1 Review Lessons From Sleeping Flies: Insights from Drosophila melanogaster on the Neuronal Circuitry and Importance of Sleep Sheetal Potdar and Vasu Sheeba Behavioural Neurogenetics Laboratory, Evolutionary and Organismal Biology Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, 560064, India Abstract: Sleep is a highly conserved behavior whose role is as yet unknown, although it is widely acknowledged as being important. Here we provide an overview of many vital questions regarding this behavior, that have been addressed in recent years using the genetically tractable model organism Drosophila melanogaster in several laboratories around the world. Rest in D. melanogaster has been compared to mammalian sleep and its homeostatic and circadian regulation have been shown to be controlled by intricate neuronal circuitry involving circadian clock neurons, mushroom bodies, and pars intercerebralis, although their exact roles are not entirely clear. We draw attention to the yet unanswered questions and contradictions regarding the nature of the interactions between the brain regions implicated in the control of sleep. Dopamine, octopamine, γ-aminobutyric acid (GABA), and serotonin are the chief neurotransmitters identified as functioning in different limbs of this circuit, either promoting arousal or sleep by modulating membrane excitability of underlying neurons. Some studies have suggested that certain brain areas may contribute towards both sleep and arousal depending on activation of specific subsets of neurons. Signaling pathways implicated in the sleep circuit include cyclic adenosine monophosphate (cAMP) and epidermal growth factor receptor–extracellular signal–regulated kinase (EGFR-ERK) signaling pathways that operate on different neural substrates. Thus, this field of research appears to be on the cusp of many new and exciting findings that may eventually help in understanding how this complex physiological phenomenon is modulated by various neuronal circuits in the brain. Finally, some efforts to approach the “Holy Grail” of why we sleep have been summarized. Keywords: arousal, circadian, dopamine, Drosophila melanogaster, homeostasis, neuronal circuit, octopamine, sleep Abbreviations: 5-HT, Serotonin; 5-HT1B, Serotonin Receptor 1B; ACER, Angiotensin-converting enzyme receptor; ATF-2, Activating transcription factor-2; ATP, Adenosine triphosphate; BiP, Immunoglobulin binding protein; cAMP, Cyclic adenosine monophosphate; CC, Central complex; Clk, Clock; cry, cryptochrome; cyc, cycle; CycA, Cyclin A; DA, Dopamine; dDA1, Drosophila dopamine receptor A1; dDAT, Drosophila dopamine transporter; dFMR1, Drosophila fragile X mental retardation; DN, Dorsal neurons; EB, Ellipsoid body; EEG, Electroencephalogram; EGFR, Epidermal growth factor receptor; ERK, Extracellular signal–regulated kinase; Fabp7, Fatty acid binding protein 7; FB, Fan-shaped body; fmn, fumin; GABA, γ-Aminobutyric acid; HCN, Hyperpolariza- tion-activated cyclic nucleotide-gated; Hk, Hyperkinetic; inc, insomniac; JNK, c-Jun N-terminal kinase; LFP, Local field potential; l-LN v , Large ventral lateral neurons; lnc-RNA, Long noncoding RNA; LN d , Dorsal lateral neuorns; LPN, Lateral posterior neurons; lsd2, Lipid storage droplet 2; PKG, c-GMP-dependent protein kinase C; bmm , Brummer; for, Foraging; LTM, Long-term memo- ry; MARCM, Mosaic analysis with repressible cell marker; MB, Mushroom bodies; METH, Methamphetamine; mns, minisleep; NO, Noduli; NREM, Non-random eye movement; OA, Octopamine; OAMB, Octopaminergic receptor in mushroom body; PDF, Pigment dispersing factor; PDFR, Pigment dispersing factor receptor; per, period; PI, Pars intercerebralis; PKA, Protein kinase A; PPL1, Protocerebral posterior lateral 1; PPM3, Protocerebral posterior medial 3; QTL, Quantitative trait loci; qvr, quiver; RDL, Resistance to Dieldrin; REM, Random eye movement; Rut, Rutabaga; Sh, Shaker; s-LN v , Small ventral lateral neurons; sss, sleepless; SWA, Slow-wave activity; SWS, Slow-wave sleep; tim, timeless; TRPA1, Transient receptor potential A1; TTFL, Transcriptional translational feedback loop; yar, Yellow achaete intergenic RNA. (Received 14 December 2012; accepted 28 March 2013) Address correspondence to Vasu Sheeba, Behavioural Neurogenetics Laboratory, Evolutionary and Organismal Biology Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O., Bangalore 560 064, India. E-mail: sheeba@jncasr.ac.in J. Neurogenetics, Early Online: 1–20 Copyright © 2013 Informa Healthcare USA, Inc. ISSN: 0167-7063 print/1563-5260 online DOI: 10.3109/01677063.2013.791692 J Neurogenet Downloaded from informahealthcare.com by Jawaharlal Nehru Centre for Advanced Scientific Research on 05/23/13 For personal use only.