sciences, Sendai 980-8577, Japan; Max Planck Institut für Neurobiologie, Martinsried 82152, Germany;

Drosophila melanogaster can acquire a stable appetitive olfactory memory when the presentation of a sugar reward and an odor are paired. However, the neuronal mechanisms by which a single training induces long-term memory are poorly understood. Here we show that two distinct subsets of dopamine neurons in the fly brain signal reward for short-term (STM) and long-term memories (LTM). One subset induces memory that decays within several hours, whereas the other induces memory that gradually develops after training. They convey reward signals to spatially segregated synaptic domains of the mushroom body (MB), a potential site for convergence. Furthermore, we identified a single type of dopamine neuron that conveys the reward signal to restricted subdomains of the mushroom body lobes and induces long-term memory. Constant appetitive memory retention after a single training session thus comprises two memory components triggered by distinct dopamine neurons.
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http://dx.doi.org/10.1073/pnas.1421930112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4299218PMC
January 2015

Mushroom body output neurons encode valence and guide memory-based action selection in Drosophila.

Elife 2014 Dec 23;3:e04580. Epub 2014 Dec 23.

Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States.

Animals discriminate stimuli, learn their predictive value and use this knowledge to modify their behavior. In Drosophila, the mushroom body (MB) plays a key role in these processes. Sensory stimuli are sparsely represented by ∼2000 Kenyon cells, which converge onto 34 output neurons (MBONs) of 21 types. We studied the role of MBONs in several associative learning tasks and in sleep regulation, revealing the extent to which information flow is segregated into distinct channels and suggesting possible roles for the multi-layered MBON network. We also show that optogenetic activation of MBONs can, depending on cell type, induce repulsion or attraction in flies. The behavioral effects of MBON perturbation are combinatorial, suggesting that the MBON ensemble collectively represents valence. We propose that local, stimulus-specific dopaminergic modulation selectively alters the balance within the MBON network for those stimuli. Our results suggest that valence encoded by the MBON ensemble biases memory-based action selection.
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http://dx.doi.org/10.7554/eLife.04580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4273436PMC
December 2014

The neuronal architecture of the mushroom body provides a logic for associative learning.

Elife 2014 Dec 23;3:e04577. Epub 2014 Dec 23.

Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States.

We identified the neurons comprising the Drosophila mushroom body (MB), an associative center in invertebrate brains, and provide a comprehensive map describing their potential connections. Each of the 21 MB output neuron (MBON) types elaborates segregated dendritic arbors along the parallel axons of ∼2000 Kenyon cells, forming 15 compartments that collectively tile the MB lobes. MBON axons project to five discrete neuropils outside of the MB and three MBON types form a feedforward network in the lobes. Each of the 20 dopaminergic neuron (DAN) types projects axons to one, or at most two, of the MBON compartments. Convergence of DAN axons on compartmentalized Kenyon cell-MBON synapses creates a highly ordered unit that can support learning to impose valence on sensory representations. The elucidation of the complement of neurons of the MB provides a comprehensive anatomical substrate from which one can infer a functional logic of associative olfactory learning and memory.
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http://dx.doi.org/10.7554/eLife.04577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4273437PMC
December 2014