Flies, genes, and learning.

Flies can learn. For the past 25 years, researchers have isolated mutants, engineered mutants with transgenes, and tested likely suspect mutants from other screens for learning ability. There have been notable surprises-conventional second messenger systems co-opted for intricate associative learning tasks, two entirely separate forms of long-term memory, a cell-adhesion molecule that is necessary for short-term memory. The most recent surprise is the mechanistic kinship revealed between learning and addictive drug response behaviors in flies. The flow of new insight is likely to quicken with the completion of the fly genome and the arrival of more selective methods of gene expression.

[1]  R. W. Siegel,et al.  Conditioned responses in courtship behavior of normal and mutant Drosophila. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[2]  R. Davis,et al.  Characterization of the memory gene dunce of Drosophila melanogaster. , 1991, Journal of molecular biology.

[3]  T. Préat,et al.  The Drosophila putative kinase Linotte (Derailed) prevents central brain axons from converging on a newly described interhemispheric ring , 1998, Mechanisms of Development.

[4]  Uli Mü Prolonged Activation of cAMP-Dependent Protein Kinase during Conditioning Induces Long-Term Memory in Honeybees , 2000 .

[5]  Liqun Luo,et al.  Mosaic Analysis with a Repressible Cell Marker for Studies of Gene Function in Neuronal Morphogenesis , 1999, Neuron.

[6]  R. Murphey,et al.  Presynaptic Calcium/Calmodulin-Dependent Protein Kinase II Regulates Habituation of a Simple Reflex in AdultDrosophila , 1998, The Journal of Neuroscience.

[7]  W. Quinn,et al.  Reward learning in normal and mutant Drosophila. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Mosaic Analysis with a Repressible Neurotechnique Cell Marker for Studies of Gene Function in Neuronal Morphogenesis , 1999 .

[9]  P. Reinhart,et al.  Distinct effects of Ca2+ and voltage on the activation and deactivation of cloned Ca(2+)‐activated K+ channels. , 1995, The Journal of physiology.

[10]  M Heisenberg,et al.  Associative odor learning in Drosophila abolished by chemical ablation of mushroom bodies. , 1994, Science.

[11]  W. Fantl,et al.  Activation of Raf-1 by 14-3-3 proteins , 1994, Nature.

[12]  W. Gehring,et al.  Homeotic genes and the homeobox. , 1986, Annual review of genetics.

[13]  J. Hirsh,et al.  Type II cAMP-dependent Protein Kinase-deficientDrosophila Are Viable but Show Developmental, Circadian, and Drug Response Phenotypes* , 2000, The Journal of Biological Chemistry.

[14]  W. Quinn,et al.  Conditioning of leg position in normal and mutant Drosophila. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[15]  W. Harris,et al.  Conditioned behavior in Drosophila melanogaster. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Ronald L. Davis,et al.  Preferential expression of the drosophila rutabaga gene in mushroom bodies, neural centers for learning in insects , 1992, Neuron.

[17]  F. Fadda,et al.  Chronic ethanol consumption:from neuroadaptation to neurodegeneration , 1998, Progress in Neurobiology.

[18]  T. Tully,et al.  The Drosophila mutation turnip has pleiotropic behavioral effects and does not specifically affect learning. , 1997, Learning & memory.

[19]  J. Dubnau,et al.  Gene discovery in Drosophila: new insights for learning and memory. , 1998, Annual review of neuroscience.

[20]  E R Kandel,et al.  Genetic approaches to memory storage. , 1999, Trends in genetics : TIG.

[21]  W. Quinn,et al.  The amnesiac Gene Product Is Expressed in Two Neurons in the Drosophila Brain that Are Critical for Memory , 2000, Cell.

[22]  A Borst,et al.  Drosophila mushroom body mutants are deficient in olfactory learning. , 1985, Journal of neurogenetics.

[23]  J. Collinge Their Causes and Molecular Basis , 2001 .

[24]  P S Harper,et al.  Molecular genetics of neurofibromatosis type 1 (NF1). , 1996, Journal of medical genetics.

[25]  Ronald L. Davis,et al.  Leonardo, a Drosophila 14-3-3 Protein Involved in Learning, Regulates Presynaptic Function , 1997, Neuron.

[26]  Y. Zhong,et al.  Requirement of Drosophila NF1 for activation of adenylyl cyclase by PACAP38-like neuropeptides. , 1997, Science.

[27]  Y. Zhong,et al.  Synaptic plasticity in Drosophila memory and hyperexcitable mutants: role of cAMP cascade , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[28]  J. Crabbe,et al.  Pavlovian conditioning of drug-induced changes in body temperature. , 1983, Pharmacology & therapeutics.

[29]  T. Tully,et al.  Defective Learning in Mutants of the Drosophila Gene for a Regulatory Subunit of cAMP-Dependent Protein Kinase , 1997, The Journal of Neuroscience.

[30]  J. Renger,et al.  Activity-dependent Functional and Developmental Plasticity of Drosophila Neurons , 1998 .

[31]  T. Tully,et al.  Ethanol Intoxication in Drosophila: Genetic and Pharmacological Evidence for Regulation by the cAMP Signaling Pathway , 1998, Cell.

[32]  Jay Hirsh,et al.  Stereotypic behavioral responses to free-base cocaine and the development of behavioral sensitization in Drosophila , 1998, Current Biology.

[33]  Y. Zhong Mediation of PACAP–like neuropeptide transmission by coactivation of Ras/Raf and cAMP signal transduction pathways in Drosophila , 1995, Nature.

[34]  P. Best,et al.  Spatial processing in the brain: the activity of hippocampal place cells. , 2001, Annual review of neuroscience.

[35]  Tim Tully,et al.  nalyot, a Mutation of the Drosophila Myb-Related Adf1 Transcription Factor, Disrupts Synapse Formation and Olfactory Memory , 2000, Neuron.

[36]  W. Quinn,et al.  cAMP-dependent protein kinase and the disruption of learning in transgenic flies , 1991, Neuron.

[37]  K. Irie,et al.  Stimulatory effects of yeast and mammalian 14-3-3 proteins on the Raf protein kinase. , 1994, Science.

[38]  Ronald L. Davis,et al.  Integrin-Mediated Regulation of Synaptic Morphology, Transmission, and Plasticity , 2000, The Journal of Neuroscience.

[39]  R. Davis,et al.  Genetic dissection of the learning/memory gene dunce of Drosophila melanogaster. , 1993, Genes & development.

[40]  W. Quinn,et al.  A neuropeptide gene defined by the Drosophila memory mutant amnesiac. , 1995, Science.

[41]  W. Quinn,et al.  Radish, a Drosophila mutant deficient in consolidated memory. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[42]  T. Aigaki,et al.  The gene search system. A method for efficient detection and rapid molecular identification of genes in Drosophila melanogaster. , 1999, Genetics.

[43]  M Heisenberg,et al.  Vision affects mushroom bodies and central complex in Drosophila melanogaster. , 1997, Learning & memory.

[44]  I. Levitan,et al.  A Dynamically Regulated 14–3–3, Slob, and Slowpoke Potassium Channel Complex in Drosophila Presynaptic Nerve Terminals , 1999, Neuron.

[45]  T. Tully,et al.  CREB as a Memory Modulator: induced expression of a dCREB2 activator isoform enhances long-term memory in drosophila , 1995, Cell.

[46]  N. Strausfeld,et al.  The organization of extrinsic neurons and their implications in the functional roles of the mushroom bodies in Drosophila melanogaster Meigen. , 1998, Learning & memory.

[47]  R. Greenspan,et al.  The Diversity of Calcium/Calmodulin‐Dependent Protein Kinase II Isoforms in Drosophila Is Generated by Alternative Splicing of a Single Gene , 1993, Journal of neurochemistry.

[48]  Ronald L. Davis,et al.  At least two genes reside within a large intron of the dunce gene of Drosophila , 1987, Nature.

[49]  J. Weiner,et al.  Time, Love, Memory: A Great Biologist and His Quest for the Origins of Behavior , 1999 .

[50]  T. Tully,et al.  latheo Encodes a Subunit of the Origin Recognition Complex and Disrupts Neuronal Proliferation and Adult Olfactory Memory When Mutant , 1999, Neuron.

[51]  Elisabeth Folkers,et al.  Visual learning and memory of Drosophila melanogaster wild type CS and the mutants dunce1, amnesiac, turnip and rutabaga , 1982 .

[52]  W. Quinn,et al.  Deficient protein kinase C activity in turnip, a Drosophila learning mutant. , 1991, The Journal of biological chemistry.

[53]  M. Sofroniew,et al.  Nerve growth factor signaling, neuroprotection, and neural repair. , 2001, Annual review of neuroscience.

[54]  N. Strausfeld,et al.  Evolution, discovery, and interpretations of arthropod mushroom bodies. , 1998, Learning & memory.

[55]  T. Préat,et al.  IDENTIFICATION OF LINOTTE, A NEW GENE AFFECTING LEARNING AND MEMORY IN DROSOPHILA MELANOGASTER , 2007, Journal of neurogenetics.

[56]  T. Tully,et al.  Molecular cloning of linotte in Drosophila: A novel gene that functions in adults during associative learning , 1995, Neuron.

[57]  Y. Zhong,et al.  A neurofibromatosis-1-regulated pathway is required for learning in Drosophila , 2000, Nature.

[58]  T. Préat,et al.  Genetic dissection of consolidated memory in Drosophila , 1994, Cell.

[59]  Richard D Fetter,et al.  Genetic Dissection of Structural and Functional Components of Synaptic Plasticity. I. Fasciclin II Controls Synaptic Stabilization and Growth , 1996, Neuron.

[60]  Richard O. Hynes,et al.  Integrins: Versatility, modulation, and signaling in cell adhesion , 1992, Cell.

[61]  D. Julius,et al.  The vanilloid receptor: a molecular gateway to the pain pathway. , 2001, Annual review of neuroscience.

[62]  W. Quinn,et al.  The Drosophila memory mutant amnesiac , 1979, Nature.

[63]  Ronald L. Davis,et al.  Olfactory Learning Deficits in Mutants for leonardo, a Drosophila Gene Encoding a 14-3-3 Protein , 1996, Neuron.

[64]  M Heisenberg,et al.  Localization of a short-term memory in Drosophila. , 2000, Science.

[65]  Tim Tully,et al.  Associative Learning Disrupted by Impaired Gs Signaling in Drosophila Mushroom Bodies , 1996, Science.

[66]  Y. Rong,et al.  Gene targeting by homologous recombination in Drosophila. , 2000, Science.

[67]  T. Tully,et al.  Effects of a conditional Drosophila PKA mutant on olfactory learning and memory. , 1996, Learning & memory.

[68]  H. Vaudry,et al.  Pituitary adenylate cyclase-activating polypeptide and its receptors: from structure to functions. , 2000, Pharmacological reviews.

[69]  J. Hirsh,et al.  Ectopic G-protein expression in dopamine and serotonin neurons blocks cocaine sensitization in Drosophila melanogaster , 2000, Current Biology.

[70]  R. Davis,et al.  Tripartite mushroom body architecture revealed by antigenic markers. , 1998, Learning & memory.

[71]  Ronald L. Davis,et al.  The Drosophila learning and memory gene rutabaga encodes a Ca 2+ calmodulin -responsive , 1992, Cell.

[72]  J. Hirsh,et al.  The trace amine tyramine is essential for sensitization to cocaine in Drosophila , 1999, Current Biology.

[73]  Ralph J. Greenspan,et al.  Inhibition of calcium/calmodulin-dependent protein kinase in drosophila disrupts behavioral plasticity , 1993, Neuron.

[74]  S. Smerdon,et al.  Structure of a 14-3-3 protein and implications for coordination of multiple signalling pathways , 1995, Nature.

[75]  W. Quinn,et al.  Learning in Normal and Mutant Drosophila Larvae , 1979, Science.

[76]  A. Hoffmann,et al.  Genetic divergence under uniform selection. II. Different responses to selection for knockdown resistance to ethanol among Drosophila melanogaster populations and their replicate lines. , 1986, Genetics.

[77]  U. Heberlein,et al.  Genetic control of acute ethanol-induced behaviors in Drosophila. , 2000, Alcoholism, clinical and experimental research.

[78]  T. Isobe,et al.  Identification of the Site of Interaction of the 14-3-3 Protein with Phosphorylated Tryptophan Hydroxylase (*) , 1995, The Journal of Biological Chemistry.

[79]  J. Mohler Developmental genetics of the Drosophila egg. I. Identification of 59 sex-linked cistrons with maternal effects on embryonic development. , 1977, Genetics.

[80]  C. Goodman,et al.  Genetic Dissection of Structural and Functional Components of Synaptic Plasticity. III. CREB Is Necessary for Presynaptic Functional Plasticity , 1996, Neuron.

[81]  R. Davis,et al.  Molecular analysis of cDNA clones and the corresponding genomic coding sequences of the Drosophila dunce+ gene, the structural gene for cAMP phosphodiesterase. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[82]  Ronald L. Davis,et al.  Defect in cyclic AMP phosphodiesterase due to the dunce mutation of learning in Drosophila melanogaster , 1981, Nature.

[83]  D. Yamamoto,et al.  The Drosophila mushroom body is a quadruple structure of clonal units each of which contains a virtually identical set of neurones and glial cells. , 1997, Development.

[84]  M. Livingstone,et al.  Mutations in the dopa decarboxylase gene affect learning in Drosophila. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[85]  R. Menzel,et al.  Associative learning modifies neural representations of odors in the insect brain , 1999, Nature Neuroscience.

[86]  S. Hyman,et al.  Addiction, Dopamine, and the Molecular Mechanisms of Memory , 2000, Neuron.

[87]  B. Guptaroy,et al.  Alternative splicing of Drosophila calcium/calmodulin-dependent protein kinase II regulates substrate specificity and activation. , 2000, Brain research. Molecular brain research.

[88]  T. Tully,et al.  Developmental Expression of an amn+ Transgene Rescues the Mutant Memory Defect of amnesiacAdults , 1999, The Journal of Neuroscience.

[89]  K. Broadie,et al.  A role for PS integrins in morphological growth and synaptic function at the postembryonic neuromuscular junction of Drosophila. , 1999, Development.

[90]  Ronald L. Davis,et al.  The cyclic AMP phosphodiesterase encoded by the drosophila dunce gene is concentrated in the mushroom body neuropil , 1991, Neuron.

[91]  Ronald L. Davis,et al.  Integrin-mediated short-term memory in Drosophila , 1998, Nature.

[92]  M. Livingstone,et al.  Loss of calcium/calmodulin responsiveness in adenylate cyclase of rutabaga, a Drosophila learning mutant , 1984, Cell.

[93]  T. Tully,et al.  latheo, a Drosophila Gene Involved in Learning, Regulates Functional Synaptic Plasticity , 1999, Neuron.

[94]  T. Préat,et al.  The Drosophila learning and memory gene linotte encodes a putative receptor tyrosine kinase homologous to the human RYK gene product , 1995, FEBS letters.

[95]  R. Menzel Memory dynamics in the honeybee , 1999, Journal of Comparative Physiology A.

[96]  N. Strausfeld,et al.  Mushroom bodies of the cockroach: Activity and identities of neurons recorded in freely moving animals , 1998, The Journal of comparative neurology.

[97]  Y. Zhong,et al.  Morphological plasticity of motor axons in Drosophila mutants with altered excitability , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[98]  U. Heberlein,et al.  Functional Ethanol Tolerance in Drosophila , 2000, Neuron.

[99]  N. Perrimon,et al.  A Drosophila CREB/CREM homolog encodes multiple isoforms, including a cyclic AMP-dependent protein kinase-responsive transcriptional activator and antagonist , 1995, Molecular and cellular biology.

[100]  J. Gusella,et al.  Rescue of a Drosophila NF1 mutant phenotype by protein kinase A. , 1997, Science.

[101]  J. Takahashi,et al.  Stopping time: the genetics of fly and mouse circadian clocks. , 2001, Annual review of neuroscience.

[102]  T. Tully,et al.  latheo, a new gene involved in associative learning and memory in Drosophila melanogaster, identified from P element mutagenesis. , 1992, Genetics.

[103]  N. Strausfeld,et al.  Subdivision of the drosophila mushroom bodies by enhancer-trap expression patterns , 1995, Neuron.

[104]  B. Tabashnik,et al.  Development time and resistance to Bt crops , 1999, Nature.

[105]  H. Bellen,et al.  Two Drosophila learning mutants, dunce and rutabaga, provide evidence of a maternal role for cAMP on embryogenesis. , 1987, Developmental biology.

[106]  L. Peña,et al.  A novel synaptic transmission mediated by a PACAP-like neuropeptide in drosophila , 1995, Neuron.

[107]  Y. Koh,et al.  Regulation of DLG Localization at Synapses by CaMKII-Dependent Phosphorylation , 1999, Cell.

[108]  R. Davis,et al.  Physiology and biochemistry of Drosophila learning mutants. , 1996, Physiological reviews.

[109]  Y. Jan,et al.  dunce, a mutant of Drosophila deficient in learning. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[110]  W. Kolch,et al.  Regulation of Raf‐1 kinase activity by the 14‐3‐3 family of proteins. , 1995, The EMBO journal.

[111]  F. McCormick,et al.  Binding of 14-3-3 proteins to the protein kinase Raf and effects on its activation. , 1994, Science.

[112]  Li Liu,et al.  Context generalization in Drosophila visual learning requires the mushroom bodies , 1999, Nature.

[113]  G. Rubin,et al.  The Berkeley Drosophila Genome Project gene disruption project: Single P-element insertions mutating 25% of vital Drosophila genes. , 1999, Genetics.

[114]  D. O'Dowd,et al.  cAMP-Dependent Plasticity at Excitatory Cholinergic Synapses inDrosophila Neurons: Alterations in the Memory MutantDunce , 2000, The Journal of Neuroscience.

[115]  W. Quinn,et al.  Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila , 1994, Cell.

[116]  U. Heberlein,et al.  Dopamine modulates acute responses to cocaine, nicotine and ethanol in Drosophila , 2000, Current Biology.

[117]  M. Heisenberg What do the mushroom bodies do for the insect brain? an introduction. , 1998, Learning & memory.

[118]  T. Carew Persistent Activation of cAMP-Dependent Protein Kinase and the Induction of Long-Term Memory , 2000, Neuron.

[119]  A. Spradling,et al.  Insertional mutagenesis of the Drosophila genome with single P elements. , 1988, Science.

[120]  Troy Zars,et al.  Behavioral functions of the insect mushroom bodies , 2000, Current Opinion in Neurobiology.

[121]  M. Livingstone,et al.  Genetic dissection of monoamine neurotransmitter synthesis in Drosophila , 1983, Nature.

[122]  N. Perrimon,et al.  Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. , 1993, Development.

[123]  M. Hammer,et al.  Multiple sites of associative odor learning as revealed by local brain microinjections of octopamine in honeybees. , 1998, Learning & memory.

[124]  R. Davis,et al.  The memory gene dunce+ encodes a remarkable set of RNAs with internal heterogeneity , 1986, Molecular and cellular biology.

[125]  G. Laurent,et al.  Short-term memory in olfactory network dynamics , 1999, Nature.

[126]  M Heisenberg,et al.  Behavioral manipulation of retrieval in a spatial memory task for Drosophila melanogaster. , 1997, Learning & memory.

[127]  M Heisenberg,et al.  Drosophila mushroom bodies are dispensable for visual, tactile, and motor learning. , 1998, Learning & memory.

[128]  D. H. Cox,et al.  Intrinsic Voltage Dependence and Ca2+ Regulation of mslo Large Conductance Ca-activated K+ Channels , 1997, The Journal of general physiology.

[129]  J. Dura,et al.  The receptor tyrosine kinase gene linotte is required for neuronal pathway selection in the Drosophila mushroom bodies , 1998, Mechanisms of Development.

[130]  Ronald L. Davis,et al.  Preferential expression in mushroom bodies of the catalytic subunit of protein kinase A and its role in learning and memory , 1993, Neuron.

[131]  M. Heisenberg,et al.  Conditioned visual flight orientation in Drosophila: dependence on age, practice, and diet. , 1996, Learning & memory.

[132]  R. W. Siegel,et al.  Conditioning Mutations in DROSOPHILA MELANOGASTER Affect an Experience-Dependent Behavioral Modification in Courting Males. , 1984, Genetics.