Synaptic transmission parallels neuromodulation in a central food-intake circuit

Abstract

NeuromedinU is a potent regulator of food intake and activity in mammals. In Drosophila , neurons producing the homologous neuropeptide hugin regulate feeding and locomotion in a similar manner. Here, we use EM-based reconstruction to generate the entire connectome of hugin-producing neurons in the Drosophila larval CNS. We demonstrate that hugin neurons use synaptic transmission in addition to peptidergic neuromodulation and identify acetylcholine as a key transmitter. Hugin neuropeptide and acetylcholine are both necessary for the regulatory effect on feeding. We further show that subtypes of hugin neurons connect chemosensory to endocrine system by combinations of synaptic and peptide-receptor connections. Targets include endocrine neurons producing DH44, a CRH-like peptide, and insulin-like peptides. Homologs of these peptides are likewise downstream of neuromedinU, revealing striking parallels in flies and mammals. We propose that hugin neurons are part of an ancient physiological control system that has been conserved at functional and molecular level.

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     van den Pol AN. Neuropeptide transmission in brain circuits. Neuron. 2012;76:98-115.

     Not in our library10.1016/j.neuron.2012.09.014

101. 101.

     Veenstra JA, Agricola HJ, Sellami A. Regulatory peptides in fruit fly midgut. Cell and Tissue Research. 2008;334:499-516.

     Not in our library10.1007/s00441-008-0708-3

102. 102.

     Venken KJ, Carlson JW, Schulze KL, Pan H, He Y, Spokony R, Wan KH, Koriabine M, de Jong PJ, White KP, Bellen HJ, Hoskins RA. Versatile P[acman] BAC libraries for transgenesis studies in Drosophila melanogaster. Nature Methods. 2009;6:431-434.

     Not in our library10.1038/nmeth.1331

103. 103.

     Venken KJ, He Y, Hoskins RA, Bellen HJ. P[acman]: a BAC transgenic platform for targeted insertion of large DNA fragments in D. melanogaster. Science. 2006;314:1747-1751.

     Not in our library10.1126/science.1134426

104. 104.

     Vilim FS, Cropper EC, Price DA, Kupfermann I, Weiss KR. Release of peptide cotransmitters in Aplysia: regulation and functional implications. Journal of Neuroscience. 1996;16:8105-8114.

     Not in our library10.1523/jneurosci.16-24-08105.1996

105. 105.

     Vogelstein JT, Park Y, Ohyama T, Kerr RA, Truman JW, Priebe CE, Zlatic M. Discovery of brainwide neural-behavioral maps via multiscale unsupervised structure learning. Science. 2014;344:386-392.

     Not in our library10.1126/science.1250298

106. 106.

     Vosshall LB, Stocker RF. Molecular architecture of smell and taste in Drosophila. Annual Review of Neuroscience. 2007;30:505-533.

     Not in our library10.1146/annurev.neuro.30.051606.094306

107. 107.

     Vosshall LB, Wong AM, Axel R. An olfactory sensory map in the fly brain. Cell. 2000;102:147-159.

     Not in our library10.1016/s0092-8674(00)00021-0

108. 108.

     Wang S, Zhao Y, Leiby M, Zhu J. A new positive/negative selection scheme for precise BAC recombineering. Molecular Biotechnology. 2009;42:110-116.

     Not in our library10.1007/s12033-009-9142-3

109. 109.

     Wang Y, Markram H, Goodman PH, Berger TK, Ma J, Goldman-Rakic PS. Heterogeneity in the pyramidal network of the medial prefrontal cortex. Nature Neuroscience. 2006;9:534-542.

     Not in our library10.1038/nn1670

110. 110.

     Wang Y, Pu Y, Shen P. Neuropeptide-gated perception of appetitive olfactory inputs in Drosophila larvae. Cell Reports. 2013;3:820-830.

     Not in our library10.1016/j.celrep.2013.02.003

111. 111.

     Warming S, Costantino N, Court DL, Jenkins NA, Copeland NG. Simple and highly efficient BAC recombineering using galK selection. Nucleic Acids Research. 2005;33:1-12.

     Not in our library10.1093/nar/gni035

112. 112.

     Weiss KR, Brezina V, Cropper EC, Heierhorst J, Hooper SL, Probst WC, Rosen SC, Vilim FS, Kupfermann I. Physiology and biochemistry of peptidergic cotransmission in Aplysia. Journal of Physiology Paris. 1993;87:141-151.

     Not in our library10.1016/0928-4257(93)90025-o

113. 113.

     Whim MD, Lloyd PE. Frequency-dependent release of peptide cotransmitters from identified cholinergic motor neurons in Aplysia. PNAS. 1989;86:9034-9038.

     Not in our library10.1073/pnas.86.22.9034

114. 114.

     Wren AM, Small CJ, Abbott CR, Jethwa PH, Kennedy AR, Murphy KG, Stanley SA, Zollner AN, Ghatei MA, Bloom SR. Hypothalamic actions of neuromedin U. Endocrinology. 2002;143:4227-4234.

     Not in our library10.1210/en.2002-220308

115. 115.

     Wu Q, Zhang Y, Xu J, Shen P. Regulation of hunger-driven behaviors by neural ribosomal S6 kinase in Drosophila. PNAS. 2005b;102:13289-13294.

     Not in our library10.1073/pnas.0501914102

116. 116.

     Wu Q, Zhao Z, Shen P. Regulation of aversion to noxious food by Drosophila neuropeptide Y- and insulin-like systems. Nature Neuroscience. 2005a;8:1350-1355.

     Not in our library10.1038/nn1540

117. 117.

     Yapici N, Cohn R, Schusterreiter C, Ruta V, Vosshall LB. A Taste Circuit that Regulates Ingestion by Integrating Food and Hunger Signals. Cell. 2016;165:715-729.

     Not in our library10.1016/j.cell.2016.02.061

118. 118.

     Yasuyama K, Salvaterra PM. Localization of choline acetyltransferase-expressing neurons in Drosophila nervous system. Microscopy Research and Technique. 1999;45:65-79.

     Not in our library10.1002/(sici)1097-0029(19990415)45:2<65::aid-jemt2>3.0.co;2-0

119. 119.

     Yoon H, Enquist LW, Dulac C. Olfactory inputs to hypothalamic neurons controlling reproduction and fertility. Cell. 2005;123:669-682.

     Not in our library10.1016/j.cell.2005.08.039

120. 120.

     Zeng H, Gragerov A, Hohmann JG, Pavlova MN, Schimpf BA, Xu H, Wu LJ, Toyoda H, Zhao MG, Rohde AD, Gragerova G, Onrust R, Bergmann JE, Zhuo M, Gaitanaris GA. Neuromedin U receptor 2-deficient mice display differential responses in sensory perception, stress, and feeding. Molecular and Cellular Biology. 2006;26:9352-9363.

     Not in our library10.1128/mcb.01148-06

Cited by papers we hold 9

• The connectome of an insect brain · 2023
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• Information flow, cell types and stereotypy in a full olfactory connectome · 2021
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• Complete Connectomic Reconstruction of Olfactory Projection Neurons in the Fly Brain · 2020
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• Metabolism and growth adaptation to environmental conditions in Drosophila · 2020
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• Integration of Parallel Opposing Memories Underlies Memory Extinction · 2018
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• Drosophila mushroom bodies integrate hunger and satiety signals to control innate food-seeking behavior · 2018
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• Functional architecture of reward learning in mushroom body extrinsic neurons of larval Drosophila · 2018
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• A Complete Electron Microscopy Volume of the Brain of Adult Drosophila melanogaster · 2018
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• Neuromodulatory connectivity defines the structure of a behavioral neural network · 2017
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