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  • 1. Altstein, Miriam
    et al.
    Nässel, Dick R
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen. Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Neuropeptide signaling in insects.2010Inngår i: Neuropeptide systems as targets for parasite and pest control / [ed] Timothy G. Geary and Aaron G. Maule, New York: Springer Science+Business Media , 2010, Vol. 692, s. 155-65Kapittel i bok, del av antologi (Annet vitenskapelig)
    Abstract [en]

    Neuropeptides represent the largest single class of signal compounds and are involved in regulation of development, growth, reproduction, metabolism and behavior of insects. Over the last few years there has been a tremendous increase in our knowledge of neuropeptide signaling due to genome sequencing, peptidomics, gene micro arrays, receptor characterization and targeted gene interference combined with physiological and behavior analysis. In this chapter we review the current knowledge of structure and distribution of insect neuropeptides and their receptors, as well as their diverse functions. We also discuss peptide biosynthesis, processing and expression, as well as classification of insect neuropeptides. Special attention is paid to the role insect neuropeptides play as potential targets for pest management and as a basis for development of insect control agents employing the rational/structural design approaches.

  • 2. Becnel, Jaime
    et al.
    Johnson, Oralee
    Luo, Jiangnan
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nichols, Charles D.
    The Serotonin 5-HT(7)Dro Receptor Is Expressed in the Brain of Drosophila, and Is Essential for Normal Courtship and Mating2011Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 6, s. e20800-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The 5-HT(7) receptor remains one of the less well characterized serotonin receptors. Although it has been demonstrated to be involved in the regulation of mood, sleep, and circadian rhythms, as well as relaxation of vascular smooth muscles in mammals, the precise mechanisms underlying these functions remain largely unknown. The fruit fly, Drosophila melanogaster, is an attractive model organism to study neuropharmacological, molecular, and behavioral processes that are largely conserved with mammals. Drosophila express a homolog of the mammalian 5-HT(7) receptor, as well as homologs for the mammalian 5-HT(1A), and 5-HT(2), receptors. Each fly receptor couples to the same effector pathway as their mammalian counterpart and have been demonstrated to mediate similar behavioral responses. Here, we report on the expression and function of the 5-HT(7)Dro receptor in Drosophila. In the larval central nervous system, expression is detected postsynaptically in discreet cells and neuronal circuits. In the adult brain there is strong expression in all large-field R neurons that innervate the ellipsoid body, as well as in a small group of cells that cluster with the PDF-positive LNvs neurons that mediate circadian activity. Following both pharmacological and genetic approaches, we have found that 5-HT(7)Dro activity is essential for normal courtship and mating behaviors in the fly, where it appears to mediate levels of interest in both males and females. This is the first reported evidence of direct involvement of a particular serotonin receptor subtype in courtship and mating in the fly.

  • 3.
    Birse, Ryan T.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Söderberg, Jeannette A. E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Luo, Jiangnan
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Winther, Åsa M. E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Regulation of insulin-producing cells in the adult Drosophila brain via the tachykinin peptide receptor DTKR2011Inngår i: Journal of Experimental Biology, ISSN 0022-0949, E-ISSN 1477-9145, Vol. 214, s. 4201-4208Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Drosophila insulin-like peptides (DILPs) play important hormonal roles in the regulation of metabolic carbohydrates and lipids, but also in reproduction, growth, stress resistance and aging. In spite of intense studies of insulin signaling in Drosophilag the regulation of DILP production and release in adult fruit flies is poorly understood. Here we investigated the role of Drosophila tachykinin-related peptides (DTKs) and their receptors, DTKR and NKD, in the regulation of brain insulin-producing cells (IPCs) and aspects of DILP signaling. First, we show DTK-immunoreactive axon terminations close to the presumed dendrites of the IPCs, and DTKR immunolabeling in these cells. Second, we utilized targeted RNA interference to knock down expression of the DTK receptor, DTKR, in IPCs and monitored the effects on Dilp transcript levels in the brains of fed and starved flies. Dilp2 and Dilp3, but not Dilp5, transcripts were significantly affected by DTKR knockdown in IPCs, both in fed and starved flies. Both Dilp2 and Dilp3 transcripts increased in fed flies with DTKR diminished in IPCs whereas at starvation the Dilp3 transcript plummeted and Dilp2 increased. We also measured trehalose and lipid levels as well as survival in transgene flies at starvation. Knockdown of DTKR in IPCs leads to increased lifespan and a faster decrease of trehalose at starvation but has no significant effect on lipid levels. Finally, we targeted the IPCs with RNAi or ectopic expression of the other DTK receptor, NKD, but found no effect on survival at starvation. Our results suggest that DTK signaling, via DTKR, regulates the brain IPCs.

  • 4.
    Carlsson, Mikael A.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Diesner, Max
    Philipps University, Marburg.
    Schachtner, Joachim
    Philipps University, Marburg.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Multiple neuropeptides in the Drosophila antennal lobe suggest complex modulatory circuits2010Inngår i: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 518, nr 16, s. 3359-3380Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The fruitfly, Drosophila, is dependent on its olfactory sense in food search and reproduction. Processing of odorant information takes place in the antennal lobes, the primary olfactory center in the insect brain. Besides classical neurotransmitters, earlier studies have indicated the presence of a few neuropeptides in the olfactory system. In the present study we made an extensive analysis of the expression of neuropeptides in the Drosophila antennal lobes by direct profiling using matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) mass spectrometry and immunocytochemistry. Neuropeptides from seven different precursor genes were unambiguously identified and their localization in neurons was subsequently revealed by immunocytochemistry. These were short neuropeptide F, tachykinin related peptide, allatostatin A, myoinhibitory peptide, SIFamide, IPNamide, and myosuppressin. The neuropeptides were expressed in subsets of olfactory sensory cells and different populations of local interneurons and extrinsic (centrifugal) neurons. In some neuron types neuropeptides were colocalized with classical neurotransmitters. Our findings suggest a huge complexity in peptidergic signaling in different circuits of the antennal lobe.

  • 5.
    Carlsson, Mikael A.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Enell, Lina E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Distribution of short neuropeptide F and its receptor in neuronal circuits related to feeding in larval Drosophila2013Inngår i: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 353, nr 3, s. 511-523Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Four forms of short neuropeptide F (sNPF1-4), derived from the gene snpf, have been identified in Drosophila and are known to act on a single G-protein-coupled receptor (sNPFR). Several functions have been suggested for sNPFs in Drosophila, including the regulation of feeding and growth in larvae, the control of insulin signalling and the modulation of neuronal circuits in adult flies. Furthermore, sNPF has been shown to act as a nutritional state-dependent neuromodulator in the olfactory system. The role of sNPF in the larval nervous system is less well known. To analyse sites of action of sNPF in the larva, we mapped the distribution of sNPF- and sNPFR-expressing neurons. In particular, we studied circuits associated with chemosensory inputs and systems involved in the regulation of feeding, including neurosecretory cell systems and the hypocerebral ganglion. We employed a combination of immunocytochemistry and enhancer trap and promoter Gal4 lines to drive green fluorescent protein. We found a good match between the distribution of the receptor and its ligand. However, several differences between the larval and adult systems were observed. Thus, neither sNPF nor its receptor was found in the olfactory (or other sensory) systems in the larva and cells producing insulin-like peptides did not co-express sNPFR, as opposed to results from adults. Moreover, sNPF was expressed in a subpopulation of Hugin cells (second-order gustatory neurons) only in adult flies. We propose that the differences in sNPF signalling between the developmental stages is explained by differences in their feeding behaviour.

  • 6.
    Carlsson, Mikael A.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Schäpers, Alexander
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Janz, Niklas
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Organization of the olfactory system of Nymphalidae butterflies2013Inngår i: Chemical Senses, ISSN 0379-864X, E-ISSN 1464-3553, Vol. 38, nr 4, s. 355-367Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Olfaction is in many species the most important sense, essential for food search, mate finding, and predator avoidance. Butterflies have been considered a microsmatic group of insects that mainly rely on vision due to their diurnal lifestyle. However, an emerging number of studies indicate that butterflies indeed use the sense of smell for locating food and oviposition sites. To unravel the neural substrates for olfaction, we performed an anatomical study of 2 related butterfly species that differ in food and host plant preference. We found many of the anatomical structures and pathways, as well as distribution of neuroactive substances, to resemble that of their nocturnal relatives among the Lepidoptera. The 2 species differed in the number of one type of olfactory sensilla, thus indicating a difference in sensitivity to certain compounds. Otherwise no differences could be observed. Our findings suggest that the olfactory system in Lepidoptera is well conserved despite the long evolutionary time since butterflies and moths diverged from a common ancestor.

  • 7.
    Dircksen, Heinrich
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Tesfai, Lily Kahsai
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Albus, Christina
    Nässel, Dick R
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Ion transport peptide splice forms in central and peripheral neurons throughout postembryogenesis of Drosophila melanogaster.2008Inngår i: The Journal of comparative neurology, ISSN 1096-9861, Vol. 509, nr 1, s. 23-41Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Ion transport peptides (ITPs) belong to a large arthropod neuropeptide family including crustacean hyperglycaemic hormones and are antidiuretic hormones in locusts. Because long and short ITP isoforms are generated by alternative splicing from a single gene in locusts and moths, we investigated whether similarly spliced gene products occur in the nervous system of Drosophila melanogaster throughout postembryogenesis. The itp gene CG13586 was reanalyzed, and we found three instead of the two previously annotated alternatively spliced mRNAs. These give rise to three different neuropeptides, two long C-terminally carboxylated isoforms (DrmITPL1 and DrmITPL2, both 87 amino acids) and one short amidated DrmITP (73 amino acids), which were partially identified biochemically. Immunocytochemistry and in situ hybridization reveal nine larval and 14 adult identified neurons: four pars lateralis neurosecretory neurons, three hindgut-innervating neurons in abdominal ganglia, and a stage-specific number of interneurons and peripheral bipolar neurons. The neurosecretory neurons persist throughout postembryogenesis, form release sites in corpora cardiaca, and invade corpora allata. One type of ITP-expressing interneuron exists only in the larval and prepupal subesophageal ganglia, whereas three types of interneurons in the adult brain arise in late pupae and invade circumscribed neuropils in superior median and lateral brain areas. One peripheral bipolar and putative sensory neuron type occurs in the larval, pupal, and adult preterminal abdominal segments. Although the neurosecretory neurons may release DrmITP and DrmITPL2 into the haemolymph, possible physiological roles of the hindgut-innervating and peripheral neurons as well as the interneurons are yet to be identified.

  • 8.
    Enell, Lina E.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Kapan, Neval
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Söderberg, Jeannette A.E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Kahsai, Lily
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Insulin Signaling, Lifespan and Stress Resistance Are Modulated by Metabotropic GABA Receptors on Insulin Producing Cells in the Brain of Drosophila2010Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, nr 12, s. e15780-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Insulin-like peptides (ILPs) regulate growth, reproduction, metabolic homeostasis, life span and stress resistance in worms, flies and mammals. A set of insulin producing cells (IPCs) in the Drosophila brain that express three ILPs (DILP2, 3 and 5) have been the main focus of interest in hormonal DILP signaling. Little is, however, known about factors that regulate DILP production and release by these IPCs. Here we show that the IPCs express the metabotropic GABA(B) receptor (GBR), but not the ionotropic GABA(A) receptor subunit RDL. Diminishing the GBR expression on these cells by targeted RNA interference abbreviates life span, decreases metabolic stress resistance and alters carbohydrate and lipid metabolism at stress, but not growth in Drosophila. A direct effect of diminishing GBR on IPCs is an increase in DILP immunofluorescence in these cells, an effect that is accentuated at starvation. Knockdown of irk3, possibly part of a G protein-activated inwardly rectifying K(+) channel that may link to GBRs, phenocopies GBR knockdown in starvation experiments. Our experiments suggest that the GBR is involved in inhibitory control of DILP production and release in adult flies at metabolic stress and that this receptor mediates a GABA signal from brain interneurons that may convey nutritional signals. This is the first demonstration of a neurotransmitter that inhibits insulin signaling in its regulation of metabolism, stress and life span in an invertebrate brain.

  • 9.
    Enell, Lina
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Hamasaka, Yasutaka
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Kolodziejczyk, Agata
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick R
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    gamma-Aminobutyric acid (GABA) signaling components in Drosophila: immunocytochemical localization of GABA(B) receptors in relation to the GABA(A) receptor subunit RDL and a vesicular GABA transporter.2007Inngår i: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 505, nr 1, s. 18-31Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    γ-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in insects and is widely distributed in the central nervous system (CNS). GABA acts on ion channel receptors (GABAAR) for fast inhibitory transmission and on G-protein-coupled ones (GABABR) for slow and modulatory action. We used immunocytochemistry to map GABABR sites in the Drosophila CNS and compared the distribution with that of the GABAAR subunit RDL. To identify GABAergic synapses, we raised an antiserum to the vesicular GABA transporter (vGAT). For general GABA distribution, we utilized an antiserum to glutamic acid decarboxylase (GAD1) and a gad1-GAL4 to drive green fluorescent protein. GABABR-immunoreactive (IR) punctates were seen in specific patterns in all major neuropils of the brain. Most abundant labeling was seen in the mushroom body calyces, ellipsoid body, optic lobe neuropils, and antennal lobes. The RDL distribution is very similar to that of GABABR-IR punctates. However, the mushroom body lobes displayed RDL-IR but not GABABR-IR material, and there were subtle differences in other areas. The vGAT antiserum labeled punctates in the same areas as the GABABR and appeared to display presynaptic sites of GABAergic neurons. Various GAL4 drivers were used to analyze the relation between GABABR distribution and identified neurons in adults and larvae. Our findings suggest that slow GABA transmission is very widespread in the Drosophila CNS and that fast RDL-mediated transmission generally occurs at the same sites. J. Comp. Neurol. 505:18–31, 2007.

  • 10. Gmeiner, Florian
    et al.
    Kolodziejczyk, Agata
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Yoshii, Taishi
    Rieger, Dirk
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Helfrich-Förster, Charlotte
    GABA(B) receptors play an essential role in maintaining sleep during the second half of the night in Drosophila melanogaster2013Inngår i: Journal of Experimental Biology, ISSN 0022-0949, E-ISSN 1477-9145, Vol. 216, nr 20, s. 3837-3843Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    GABAergic signalling is important for normal sleep in humans and flies. Here we advance the current understanding of GABAergic modulation of daily sleep patterns by focusing on the role of slow metabotropic GABA(B) receptors in the fruit fly Drosophila melanogaster. We asked whether GABA(B)-R2 receptors are regulatory elements in sleep regulation in addition to the already identified fast ionotropic Rdl GABA(A) receptors. By immunocytochemical and reporter-based techniques we show that the pigment dispersing factor (PDF)-positive ventrolateral clock neurons (LNv) express GABA(B)-R2 receptors. Downregulation of GABA(B)-R2 receptors in the large PDF neurons (l-LNv) by RNAi reduced sleep maintenance in the second half of the night, whereas sleep latency at the beginning of the night that was previously shown to depend on ionotropic Rdl GABA(A) receptors remained unaltered. Our results confirm the role of the l-LNv neurons as an important part of the sleep circuit in D. melanogaster and also identify the GABA(B)-R2 receptors as the thus far missing component in GABA-signalling that is essential for sleep maintenance. Despite the significant effects on sleep, we did not observe any changes in circadian behaviour in flies with downregulated GABA(B)-R2 receptors, indicating that the regulation of sleep maintenance via l-LNv neurons is independent of their function in the circadian clock circuit.

  • 11.
    Gáliková, Martina
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Dircksen, Heinrich
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    The thirsty fly: Ion transport peptide (ITP) is a novel endocrine regulator of water homeostasis in Drosophila2018Inngår i: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 14, nr 8, artikkel-id e1007618Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Animals need to continuously adjust their water metabolism to the internal and external conditions. Homeostasis of body fluids thus requires tight regulation of water intake and excretion, and a balance between ingestion of water and solid food. Here, we investigated how these processes are coordinated in Drosophila melanogaster. We identified the first thirst-promoting and anti-diuretic hormone of Drosophila, encoded by the gene Ion transport peptide (ITP). This endocrine regulator belongs to the CHH (crustacean hyperglycemic hormone) family of peptide hormones. Using genetic gain- and loss-of-function experiments, we show that ITP signaling acts analogous to the human vasopressin and renin-angiotensin systems; expression of ITP is elevated by dehydration of the fly, and the peptide increases thirst while repressing excretion, promoting thus conservation of water resources. ITP responds to both osmotic and desiccation stress, and dysregulation of ITP signaling compromises the fly’s ability to cope with these stressors. In addition to the regulation of thirst and excretion, ITP also suppresses food intake. Altogether, our work identifies ITP as an important endocrine regulator of thirst and excretion, which integrates water homeostasis with feeding of Drosophila.

  • 12.
    Hamasaka, Yasutaka
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick
    Mapping of serotonin, dopamine, and histamine in relation to different clock neurons in the brain of Drosophila2006Inngår i: The Journal of Comparative Neurology, ISSN 0021-9967, Vol. 494, nr 2, s. 314-330Artikkel i tidsskrift (Fagfellevurdert)
  • 13.
    Hamasaka, Yasutaka
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Rieger, Dirk
    Parmentier, Marie-Laure
    Grau, Yves
    Helfrich-Förster, Charlotte
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Glutamate and its metabotropic receptor in Drosophila clock neuron circuits2007Inngår i: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 505, nr 1, s. 32-45Artikkel i tidsskrift (Fagfellevurdert)
  • 14.
    Hamasaka, Yasutaka
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Wegener, Christian
    Nässel, Dick
    GABA modulates Drosophila circadian clock neurons via GABAB receptors and decreases in calcium2005Inngår i: Journal of Neurobiology, ISSN 0022-3034, Vol. 65, nr 3, s. 225-240Artikkel i tidsskrift (Fagfellevurdert)
  • 15. Hentze, Julie L.
    et al.
    Carlsson, Mikael A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Kondo, Shu
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Rewitz, Kim F.
    The Neuropeptide Allatostatin A Regulates Metabolism and Feeding Decisions in Drosophila2015Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, artikkel-id 11680Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Coordinating metabolism and feeding is important to avoid obesity and metabolic diseases, yet the underlying mechanisms, balancing nutrient intake and metabolic expenditure, are poorly understood. Several mechanisms controlling these processes are conserved in Drosophila, where homeostasis and energy mobilization are regulated by the glucagon-related adipokinetic hormone (AKH) and the Drosophila insulin-like peptides (DILPs). Here, we provide evidence that the Drosophila neuropeptide Allatostatin A (AstA) regulates AKH and DILP signaling. The AstA receptor gene, Dar-2, is expressed in both the insulin and AKH producing cells. Silencing of Dar-2 in these cells results in changes in gene expression and physiology associated with reduced DILP and AKH signaling and animals lacking AstA accumulate high lipid levels. This suggests that AstA is regulating the balance between DILP and AKH, believed to be important for the maintenance of nutrient homeostasis in response to changing ratios of dietary sugar and protein. Furthermore, AstA and Dar-2 are regulated differentially by dietary carbohydrates and protein and AstA-neuronal activity modulates feeding choices between these types of nutrients. Our results suggest that AstA is involved in assigning value to these nutrients to coordinate metabolic and feeding decisions, responses that are important to balance food intake according to metabolic needs.

  • 16. Ignell, Rickard
    et al.
    Root, Cory M
    Birse, Ryan T
    Wang, Jing W
    Nässel, Dick R
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Winther, Åsa M E
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Presynaptic peptidergic modulation of olfactory receptor neurons in Drosophila.2009Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, nr 31, s. 13070-13075Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The role of classical neurotransmitters in the transfer and processing of olfactory information is well established in many organisms. Neuropeptide action, however, is largely unexplored in any peripheral olfactory system. A subpopulation of local interneurons (LNs) in the Drosophila antannal lobe is peptidergic, expressing Drosophila tachykinins (DTKs). We show here that olfactory receptor neurons (ORNs) express the DTK receptor (DTKR). Using two-photon microscopy, we found that DTK applied to the antennal lobe suppresses presynaptic calcium and synaptic transmission in the ORNs. Furthermore, reduction of DTKR expression in ORNs by targeted RNA interference eliminates presynaptic suppression and alters olfactory behaviors. We detect opposite behavioral phenotypes after reduction and over expression of DTKR in ORNs. Our findings suggest a presynaptic inhibitory feedback to ORNs from peptidergic LNs in the antennal lobe.

  • 17. Jansen, Anna M
    et al.
    Nässel, Dick R
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Madsen, Kenneth L
    Jung, Anita G
    Gether, Ulrik
    Kjaerulff, Ole
    PICK1 expression in the Drosophila central nervous system primarily occurs in the neuroendocrine system.2009Inngår i: The Journal of comparative neurology, ISSN 1096-9861, Vol. 517, nr 3, s. 313-32Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The protein interacting with C kinase 1 (PICK1) protein was first identified as a novel binding partner for protein kinase C. PICK1 contains a membrane-binding BAR domain and a PDZ domain interacting with many synaptic proteins, including the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunit GluR2 and the dopamine transporter. PICK1 is strongly implicated in GluR2 trafficking and synaptic plasticity. In mammals, PICK1 has been characterized extensively in cell culture studies. To study PICK1 in an intact system, we characterized PICK1 expression immunohistochemically in the adult and larval Drosophila central nervous system. PICK1 was found in cell bodies in the subesophageal ganglion, the antennal lobe, the protocerebrum, and the neuroendocrine center pars intercerebralis. The cell types that express PICK1 were identified using GAL4 enhancer trap lines. The PICK1-expressing cells form a subpopulation of neurons. PICK1 immunoreactivity was neither detected in glutamatergic nor in dopaminergic neurons. Also, we observed PICK1 expression in only a few GABAergic neurons, located in the antennal lobe. In contrast, we detected robust PICK1 immunolabeling of peptidergic neurons in the neuroendocrine system, which express the transcription factor DIMM and the amidating enzyme peptidylglycine-alpha-hydroxylating monooxygenase (PHM). The PICK1-positive cells include neurosecretory cells that produce the insulin-like peptide dILP2. PICK1 expression in insulin-producing cells also occurs in mammals, as it was also observed in a rat insulinoma cell line derived from pancreatic beta-cells. At the subcellular level, PICK1 was found in the perinuclear zone but surprisingly not in synaptic domains. We conclude that PICK1 may serve an important role in the neuroendocrine system both in insects and vertebrates.

  • 18.
    Johard, Helena A D
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Yoishii, Taishi
    Dircksen, Heinrich
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Cusumano, Paola
    Rouyer, Francois
    Helfrich-Förster, Charlotte
    Nässel, Dick R
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Peptidergic clock neurons in Drosophila: ion transport peptide and short neuropeptide F in subsets of dorsal and ventral lateral neurons2009Inngår i: The Journal of comparative neurology, ISSN 1096-9861, Vol. 516, nr 1, s. 59-73Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    About 150 clock neurons are clustered in different groups in the brain of Drosophila. Among these clock neurons, some pigment-dispersing factor (PDF)-positive and PDF-negative lateral neurons (LNs) are principal oscillators responsible for bouts of activity in the morning and evening, respectively. The full complement of neurotransmitters in these morning and evening oscillators is not known. By using a screen for candidate neuromediators in clock neurons, we discovered ion transport peptide (ITP) and short neuropeptide F (sNPF) as novel neuropeptides in subpopulations of dorsal (LN(d)s) and ventral (s-LN(v)s) LNs. Among the six LN(d)s, ITP was found in one that coexpresses long neuropeptide F (NPF) and cryptochrome. We detected sNPF in two LN(d)s that also express cryptochrome; these cells are distinct from three LN(d)s expressing NPF. Thus, we have identified neuropeptides in five of the six LN(d)s. The three LN(d)s expressing cryptochrome, with either ITP or sNPF, are the only ones with additional projections to the accessory medulla. Among the five s-LN(v)s in the adult brain, ITP was detected in the fifth neuron that is devoid of PDF and sNPF in the four neurons that also express PDF. By using a choline acetyltransferase (Cha) Gal4, we detected Cha expression in the two sNPF producing LN(d)s and in the fifth s-LN(v). In the larval brain, two of the four PDF-producing s-LN(v)s coexpress sNPF. Our findings emphasize that the LN(d)s are heterogeneous both anatomically and with respect to content of neuropeptides, cryptochrome, and other markers and suggest diverse functions of these neurons.

  • 19.
    Johard, Helena
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen. Funktionell zoomorfologi.
    Enell, Lina
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen. Funktionell zoomorfologi.
    Gustafsson, Elisabeth
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen. Funktionell zoomorfologi.
    Trifilieff, Pierre
    Veenstra, Jan
    Nässel, Dick
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen. Funktionell zoomorfologi.
    Intrinsic neurons of Drosophila mushroom bodies express short neuropeptide F:: relations to extrinsic neurons expressing different neurotransmitters2008Inngår i: The Journal of comparative neurology, ISSN 0021-9967, Vol. 507, nr 4, s. 1479-96Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mushroom bodies constitute prominent paired neuropils in the brain of insects, known to be involved in higher olfactory processing and learning and memory. In Drosophila there are about 2,500 intrinsic mushroom body neurons, Kenyon cells, and a large number of different extrinsic neurons connecting the calyx, peduncle, and lobes to other portions of the brain. The neurotransmitter of the Kenyon cells has not been identified in any insect. Here we show expression of the gene snpf and its neuropeptide products (short neuropeptide F; sNPFs) in larval and adult Drosophila Kenyon cells by means of in situ hybridization and antisera against sequences of the precursor and two of the encoded peptides. Immunocytochemistry displays peptide in intrinsic neuronal processes in most parts of the mushroom body structures, except for a small core in the center of the peduncle and lobes and in the alpha'- and beta'-lobes. Weaker immunolabeling is seen in Kenyon cell bodies and processes in the calyx and initial peduncle and is strongest in the more distal portions of the lobes. We used different antisera and Gal4-driven green fluorescent protein to identify Kenyon cells and different populations of extrinsic neurons defined by their signal substances. Thus, we display neurotransmitter systems converging on Kenyon cells: neurons likely to utilize dopamine, tyramine/octopami

  • 20.
    Kahsai, Lily
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Carlsson, Mikael A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Winther, Åsa M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Distribution of metabotropic receptors of serotonin, dopamine, GABA, glutamate, and short neuropeptide F in the central complex of Drosophila2012Inngår i: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 208, s. 11-26Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The central complex is a prominent set of midline neuropils in the insect brain, known to be a higher locomotor control center that integrates visual inputs and modulates motor outputs. It is composed of four major neuropil structures, the ellipsoid body (EB), fan-shaped body (FB), noduli (NO), and protocerebral bridge (PB). In Drosophila different types of central complex neurons have been shown to express multiple neuropeptides and neurotransmitters; however, the distribution of corresponding receptors is not known. Here, we have mapped metabotropic, G-protein–coupled receptors (GPCRs) of several neurotransmitters to neurons of the central complex. By combining immunocytochemistry with GAL4 driven green fluorescent protein, we examined the distribution patterns of six different GPCRs: two serotonin receptor subtypes (5-HT1B and 5-HT7), a dopamine receptor (DopR), the metabotropic GABAB receptor (GABABR), the metabotropic glutamate receptor (DmGluRA) and a short neuropeptide F receptor (sNPFR1). Five of the six GPCRs were mapped to different neurons in the EB (sNPFR1 was not seen). Different layers of the FB express DopR, GABABR, DmGluRA, and sNPFR1, whereas only GABABR and DmGluRA were localized to the PB. Finally, strong expression of DopR and DmGluRA was detected in the NO. In most cases the distribution patterns of the GPCRs matched the expression of markers for their respective ligands. In some nonmatching regions it is likely that other types of dopamine and serotonin receptors or ionotropic GABA and glutamate receptors are expressed. Our data suggest that chemical signaling and signal modulation are diverse and highly complex in the different compartments and circuits of the Drosophila central complex. The information provided here, on receptor distribution, will be very useful for future analysis of functional circuits in the central complex, based on targeted interference with receptor expression.

  • 21.
    Kahsai, Lily
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Kapan, Neval
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Dircksen, Heinrich
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Winther, Åsa ME
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick R
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Metabolic stress responses in Drosophila are modulated by brain neurosecretory cells that produce multiple neuropeptides2010Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, nr 7, s. e11480-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In Drosophila, neurosecretory cells that release peptide hormones play a prominent role in the regulation of development, growth, metabolism, and reproduction. Several types of peptidergic neurosecretory cells have been identified in the brain of Drosophila with release sites in the corpora cardiaca and anterior aorta. We show here that in adult flies the products of three neuropeptide precursors are colocalized in five pairs of large protocerebral neurosecretory cells in two clusters (designated ipc-1 and ipc-2a): Drosophila tachykinin (DTK), short neuropeptide F (sNPF) and ion transport peptide (ITP). These peptides were detected by immunocytochemistry in combination with GFP expression driven by the enhancer trap Gal4 lines c929 and Kurs-6, both of which are expressed in ipc-1 and 2a cells. This mix of colocalized peptides with seemingly unrelated functions is intriguing and prompted us to initiate analysis of the function of the ten neurosecretory cells. We investigated the role of peptide signaling from large ipc-1 and 2a cells in stress responses by monitoring the effect of starvation and desiccation in flies with levels of DTK or sNPF diminished by RNA interference. Using the Gal4-UAS system we targeted the peptide knockdown specifically to ipc-1 and 2a cells with the c929 and Kurs-6 drivers. Flies with reduced DTK or sNPF levels in these cells displayed decreased survival time at desiccation and starvation, as well as increased water loss at desiccation. Our data suggest that homeostasis during metabolic stress requires intact peptide signaling by ipc-1 and 2a neurosecretory cells.

  • 22.
    Kahsai Tesfai, Lily
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Nässel, Dick
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Winther, Åsa ME
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Distribution of metabotropic receptors of serotonin, dopamine, GABA andglutamate in the central complex of DrosophilaManuskript (preprint) (Annet vitenskapelig)
  • 23.
    Kapan, Neval
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Lushchak, Oleh V.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Luo, Jiangnan
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Identified peptidergic neurons in the Drosophila brain regulate insulin-producing cells, stress responses and metabolism by coexpressed short neuropeptide F and corazonin2012Inngår i: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 69, nr 23, s. 4051-4066Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Insulin/IGF-like signaling regulates the development, growth, fecundity, metabolic homeostasis, stress resistance and lifespan in worms, flies and mammals. Eight insulin-like peptides (DILP1-8) are found in Drosophila. Three of these (DILP2, 3 and 5) are produced by a set of median neurosecretory cells (insulin-producing cells, IPCs) in the brain. Activity in the IPCs of adult flies is regulated by glucose and several neurotransmitters and neuropeptides. One of these, short neuropeptide F (sNPF), regulates food intake, growth and Dilp transcript levels in IPCs via the sNPF receptor (sNPFR1) expressed on IPCs. Here we identify a set of brain neurons that utilizes sNPF to activate the IPCs. These sNPF-expressing neurons (dorsal lateral peptidergic neurons, DLPs) also produce the neuropeptide corazonin (CRZ) and have axon terminations impinging on IPCs. Knockdown of either sNPF or CRZ in DLPs extends survival in flies exposed to starvation and alters carbohydrate and lipid metabolism. Expression of sNPF in DLPs in the sNPF mutant background is sufficient to rescue wild-type metabolism and response to starvation. Since CRZ receptor RNAi in IPCs affects starvation resistance and metabolism, similar to peptide knockdown in DLPs, it is likely that also CRZ targets the IPCs. Knockdown of sNPF, but not CRZ in DLPs decreases transcription of Dilp2 and 5 in the brain, suggesting different mechanisms of action on IPCs of the two co-released peptides. Our findings indicate that sNPF and CRZ co-released from a small set of neurons regulate IPCs, stress resistance and metabolism in adult Drosophila.

  • 24. Knapek, Stephan
    et al.
    Kahsai, Lily
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Winther, Åsa M. E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Tanimoto, Hiromu
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Short Neuropeptide F Acts as a Functional Neuromodulator for Olfactory Memory in Kenyon Cells of Drosophila Mushroom Bodies2013Inngår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 33, nr 12, s. 5340-+Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In insects, many complex behaviors, including olfactory memory, are controlled by a paired brain structure, the so-called mushroom bodies (MB). In Drosophila, the development, neuroanatomy, and function of intrinsic neurons of the MB, the Kenyon cells, have been well characterized. Until now, several potential neurotransmitters or neuromodulators of Kenyon cells have been anatomically identified. However, whether these neuroactive substances of the Kenyon cells are functional has not been clarified yet. Here we show that a neuropeptide precursor gene encoding four types of short neuropeptide F (sNPF) is required in the Kenyon cells for appetitive olfactory memory. We found that activation of Kenyon cells by expressing a thermosensitive cation channel (dTrpA1) leads to a decrease in sNPF immunoreactivity in the MB lobes. Targeted expression of RNA interference against the sNPF precursor in Kenyon cells results in a highly significant knockdown of sNPF levels. This knockdown of sNPF in the Kenyon cells impairs sugar-rewarded olfactory memory. This impairment is not due to a defect in the reflexive sugar preference or odor response. Consistently, knockdown of sNPF receptors outside theMBcauses deficits in appetitive memory. Altogether, these results suggest that sNPF is a functional neuromodulator released by Kenyon cells.

  • 25.
    Kolodziejczyk, Agata
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nichols, Charles
    Nässel, Dick
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Distribution of serotonin receptors in the visual system of the DrosophilaManuskript (preprint) (Annet vitenskapelig)
  • 26.
    Kolodziejczyk, Agata
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    A novel wide-field neuron with branches in the lamina of the Drosophila visual system expresses myoinhibitory peptide and may be associated with the clock2011Inngår i: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 343, nr 2, s. 357-369Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Although neuropeptides are widespread throughout the central nervous system of the fruifly Drosophila, no records exist of peptidergic neurons in the first synaptic region of the visual system, the lamina. Here, we describe a novel type of neuron that has wide-field tangential arborizations just distal to the lamina neuropil and that expresses myoinhibitory peptide (MIP). The cell bodies of these neurons, designated lateral MIP-immunoreactive optic lobe (LMIo) neurons, lie anteriorly at the base of the medulla of the optic lobe. The LMIo neurons also arborize in several layers of the medulla and in the dorso-lateral and lateral protocerebrum. Since the LMIo resemble LN(v) clock neurons, we have investigated the relationships between these two sets of neurons by combining MIP-immunolabeling with markers for two of the clock genes, viz., Cryptochrome and Timeless, or with antisera to two peptides expressed in clock neurons, viz., pigment-dispersing factor and ion transport peptide. LMIo neurons do not co-express any of these clock neuron markers. However, branches of LMIo and clock neurons overlap in several regions. Furthermore, the varicose lamina branches of LMIo neurons superimpose those of two large bilateral serotonergic neurons. The close apposition of the terminations of MIP- and serotonin-producing neurons distal to the lamina suggests that they have the same peripheral targets. Our data indicate that the LMIo neurons are not bona fide clock neurons, but they may be associated with the clock system and regulate signaling peripherally in the visual system.

  • 27.
    Kolodziejczyk, Agata
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Myoinhibitory peptide (MIP) immunoreactivity in the visual system of the blowfly Calliphora vomitoria in relation to putative clock neurons and serotonergic neurons2011Inngår i: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 345, nr 1, s. 125-135Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A few types of peptidergic clock neurons have been identified in the fruitfly Drosophila, whereas in blowflies, only pigment-dispersing factor (PDF)-immunoreactive lateral ventral clock neurons (LNvs) have been described. In blowflies, but not Drosophila, a subset of these PDF-expressing neurons supplies axon branches to a region outside the synaptic layer of the lamina, the most peripheral optic lobe neuropil. In Drosophila, similar lamina processes are instead supplied by non-clock neurons (LMIo) that express myoinhibitory peptide (MIP). We have investigated the distribution of MIP-immunoreactive neurons in the visual system of the blowfly Calliphora vomitoria and found neurons resembling the three LMIos, but without processes to the lamina. In Calliphora, PDF-immunoreactive processes of LNvs in the lamina closely impinge on branching serotonin-immunoreactive axon terminations in the same region. We have also identified, in the blowfly, two types of putative clock neurons that label with an antiserum to ion-transport peptide (ITP). The presence of serotonin-immunoreactive neurons supplying processes to the lamina seems to be a conserved feature in dipteran flies. The morphology of the two types of ITP-immunoreactive clock neurons might also be conserved. However, peptidergic neurons with branches converging on the serotonin-immunoreactive neurons in the lamina are of different morphological types and express PDF in blowflies and MIP in Drosophila. The central circuitry of these PDF- and MIP-expressing neurons probably differs; consequently, whether their convergence on serotonergic neurons subserves similar functions in the two species is unclear.

  • 28.
    Kolodziejczyk, Agata
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Sun, Xuejun
    Meinertzhagen, Ian A.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Glutamate, GABA and acetylcholine signaling components in the lamina of the Drosophila visual system2008Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 3, nr 5, s. e2110-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Synaptic connections of neurons in the Drosophila lamina, the most peripheral synaptic region of the visual system, have been comprehensively described. Although the lamina has been used extensively as a model for the development and plasticity of synaptic connections, the neurotransmitters in these circuits are still poorly known. Thus, to unravel possible neurotransmitter circuits in the lamina of Drosophila we combined Gal4 driven green fluorescent protein in specific lamina neurons with antisera to γ-aminobutyric acid (GABA), glutamic acid decarboxylase, a GABAB type of receptor, L-glutamate, a vesicular glutamate transporter (vGluT), ionotropic and metabotropic glutamate receptors, choline acetyltransferase and a vesicular acetylcholine transporter. We suggest that acetylcholine may be used as a neurotransmitter in both L4 monopolar neurons and a previously unreported type of wide-field tangential neuron (Cha-Tan). GABA is the likely transmitter of centrifugal neurons C2 and C3 and GABAB receptor immunoreactivity is seen on these neurons as well as the Cha-Tan neurons. Based on an rdl-Gal4 line, the ionotropic GABAA receptor subunit RDL may be expressed by L4 neurons and a type of tangential neuron (rdl-Tan). Strong vGluT immunoreactivity was detected in α-processes of amacrine neurons and possibly in the large monopolar neurons L1 and L2. These neurons also express glutamate-like immunoreactivity. However, antisera to ionotropic and metabotropic glutamate receptors did not produce distinct immunosignals in the lamina. In summary, this paper describes novel features of two distinct types of tangential neurons in the Drosophila lamina and assigns putative neurotransmitters and some receptors to a few identified neuron types.

  • 29.
    Kubrak, Olga I.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Kucerova, Lucie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Theopold, Ulrich
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nylin, Sören
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Characterization of Reproductive Dormancy in Male Drosophila melanogaster2016Inngår i: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 7, artikkel-id 572Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Insects are known to respond to seasonal and adverse environmental changes by entering dormancy, also known as diapause. In some insect species, including Drosophila melanogaster, dormancy occurs in the adult organism and postpones reproduction. This adult dormancy has been studied in female flies where it is characterized by arrested development of ovaries, altered nutrient stores, lowered metabolism, increased stress and immune resistance and drastically extended lifespan. Male dormancy, however, has not been investigated in D. melanogaster, and its physiology is poorly known in most insects. Here we show that unmated 3-6 h old male flies placed at low temperature (11 degrees C) and short photoperiod (10 Light:14 Dark) enter a state of dormancy with arrested spermatogenesis and development of testes and male accessory glands. Over 3 weeks of diapause we see a dynamic increase in stored carbohydrates and an initial increase and then a decrease in lipids. We also note an up-regulated expression of genes involved in metabolism, stress responses and innate immunity. Interestingly, we found that male flies that entered reproductive dormancy do not attempt to mate females kept under non-diapause conditions (25 degrees C, 1 2L:1 2D), and conversely non-diapausing males do not mate females in dormancy. In summary, our study shows that male D. melanogaster can enter reproductive dormancy. However, our data suggest that dormant male flies deplete stored nutrients faster than females, studied earlier, and that males take longer to recover reproductive capacity after reintroduction to non-diapause conditions.

  • 30.
    Kubrak, Olga I.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Kucerova, Lucie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Theopold, Ulrich
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    The Sleeping Beauty: How Reproductive Diapause Affects Hormone Signaling, Metabolism, Immune Response and Somatic Maintenance in Drosophila melanogaster2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 11, artikkel-id e113051Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Some organisms can adapt to seasonal and other environmental challenges by entering a state of dormancy, diapause. Thus, insects exposed to decreased temperature and short photoperiod enter a state of arrested development, lowered metabolism, and increased stress resistance. Drosophila melanogaster females can enter a shallow reproductive diapause in the adult stage, which drastically reduces organismal senescence, but little is known about the physiology and endocrinology associated with this dormancy, and the genes involved in its regulation. We induced diapause in D. melanogaster and monitored effects over 12 weeks on dynamics of ovary development, carbohydrate and lipid metabolism, as well as expression of genes involved in endocrine signaling, metabolism and innate immunity. During diapause food intake diminishes drastically, but circulating and stored carbohydrates and lipids are elevated. Gene transcripts of glucagonand insulin-like peptides increase, and expression of several target genes of these peptides also change. Four key genes in innate immunity can be induced by infection in diapausing flies, and two of these, drosomycin and cecropin A1, are upregulated by diapause independently of infection. Diapausing flies display very low mortality, extended lifespan and decreased aging of the intestinal epithelium. Many phenotypes induced by diapause are reversed after one week of recovery from diapause conditions. Furthermore, mutant flies lacking specific insulin-like peptides (dilp5 and dilp2-3) display increased diapause incidence. Our study provides a first comprehensive characterization of reproductive diapause in D. melanogaster, and evidence that glucagon- and insulin-like signaling are among the key regulators of the altered physiology during this dormancy.

  • 31.
    Kubrak, Olga I.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Lushchak, Oleh V.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Zandawala, Meet
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Systemic corazonin signalling modulates stress responses and metabolism in Drosophila2016Inngår i: Open Biology, ISSN 2046-2441, E-ISSN 2046-2441, Vol. 6, nr 11, artikkel-id 160152Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Stress triggers cellular and systemic reactions in organisms to restore homeostasis. For instance, metabolic stress, experienced during starvation, elicits a hormonal response that reallocates resources to enable food search and readjustment of physiology. Mammalian gonadotropin-releasing hormone (GnRH) and its insect orthologue, adipokinetic hormone (AKH), are known for their roles in modulating stress-related behaviour. Here we show that corazonin (Crz), a peptide homologous to AKH/GnRH, also alters stress physiology in Drosophila. The Crz receptor (CrzR) is expressed in salivary glands and adipocytes of the liver-like fat body, and CrzR knockdown targeted simultaneously to both these tissues increases the fly's resistance to starvation, desiccation and oxidative stress, reduces feeding, alters expression of transcripts of Drosophila insulin-like peptides (DILPs), and affects gene expression in the fat body. Furthermore, in starved flies, CrzR-knockdown increases circulating and stored carbohydrates. Thus, our findings indicate that elevated systemic Crz signalling during stress coordinates increased food intake and diminished energy stores to regain metabolic homeostasis. Our study suggests that an ancient stress-peptide in Urbilateria evolved to give rise to present-day GnRH, AKH and Crz signalling systems.

  • 32.
    Kubrak, Olga I.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nylin, Sören
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Flatt, Thomas
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Leimar, Olof
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Adaptation to fluctuating environments in a selection experiment with Drosophila melanogaster2017Inngår i: Ecology and Evolution, ISSN 2045-7758, E-ISSN 2045-7758, Vol. 7, nr 11, s. 3796-3807Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A fundamental question in life-history evolution is how organisms cope with fluctuating environments, including variation between stressful and benign conditions. For short-lived organisms, environments commonly vary between generations. Using a novel experimental design, we exposed wild-derived Drosophila melanogaster to three different selection regimes: one where generations alternated between starvation and benign conditions, and starvation was always preceded by early exposure to cold; another where starvation and benign conditions alternated in the same way, but cold shock sometimes preceded starvation and sometimes benign conditions; and a third where conditions were always benign. Using six replicate populations per selection regime, we found that selected flies increased their starvation resistance, most strongly for the regime where cold and starvation were reliably combined, and this occurred without decreased fecundity or extended developmental time. The selected flies became stress resistant, displayed a pronounced increase in early life food intake and resource storage. In contrast to previous experiments selecting for increased starvation resistance in D. melanogaster, we did not find increased storage of lipids as the main response, but instead that, in particular for females, storage of carbohydrates was more pronounced. We argue that faster mobilization of carbohydrates is advantageous in fluctuating environments and conclude that the phenotype that evolved in our experiment corresponds to a compromise between the requirements of stressful and benign environments.

  • 33.
    Kucerova, Lucie
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Kubrak, Olga I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Bengtsson, Jonas M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Strnad, Hynek
    Nylin, Sören
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Theopold, Ulrich
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Slowed aging during reproductive dormancy is reflected in genome-wide transcriptome changes in Drosophila melanogaster2016Inngår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 17, artikkel-id 50Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: In models extensively used in studies of aging and extended lifespan, such as C. elegans and Drosophila, adult senescence is regulated by gene networks that are likely to be similar to ones that underlie lifespan extension during dormancy. These include the evolutionarily conserved insulin/IGF, TOR and germ line-signaling pathways. Dormancy, also known as dauer stage in the larval worm or adult diapause in the fly, is triggered by adverse environmental conditions, and results in drastically extended lifespan with negligible senescence. It is furthermore characterized by increased stress resistance and somatic maintenance, developmental arrest and reallocated energy resources. In the fly Drosophila melanogaster adult reproductive diapause is additionally manifested in arrested ovary development, improved immune defense and altered metabolism. However, the molecular mechanisms behind this adaptive lifespan extension are not well understood. Results: A genome wide analysis of transcript changes in diapausing D. melanogaster revealed a differential regulation of more than 4600 genes. Gene ontology (GO) and KEGG pathway analysis reveal that many of these genes are part of signaling pathways that regulate metabolism, stress responses, detoxification, immunity, protein synthesis and processes during aging. More specifically, gene readouts and detailed mapping of the pathways indicate downregulation of insulin-IGF (IIS), target of rapamycin (TOR) and MAP kinase signaling, whereas Toll-dependent immune signaling, Jun-N-terminal kinase (JNK) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways are upregulated during diapause. Furthermore, we detected transcriptional regulation of a large number of genes specifically associated with aging and longevity. Conclusions: We find that many affected genes and signal pathways are shared between dormancy, aging and lifespan extension, including IIS, TOR, JAK/STAT and JNK. A substantial fraction of the genes affected by diapause have also been found to alter their expression in response to starvation and cold exposure in D. melanogaster, and the pathways overlap those reported in GO analysis of other invertebrates in dormancy or even hibernating mammals. Our study, thus, shows that D. melanogaster is a genetically tractable model for dormancy in other organisms and effects of dormancy on aging and lifespan.

  • 34. Lebreton, Sébastien
    et al.
    Trona, Federica
    Borrero-Echeverry, Felipe
    Bilz, Florian
    Grabe, Veit
    Becher, Paul G.
    Carlsson, Mikael A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Hansson, Bill S.
    Sachse, Silke
    Witzgall, Peter
    Feeding regulates sex pheromone attraction and courtship in Drosophila females2015Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, artikkel-id 13132Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In Drosophila melanogaster, gender-specific behavioural responses to the male-produced sex pheromone cis-vaccenyl acetate (cVA) rely on sexually dimorphic, third-order neural circuits. We show that nutritional state in female flies modulates cVA perception in first-order olfactory neurons. Starvation increases, and feeding reduces attraction to food odour, in both sexes. Adding cVA to food odour, however, maintains attraction in fed females, while it has no effect in males. Upregulation of sensitivity and behavioural responsiveness to cVA in fed females is paralleled by a strong increase in receptivity to male courtship. Functional imaging of the antennal lobe (AL), the olfactory centre in the insect brain, shows that olfactory input to DA1 and VM2 glomeruli is also modulated by starvation. Knocking down insulin receptors in neurons converging onto the DA1 glomerulus suggests that insulin-signalling partly controls pheromone perception in the AL, and adjusts cVA attraction according to nutritional state and sexual receptivity in Drosophila females.

  • 35.
    Liao, Sifang
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Broughton, Susan
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Behavioral Senescence and Aging-Related Changes in Motor Neurons and Brain Neuromodulator Levels Are Ameliorated by Lifespan-Extending Reproductive Dormancy in Drosophila2017Inngår i: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 11, artikkel-id 111Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The lifespan of Drosophila melanogaster can be extended substantially by inducing reproductive dormancy (also known as diapause) by lowered temperature and short days. This increase of longevity is accompanied by lowered metabolism and increased stress tolerance. We ask here whether behavioral senescence is ameliorated during adult dormancy. To study this we kept flies for seven or more weeks in normal rearing conditions or in diapause conditions and compared to 1-week-old flies in different behavioral assays of sleep, negative geotaxis and exploratory walking. We found that the senescence of geotaxis and locomotor behavior seen under normal rearing conditions was negligible in flies kept in dormancy. The normal senescence of rhythmic activity and sleep patterns during the daytime was also reduced by adult dormancy. Investigating the morphology of specific neuromuscular junctions (NMJs), we found that changes normally seen with aging do not take place in dormant flies. To monitor age-associated changes in neuronal circuits regulating activity rhythms, sleep and walking behavior we applied antisera to tyrosine hydroxylase (TH), serotonin and several neuropeptides to examine changes in expression levels and neuron morphology. In most neuron types the levels of stored neuromodulators decreased during normal aging, but not in diapause treated flies. No signs of neurodegeneration were seen in either condition. Our data suggest that age-related changes in motor neurons could be the cause of part of the behavioral senescence and that this is ameliorated by reproductive diapause. Earlier studies established a link between age-associated decreases in neuromodulator levels and behavioral decline that could be rescued by overexpression of neuromodulator. Thus, it is likely that the retained levels of neuromodulators in dormant flies alleviate behavioral senescence.

  • 36.
    Liao, Sifang
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Post, Stephanie
    A. Veenstra, Jan
    Tatar, Marc
    Nässel, Dick
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Drosophila insulin-like peptide 1 (DILP1) promotes organismal growth during non-feeding stagesManuskript (preprint) (Annet vitenskapelig)
  • 37.
    Liu, Yiting
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Liao, Sifang
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Veenstra, Jan A.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Drosophila insulin-like peptide 1 (DILP1) is transiently expressed during non-feeding stages and reproductive dormancy2016Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikkel-id 26620Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The insulin/insulin-like growth factor signaling pathway is evolutionarily conserved in animals, and is part of nutrient-sensing mechanisms that control growth, metabolism, reproduction, stress responses, and lifespan. In Drosophila, eight insulin-like peptides (DILP1-8) are known, six of which have been investigated in some detail, whereas expression and functions of DILP1 and DILP4 remain enigmatic. Here we demonstrate that dilp1/DILP1 is transiently expressed in brain insulin producing cells (IPCs) from early pupa until a few days of adult life. However, in adult female flies where diapause is triggered by low temperature and short days, within a time window 0-10h post-eclosion, the dilp1/DILP1 expression remains high for at least 9 weeks. The dilp1 mRNA level is increased in dilp2, 3, 5 and dilp6 mutant flies, indicating feedback regulation. Furthermore, the DILP1 expression in IPCs is regulated by short neuropeptide F, juvenile hormone and presence of larval adipocytes. Male dilp1 mutant flies display increased lifespan and reduced starvation resistance, whereas in female dilp1 mutants oviposition is reduced. Thus, DILP1 is expressed in non-feeding stages and in diapausing flies, is under feedback regulation and appears to play sex-specific functional roles.

  • 38.
    Liu, Yiting
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Luo, Jiangnan
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen. National Institutes of Health, Bethesda, MD, USA.
    Carlsson, Mikael A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Serotonin and insulin-like peptides modulate leucokinin-producing neurons that affect feeding and water homeostasis in Drosophila2015Inngår i: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 523, nr 12, s. 1840-1863Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Metabolic homeostasis and water balance is maintained by tight hormonal and neuronal regulation. In Drosophila, insulin-like peptides (DILPs) are key regulators of metabolism, and the neuropeptide leucokinin (LK) is a diuretic hormone that also modulates feeding. However, it is not known whether LK and DILPs act together to regulate feeding and water homeostasis. Because LK neurons express the insulin receptor (dInR), we tested functional links between DILP and LK signaling in feeding and water balance. Thus, we performed constitutive and conditional manipulations of activity in LK neurons and insulin-producing cells (IPCs) in adult flies and monitored food intake, responses to desiccation, and peptide expression levels. We also measured in vivo changes in LK and DILP levels in neurons in response to desiccation and drinking. Our data show that activated LK cells stimulate diuresis in vivo, and that LK and IPC signaling affect food intake in opposite directions. Overexpression of the dInR in LK neurons decreases the LK peptide levels, but only caused a subtle decrease in feeding, and had no effect on water balance. Next we demonstrated that LK neurons express the serotonin receptor 5-HT1B. Knockdown of this receptor in LK neurons diminished LK expression, increased desiccation resistance, and diminished food intake. Live calcium imaging indicates that serotonin inhibits spontaneous activity in abdominal LK neurons. Our results suggest that serotonin via 5-HT1B diminishes activity in the LK neurons and thereby modulates functions regulated by LK peptide, but the action of the dInR in these neurons remains less clear.

  • 39.
    Liu, Yiting
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Luo, Jiangnan
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Multiple effects of the transcription factor Dimmed and the insulin receptor on growth and differentiation vary among neuron types and developmental stages in DrosophilaManuskript (preprint) (Annet vitenskapelig)
  • 40.
    Liu, Yiting
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Luo, Jiangnan
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    The Drosophila Transcription Factor Dimmed Affects Neuronal Growth and Differentiation in Multiple Ways Depending on Neuron Type and Developmental Stage2016Inngår i: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 9, artikkel-id 97Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Growth of postmitotic neurons occurs during different stages of development, including metamorphosis, and may also be part of neuronal plasticity and regeneration. Recently we showed that growth of post-mitotic neuroendocrine cells expressing the basic helix loop helix (bHLH) transcription factor Dimmed (Dimm) in Drosophila could be regulated by insulin/IGF signaling and the insulin receptor (dlnR). Dimm is also known to confer a secretory phenotype to neuroendocrine cells and can be part of a combinatorial code specifying terminal differentiation in peptidergic neurons. To further understand the mechanisms of Down function we ectopically expressed Dimm or Dimm together with dlnR in a wide range of Dimm positive and Dimm negative peptidergic neurons, sensory neurons, interneurons, motor neurons, and gut endocrine cells. We provide further evidence that dlnR mediated cell growth occurs in a Dimm dependent manner and that one source of insulin-like peptide (DILP) for dlnR mediated cell growth in the OHS is DILP6 from glial cells. Expressing both Dimm and dlnR in Dimm negative neurons induced growth of cell bodies, whereas dlnR alone did not. We also found that Dimm alone can regulate cell growth depending on specific cell type. This may be explained by the finding that the dlnR is a direct target of Dimm. Conditional gene targeting experiments showed that Dimm alone could affect cell growth in certain neuron types during metamorphosis or in the adult stage. Another important finding was that ectopic Dimm inhibits apoptosis of several types of neurons normally destined for programmed cell death (PCD). Taken together our results suggest that Dimm plays multiple transcriptional roles at different developmental stages in a cell type-specific manner. In some cell types ectopic Dimm may act together with resident combinatorial code transcription factors and affect terminal differentiation, as well as act in transcriptional networks that participate in long term maintenance of neurons which might lead to blocked apoptosis.

  • 41.
    Luo, Jiangnan
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Becnel, Jaime
    Nichols, Charles D
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Insulin-producing cells in the brain of adult Drosophila are regulated by the serotonin 5-HT(1A) receptor.2012Inngår i: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 69, nr 3, s. 471-484Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Insulin signaling regulates lifespan, reproduction, metabolic homeostasis, and resistance to stress in the adult organism. In Drosophila, there are seven insulin-like peptides (DILP1-7). Three of these (DILP2, 3 and 5) are produced in median neurosecretory cells of the brain, designated IPCs. Previous work has suggested that production or release of DILPs in IPCs can be regulated by a factor secreted from the fat body as well as by neuronal GABA or short neuropeptide F. There is also evidence that serotonergic neurons may regulate IPCs. Here, we investigated mechanisms by which serotonin may regulate the IPCs. We show that the IPCs in adult flies express the 5-HT(1A), but not the 5-HT(1B) or 5-HT(7) receptors, and that processes of serotonergic neurons impinge on the IPC branches. Knockdown of 5-HT(1A) in IPCs by targeted RNA interference (RNAi) leads to increased sensitivity to heat, prolonged recovery after cold knockdown and decreased resistance to starvation. Lipid metabolism is also affected, but no effect on growth was seen. Furthermore, we show that DILP2-immunolevels in IPCs increase after 5-HT(1A) knockdown; this is accentuated by starvation. Heterozygous 5-HT(1A) mutant flies display the same phenotype in all assays, as seen after targeted 5-HT(1A) RNAi, and flies fed the 5-HT(1A) antagonist WAY100635 display reduced lifespan at starvation. Our findings suggest that serotonin acts on brain IPCs via the 5-HT(1A) receptor, thereby affecting their activity and probably insulin signaling. Thus, we have identified a second inhibitory pathway regulating IPC activity in the Drosophila brain.

  • 42.
    Luo, Jiangnan
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Liu, Yiting
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Roles of insulin-like peptides and leucokinin in feeding and water homeostasis in DrosophilaManuskript (preprint) (Annet vitenskapelig)
  • 43.
    Luo, Jiangnan
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Liu, Yiting
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Insulin/IGF-Regulated Size Scaling of Neuroendocrine Cells Expressing the bHLH Transcription Factor Dimmed in Drosophila2013Inngår i: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, nr 12, artikkel-id e1004052Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Neurons and other cells display a large variation in size in an organism. Thus, a fundamental question is how growth of individual cells and their organelles is regulated. Is size scaling of individual neurons regulated post-mitotically, independent of growth of the entire CNS? Although the role of insulin/IGF-signaling (IIS) in growth of tissues and whole organisms is well established, it is not known whether it regulates the size of individual neurons. We therefore studied the role of IIS in the size scaling of neurons in the Drosophila CNS. By targeted genetic manipulations of insulin receptor (dInR) expression in a variety of neuron types we demonstrate that the cell size is affected only in neuroendocrine cells specified by the bHLH transcription factor DIMMED (DIMM). Several populations of DIMM-positive neurons tested displayed enlarged cell bodies after overexpression of the dInR, as well as PI3 kinase and Akt1 (protein kinase B), whereas DIMM-negative neurons did not respond to dInR manipulations. Knockdown of these components produce the opposite phenotype. Increased growth can also be induced by targeted overexpression of nutrient-dependent TOR (target of rapamycin) signaling components, such as Rheb (small GTPase), TOR and S6K (S6 kinase). After Dimm-knockdown in neuroendocrine cells manipulations of dInR expression have significantly less effects on cell size. We also show that dInR expression in neuroendocrine cells can be altered by up or down-regulation of Dimm. This novel dInR-regulated size scaling is seen during postembryonic development, continues in the aging adult and is diet dependent. The increase in cell size includes cell body, axon terminations, nucleus and Golgi apparatus. We suggest that the dInR-mediated scaling of neuroendocrine cells is part of a plasticity that adapts the secretory capacity to changing physiological conditions and nutrient-dependent organismal growth.

  • 44.
    Luo, Jiangnan
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Liu, Yiting
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Transcriptional Reorganization of Drosophila Motor Neurons and Their Muscular Junctions toward a Neuroendocrine Phenotype by the bHLH Protein Dimmed2017Inngår i: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 10, artikkel-id 260Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Neuroendocrine cells store and secrete bulk amounts of neuropeptides, and display morphological and molecular characteristics distinct from neurons signaling with classical neurotransmitters. In Drosophila the transcription factor Dimmed (Dimm), is a prime organizer of neuroendocrine capacity in a majority of the peptidergic neurons. These neurons display large cell bodies and extensive axon terminations that commonly do not form regular synapses. We ask which molecular compartments of a neuron are affected by Dimm to generate these morphological features. Thus, we ectopically expressed Dimm in glutamatergic, Dimm-negative, motor neurons and analyzed their characteristics in the central nervous system and the neuromuscular junction. Ectopic Dimm results in motor neurons with enlarged cell bodies, diminished dendrites, larger axon terminations and boutons, as well as reduced expression of synaptic proteins both pre and post-synaptically. Furthermore, the neurons display diminished vesicular glutamate transporter, and signaling components known to sustain interactions between the developing axon termination and muscle, such as wingless and frizzled are down regulated. Ectopic co-expression of Dimm and the insulin receptor augments most of the above effects on the motor neurons. In summary, ectopic Dimm expression alters the glutamatergic motor neuron phenotype toward a neuroendocrine one, both pre- and post-synaptically. Thus, Dimm is a key organizer of both secretory capacity and morphological features characteristic of neuroendocrine cells, and this transcription factor affects also post- synaptic proteins.

  • 45.
    Luo, Jiangnan
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Lushchak, Oleh
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Insulin producing cells are differentially regulated by serotonin and octopamine receptorsManuskript (preprint) (Annet vitenskapelig)
  • 46.
    Luo, Jiangnan
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Lushchak, Oleh V.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Goergen, Philip
    Williams, Michael J.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Drosophila Insulin-Producing Cells Are Differentially Modulated by Serotonin and Octopamine Receptors and Affect Social Behavior2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 6, s. e99732-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A set of 14 insulin-producing cells (IPCs) in the Drosophila brain produces three insulin-like peptides (DILP2, 3 and 5). Activity in IPCs and release of DILPs is nutrient dependent and controlled by multiple factors such as fat body-derived proteins, neurotransmitters, and neuropeptides. Two monoamine receptors, the octopamine receptor OAMB and the serotonin receptor 5-HT1A, are expressed by the IPCs. These receptors may act antagonistically on adenylate cyclase. Here we investigate the action of the two receptors on activity in and output from the IPCs. Knockdown of OAMB by targeted RNAi led to elevated Dilp3 transcript levels in the brain, whereas 5-HT1A knockdown resulted in increases of Dilp2 and 5. OAMB-RNAi in IPCs leads to extended survival of starved flies and increased food intake, whereas 5-HT1A-RNAi produces the opposite phenotypes. However, knockdown of either OAMB or 5-HT1A in IPCs both lead to increased resistance to oxidative stress. In assays of carbohydrate levels we found that 5-HT1A knockdown in IPCs resulted in elevated hemolymph glucose, body glycogen and body trehalose levels, while no effects were seen after OAMB knockdown. We also found that manipulations of the two receptors in IPCs affected male aggressive behavior in different ways and 5-HT1A-RNAi reduced courtship latency. Our observations suggest that activation of 5-HT1A and OAMB signaling in IPCs generates differential effects on Dilp transcription, fly physiology, metabolism and social interactions. However the findings do not support an antagonistic action of the two monoamines and their receptors in this particular system.

  • 47.
    Lushchak, Oleh V.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Carlsson, Mikael A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Food odors trigger an endocrine response that affects food ingestion and metabolism2015Inngår i: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 72, nr 16, s. 3143-3155Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Food odors stimulate appetite and innate food-seeking behavior in hungry animals. The smell of food also induces salivation and release of gastric acid and insulin. Conversely, sustained odor exposure may induce satiation. We demonstrate novel effects of food odors on food ingestion, metabolism and endocrine signaling in Drosophila melanogaster. Acute exposure to attractive vinegar odor triggers a rapid and transient increase in circulating glucose, and a rapid upregulation of genes encoding the glucagon-like hormone adipokinetic hormone (AKH), four insulin-like peptides (DILPs) and some target genes in peripheral tissues. Sustained exposure to food odors, however, decreases food intake. Hunger-induced strengthening of synaptic signaling from olfactory sensory neurons (OSNs) to brain neurons increases food-seeking behavior, and conversely fed flies display reduced food odor sensitivity and feeding. We show that increasing the strength of OSN signaling chronically by genetic manipulation of local peptide neuromodulation reduces feeding, elevates carbohydrates and diminishes lipids. Furthermore, constitutively strengthened odor sensitivity altered gene transcripts for AKH, DILPs and some of their targets. Thus, we show that food odor can induce a transient anticipatory endocrine response, and that boosted sensitivity to this odor affects food intake, as well as metabolism and hormonal signaling.

  • 48. Nachman, Ronald J.
    et al.
    Mahdian, Kamran
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Isaac, R. Elwyn
    Pryor, Nan
    Smagghe, Guy
    Biostable multi-Aib analogs of tachykinin-related peptides demonstrate potent oral aphicidal activity in the pea aphid Acyrthosiphon pisum (Hemiptera : Aphidae)2011Inngår i: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 32, nr 3, s. 587-594Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The tachykinin-related peptides (TRPs) are multifunctional neuropeptides found in a variety of arthropod species, including the pea aphid Acyrthosiphon pisum (Hemiptera: Aphidae). Two new biostable TRP analogs containing multiple, sterically hindered Aib residues were synthesized and found to exhibit significantly enhanced resistance to hydrolysis by angiotensin converting enzyme and neprilysin, membrane-bound enzymes that degrade and inactivate natural TRPs. The two biostable analogs were also found to retain significant myostimulatory activity in an isolated cockroach hindgut preparation, the bioassay used to isolate and identify the first members of the TRP family. Indeed one of the analogs (Leuma-TRP-Aib-1) matched the potency and efficacy of the natural, parent TRP peptide in this myotropic bioassay. The two biostable TRP analogs were further fed in solutions of artificial diet to the pea aphid over a period of 3 days and evaluated for antifeedant and aphicidal activity and compared with the effect of treatment with three natural, unmodified TRPs. The two biostable multi-Aib TRP analogs were observed to elicit aphicidal effects within the first 24h. In contrast natural, unmodified TRPs, including two that are native to the pea aphid, demonstrated little or no activity. The most active analog, double-Aib analog Leuma-TRP-Aib-1 (pEA[Aib]SGFL[Aib]VR-NH(2)), featured aphicidal activity calculated at an LC(50) of 0.0083nmol/μl (0.0087μg/μl) and an LT(50) of 1.4 days, matching or exceeding the potency of commercially available aphicides. The mechanism of this activity has yet to be established. The aphicidal activity of the biostable TRP analogs may result from disruption of digestive processes by interfering with gut motility patterns and/or with fluid cycling in the gut; processes shown to be regulated by the TRPs in other insects. These active TRP analogs and/or second generation analogs offer potential as environmentally friendly pest aphid control agents.

  • 49. Neupert, Susanne
    et al.
    Johard, Helena A D
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick R
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Predel, Reinhard
    Single-cell peptidomics of drosophila melanogaster neurons identified by Gal4-driven fluorescence.2007Inngår i: Anal Chem, ISSN 0003-2700, Vol. 79, nr 10, s. 3690-4Artikkel i tidsskrift (Fagfellevurdert)
  • 50.
    Nässel, Dick
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen. Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi.
    Neuropeptide signaling near and far: how localized and timed is the action of neuropeptides in brain circuits?2009Inngår i: Invertebrate neuroscience, ISSN 1439-1104, Vol. 9, s. 57-75Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Neuropeptide signaling is functionally very diverse and one and the same neuropeptide may act as a circulating neurohormone, as a locally released neuromodulator or even as a cotransmitter of classical fast-acting neurotransmitters. Thus, neuropeptides are produced by a huge variety of neuron types in different parts of the nervous system. Within the central nervous system (CNS) there are numerous types of peptidergic interneurons, some with strictly localized and patterned branching morphologies, others with widespread and diffuse arborizations. From morphology alone it is often difficult to predict the sphere of influence of a peptidergic interneuron, especially since it has been shown that neuropeptides can diffuse over tens of micrometers within neuropils, and that peptides probably are released exclusively in perisynaptic (or non-synaptic) regions. This review addresses some questions related to peptidergic signaling in the insect CNS. How diverse are the spatial relations between peptidergic neurons and their target neurons and what determines the sphere of functional influence? At one extreme there is volume transmission and at the other targeted cotransmission at synapses. Also temporal aspects of peptidergic signaling are of interest: how transient are peptidergic messages? Factors important for these spatial and temporal aspects of peptidergic signaling are proximity between release sites and cognate receptors, distribution of peptidase activity that can terminate peptide action and colocalization of other neuroactive compounds in the presynaptic peptidergic neuron (and corresponding receptors in target neurons). Other factors such as expression of different channel types, receptor inactivation mechanisms and second messenger systems probably also contribute to the diversity in temporal properties of peptide signaling.

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