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1.  Genetic transformation of structural and functional circuitry rewires the Drosophila brain 
eLife  null;3:e04407.
Acquisition of distinct neuronal identities during development is critical for the assembly of diverse functional neural circuits in the brain. In both vertebrates and invertebrates, intrinsic determinants are thought to act in neural progenitors to specify their identity and the identity of their neuronal progeny. However, the extent to which individual factors can contribute to this is poorly understood. We investigate the role of orthodenticle in the specification of an identified neuroblast (neuronal progenitor) lineage in the Drosophila brain. Loss of orthodenticle from this neuroblast affects molecular properties, neuroanatomical features, and functional inputs of progeny neurons, such that an entire central complex lineage transforms into a functional olfactory projection neuron lineage. This ability to change functional macrocircuitry of the brain through changes in gene expression in a single neuroblast reveals a surprising capacity for novel circuit formation in the brain and provides a paradigm for large-scale evolutionary modification of circuitry.
eLife digest
The cells in the brain—including the neurons that transmit information—work together in groups called neural circuits. These cells develop from precursor cells called neuroblasts. Each neuroblast can produce many cells, and it is likely that cells that develop from the same neuroblast work together in the adult brain in the same neural circuit. How the adult cells develop into their final form plays an important role in creating a neural circuit, but this process is not fully understood.
In many animals, the complexity of their brain makes it difficult to follow how each individual neuroblast develops. However, all of the neuroblasts in the relatively simple brain of the fruit fly Drosophila have been identified. Furthermore, the genes responsible for establishing the initial identity of each neuroblast in the Drosophila brain are known. These genes may also determine which adult neurons develop from the neuroblast, and when each type of neuron is produced. However, the extent to which a single gene can influence the identity of neurons is unclear.
Sen et al. focused on two types of neuroblasts, each of which, although found next to each other in the developing Drosophila brain, produces neurons for different neural circuits. One of the neuroblasts generates the olfactory neurons responsible for detecting smells; the other innervates the ‘central complex’ that has a number of roles, including controlling the fly's movements. A gene called orthodenticle is expressed by the central complex neuroblast, but not by the olfactory neuroblast, and helps to separate the two neural circuits into different regions of the fly brain.
Sen et al. found that deleting the orthodenticle gene from the central complex neuroblast causes it to develop into olfactory neurons instead of central complex neurons. Tests showed that the modified neurons are completely transformed; they not only work like olfactory neurons, but they also have the same structure and molecular properties. Sen et al. have therefore demonstrated that it is possible to drastically alter the circuitry of the fruit fly brain by changing how one gene is expressed in one neuroblast. This suggests that new neural circuits can form relatively easily, and so could help us to understand how different brain structures and neural circuits evolved.
PMCID: PMC4307181  PMID: 25546307
neuroblast lineage; central complex; olfactory projection neurons; functional imaging; orthodenticle; D. melanogaster
2.  Presynaptic Facilitation by Neuropeptide Signaling Mediates Odor-Driven Food Search 
Cell  2011;145(1):133-144.
Internal physiological states influence behavioral decisions. We have investigated the underlying cellular and molecular mechanisms at the first olfactory synapse for starvation modulation of food search behavior in Drosophila. We found that a local signal by short neuropeptide F (sNPF) and a global metabolic cue by insulin are integrated at specific odorant receptor neurons (ORNs) to modulate olfactory sensitivity. Results from two-photon calcium imaging show that starvation increases presynaptic activity via intraglomerular sNPF signaling. Expression of sNPF and its receptor (sNPFR1) in Or42b neurons is necessary for starvation-induced food search behavior. Presynaptic facilitation in Or42b neurons is sufficient to mimic starvation-like behavior in fed flies. Furthermore, starvation elevates the transcription level of sNPFR1 but not that of sNPF, and insulin signaling suppresses sNPFR1 expression. Thus, starvation increases expression of sNPFR1 to change the odor map, resulting in more robust food search behavior.
PMCID: PMC3073827  PMID: 21458672
Drosophila; olfaction; sNPF; gain control; feeding behavior; two-photon imaging; Insulin; PI3K; wortmannin; LY294002
3.  Modulation of the Frequency Response of Shaker Potassium Channels by the Quiver Peptide Suggesting a Novel Extracellular Interaction Mechanism 
Journal of neurogenetics  2010;24(2):67-74.
Recent studies have indicated that the Shaker potassium channel regulates sleep in Drosophila. The Drosophila quiver (qvr) gene encodes a novel potassium channel subunit that modulates the Shaker potassium channel. The Qvr peptide contains a signal sequence for extracellular localization. Qvr may regulate a unique feature of the Shaker IA current that confers special neuronal excitability patterns. Studies of the Shaker channel properties in the qvr mutation background should provide an opportunity to uncover physiologic modulation of potassium channels. We have begun to investigate the impact of qvr protein on the Shaker channel properties and its implications in synaptic function in vivo. We studied synaptic transmission at the larval neuromuscular junction and characterized the transient potassium current IA in larval muscles. We identified two different functional states of IA in qvr larval muscles, as reflected by two distinct components, IAF and IAS, differing in their kinetics of recovery from inactivation and sensitivity to a K+ channel blocker. Correspondingly, qvr mutant larvae exhibit multiple synaptic discharges following individual nerve stimuli during repetitive activity.
PMCID: PMC3115930  PMID: 20429677
4.  Select Drosophila glomeruli mediate innate olfactory attraction and aversion 
Nature  2009;459(7244):218-223.
Fruit flies exhibit robust attraction to food odors, which usually excite multiple glomeruli. To understand how the representation of such odors leads to behavior, we used genetic tools to dissect the contribution of each activated glomerulus. Apple cider vinegar triggers robust innate attraction at a relatively low concentration, which activates six glomeruli. By silencing individual glomeruli, we found that the absence of activity in two glomeruli, DM1 and VA2, markedly reduced attraction. Conversely, when each of these two glomeruli was selectively activated, flies exhibited as robust an attraction to vinegar as wild type flies. Notably, a higher concentration of vinegar excites an additional glomerulus and is less attractive to flies. Here we show that the activation of the additional glomerulus is necessary and sufficient to mediate the behavioral switch. Together, these results indicate that individual glomeruli, rather than the entire pattern of active glomeruli, mediate innate behavioral output.
PMCID: PMC2702439  PMID: 19396157
5.  A Presynaptic Gain Control Mechanism Fine-Tunes Olfactory Behavior 
Neuron  2008;59(2):311-321.
Early sensory processing can play a critical role in sensing environmental cues. We have investigated the physiological and behavioral function of gain control at the first synapse of olfactory processing in Drosophila. We report that olfactory receptor neurons (ORNs) express the GABAB receptor (GABABR) and its expression expands the dynamic range of ORN synaptic transmission that is preserved in projection neuron responses. Strikingly, we find that different ORN channels have unique baseline levels of GABABR expression. ORNs that sense the aversive odorant CO2 do not express GABABRs nor exhibit any presynaptic inhibition. In contrast, pheromone-sensing ORNs express a high level of GABABRs and exhibit strong presynaptic inhibition. Furthermore, a behavioral significance of presynaptic inhibition was revealed by a courtship behavior in which pheromone-dependent mate localization is impaired in flies that lack GABABRs in specific ORNs. Together, these findings indicate that different olfactory receptor channels may employ heterogeneous presynaptic gain control as a mechanism to allow an animal’s innate behavioral responses to match its ecological needs.
PMCID: PMC2539065  PMID: 18667158
Drosophila; olfaction; GABAB; presynaptic inhibition; gain control; dynamic range; two-photon imaging
6.  Caspase Inhibition in Select Olfactory Neurons Restores Innate Attraction Behavior in Aged Drosophila 
PLoS Genetics  2014;10(6):e1004437.
Sensory and cognitive performance decline with age. Neural dysfunction caused by nerve death in senile dementia and neurodegenerative disease has been intensively studied; however, functional changes in neural circuits during the normal aging process are not well understood. Caspases are key regulators of cell death, a hallmark of age-related neurodegeneration. Using a genetic probe for caspase-3-like activity (DEVDase activity), we have mapped age-dependent neuronal changes in the adult brain throughout the lifespan of Drosophila. Spatio-temporally restricted caspase activation was observed in the antennal lobe and ellipsoid body, brain structures required for olfaction and visual place memory, respectively. We also found that caspase was activated in an age-dependent manner in specific subsets of Drosophila olfactory receptor neurons (ORNs), Or42b and Or92a neurons. These neurons are essential for mediating innate attraction to food-related odors. Furthermore, age-induced impairments of neural transmission and attraction behavior could be reversed by specific inhibition of caspase in these ORNs, indicating that caspase activation in Or42b and Or92a neurons is responsible for altering animal behavior during normal aging.
Author Summary
The approaching era of an “aging society” is receiving considerable attention amongst biomedical researchers in advanced nations. In order to understand the molecular mechanisms underlying age-related alterations of neural circuitry, we focused on caspase-3, a cysteine protease that induces apoptotic cell death, using the fruit fly Drosophila melanogaster, a model often used to study aging due to a short lifespan of approximately 30–60 days. Here, we describe the spatiotemporal activation of caspase-3 in aged fly brains and show that caspase-3 is specifically activated in select olfactory neurons essential for innate odor attraction behavior. Furthermore, we discuss how inhibition of caspase-3 activation in those select olfactory neurons can rejuvenate the sensitivity of innate attraction behavior in aged flies. These findings suggest that caspase-3 plays an active role in producing age-related alterations to neuronal physiology and circuit function associated with animal behavior.
PMCID: PMC4072539  PMID: 24967585
7.  Mapping Neural Circuits with Activity-Dependent Nuclear Import of a Transcription Factor 
Journal of Neurogenetics  2012;26(1):89-102.
Nuclear factor of activated T cells (NFAT) is a calcium-responsive transcription factor. We describe here an NFAT-based neural tracing method—CaLexA (calcium-dependent nuclear import of Lex A)—for labeling active neurons in behaving animals. In this system, sustained neural activity induces nuclear import of the chimeric transcription factor LexA-VP16-NFAT, which in turn drives green fluorescent protein (GFP) reporter expression only in active neurons. We tested this system in Drosophila and found that volatile sex pheromones excite specific neurons in the olfactory circuit. Furthermore, complex courtship behavior associated with multi-modal sensory inputs activated neurons in the ventral nerve cord. This method harnessing the mechanism of activity-dependent nuclear import of a transcription factor can be used to identify active neurons in specific neuronal population in behaving animals.
PMCID: PMC3357894  PMID: 22236090
Drosophila; olfaction; antennal lobe; pheromone; NFAT; activity dependent; N2A; immediate-early gene
8.  Molecular Genetic Analysis of Sexual Rejection: Roles of Octopamine and Its Receptor OAMB in Drosophila Courtship Conditioning 
After Drosophila males are rejected by mated females, their subsequent courtship is inhibited even when encountering virgin females. Molecular mechanisms underlying courtship conditioning in the CNS are unclear. In this study, we find that tyramine β hydroxylase (TβH) mutant males unable to synthesize octopamine (OA) showed impaired courtship conditioning, which could be rescued by transgenic TβH expression in the CNS. Inactivation of octopaminergic neurons mimicked the TβH mutant phenotype. Transient activation of octopaminergic neurons in males not only decreased their courtship of virgin females, but also produced courtship conditioning. Single cell analysis revealed projection of octopaminergic neurons to the mushroom bodies. Deletion of the OAMB gene encoding an OA receptor expressed in the mushroom bodies disrupted courtship conditioning. Inactivation of neurons expressing OAMB also eliminated courtship conditioning. OAMB neurons responded robustly to male-specific pheromone cis-vaccenyl acetate in a dose-dependent manner. Our results indicate that OA plays an important role in courtship conditioning through its OAMB receptor expressed in a specific neuronal subset of the mushroom bodies.
PMCID: PMC3670963  PMID: 23055498
9.  Eliminating the scattering ambiguity in multifocal, multimodal multiphoton imaging systems 
Journal of biophotonics  2012;5(0):425-436.
Four images of Drosophila Melanogaster antennal lobe structure labeled with red fluorescent protein. The images are separated axially by 7 μm in depth, and were all acquired simultaneously from a single-element detector.
PMCID: PMC3670971  PMID: 22461190
10.  Presynaptic modulation of early olfactory processing in Drosophila 
Developmental neurobiology  2012;72(1):87-99.
Most animals are endowed with an olfactory system that is essential for finding foods, avoiding predators, and locating mating partners. The olfactory system must encode the identity and intensity of behaviorally relevant stimuli in a dynamic environmental landscape. How is olfactory information represented? How is a large dynamic range of odor concentrations represented in the olfactory system? How is this representation modulated to meet the demands of different internal physiological states? Recent studies have found that sensory terminals are important targets for neuromodulation. The emerging evidence suggests that presynaptic inhibition scales with sensory input and thus, provides a mechanism to increase dynamic range of odor representation. In addition, presynaptic facilitation could be a mechanism to alter behavioral responses in hungry animals. This review will focus on the GABAB receptor-mediated presynaptic inhibition, and neuropeptide-mediated presynaptic modulation in Drosophila.
PMCID: PMC3246013  PMID: 21688402
11.  The coding of temperature in the Drosophila brain 
Cell  2011;144(4):614-624.
Thermosensation is an indispensable sensory modality. Here, we study temperature coding in Drosophila, and show that temperature is represented by a spatial map of activity in the brain. First, we identify new TRP channels and demonstrate they function in the fly antenna to mediate the detection of cold stimuli. Next, we identify the hot-sensing neurons and show that hot and cold antennal receptors project onto distinct, but adjacent glomeruli in the Proximal-Antennal-Protocerebrum (PAP) forming a thermotopic map in the brain. We use two-photon imaging to reveal the functional segregation of hot and cold responses in the PAP, and show that silencing the hot- or cold-sensing neurons produces animals with distinct and discrete deficits in their behavioral responses to thermal stimuli. Together, these results demonstrate that dedicated populations of cells orchestrate behavioral responses to different temperature stimuli, and reveal a labeled-line logic for the coding of temperature information in the brain.
PMCID: PMC3336488  PMID: 21335241
12.  Serotonin Modulates Olfactory Processing in the Antennal Lobe of Drosophila 
Journal of neurogenetics  2009;23(4):366-377.
Sensory systems must be able to extract features of environmental cues within the context of the different physiological states of the organism and often temper their activity in a state-dependent manner via the process of neuromodulation. We examined the effects of the neuromodulator serotonin on a well-characterized sensory circuit, the antennal lobe of Drosophila melanogaster, using two-photon microscopy and the genetically expressed calcium indicator, G-CaMP. Serotonin enhances sensitivity of the antennal lobe output projection neurons in an odor-specific manner. For odorants that sparsely activate the antennal lobe, serotonin enhances projection neuron responses and causes an offset of the projection neuron tuning curve, most likely by increasing projection neuron sensitivity. However, for an odorant that evokes a broad activation pattern, serotonin enhances projection neuron responses in some, but not all, glomeruli. Further, serotonin enhances the responses of inhibitory local interneurons, resulting in a reduction of neurotransmitter release from the olfactory sensory neurons via GABAB receptor-dependent presynaptic inhibition, which may be a mechanism underlying the odorant-specific modulation of projection neuron responses. Our data suggest that the complexity of serotonin modulation in the antennal lobe accommodates coding stability in a glomerular pattern and flexible projection neuron sensitivity under different physiological conditions.
PMCID: PMC2850205  PMID: 19863268
olfaction; neuromodulation; serotonin; antennal lobes
13.  The Neural Substrate of Spectral Preference in Drosophila 
Neuron  2008;60(2):328-342.
Drosophila vision is mediated by inputs from three types of photoreceptor neurons: R1–R6 mediate achromatic motion detection while R7 and R8 constitute two chromatic channels. Neural circuits for processing chromatic information are not known. Here we identified the first-order interneurons downstream of the chromatic channels. Serial-EM revealed that small-field projection neurons Tm5 and Tm9 receive direct synaptic input from R7 and R8, respectively, and indirect input from R1–R6, qualifying them to function as color-opponent neurons. Wide-field Dm8 amacrine neurons receive input from 13–16 UV-sensing R7s and provide output to projection neurons. Using a combinatorial expression system to manipulate activity in different neuron subtypes, we determined that Dm8 neurons are both necessary and sufficient for phototaxis to ultraviolet in preference to green light. We propose that Dm8 sacrifices spatial resolution for sensitivity by relaying signals from multiple R7s to projection neurons, which then provide output to higher visual centers.
PMCID: PMC2665173  PMID: 18957224
14.  Lateral inhibition and concentration-invariant odor perception 
Journal of Biology  2009;8(1):4.
Sensory identity usually remains constant across a large intensity range. Vertebrates use lateral inhibition to match the sensitivity of retinal ganglion cells to the intensity of light. A new study published in Journal of Biology suggests that lateral inhibition in the Drosophila antennal lobe is similarly required for concentration-invariant perception of odors.
PMCID: PMC2656212  PMID: 19216732

Results 1-14 (14)