Drosophila Memory: Dopamine Signals Punishment?
2005; Elsevier BV; Volume: 15; Issue: 22 Linguagem: Inglês
10.1016/j.cub.2005.10.058
ISSN1879-0445
Autores Tópico(s)Insect Utilization and Effects
ResumoDopamine-containing neurons are widespread in the fly brain and have been implicated in negatively reinforced memory. Current technology allows the investigator to watch dopaminergic neurons in action in the brain of a learning fly. Dopamine-containing neurons are widespread in the fly brain and have been implicated in negatively reinforced memory. Current technology allows the investigator to watch dopaminergic neurons in action in the brain of a learning fly. The reward of suffering is experience — AeschylusUnderstanding the molecular and cellular basis of memory is a goal of modern neuroscience. The question can be addressed on many different levels including: What genes are involved? What is the relevant neural circuitry? And, how does that circuitry change when an animal learns? Drosophila is a fantastic model system for a rigorous, multi-level analysis of memory. In a recent issue of Current Biology, Reimensperger et al. [1Reimensperger, T., Völler, T., Stock, P., Buchner, E., and Fiala, A. (2005). Punishment prediction by dopaminergic neurons in Drosophila. Curr. Biol. November 8 issue.Google Scholar] report the use of a genetically encoded calcium sensor to image activity of a subset of dopaminergic neuron synapses during aversive olfactory conditioning in Drosophila. Flies can be taught to associate an odor conditioned stimulus (CS) with either a punitive shock or a sugar reward unconditioned stimulus (US). The memory of this learned association is subsequently displayed as a preferential avoidance of, or attraction to, the reinforced odor. The mushroom bodies, comprising approximately 5000 neurons of the fly brain, are critically important for olfactory memory [2Heisenberg M. Mushroom body memoir: from maps to models.Nat. Rev. Neurosci. 2003; 4: 266-275Crossref PubMed Scopus (874) Google Scholar]. Mushroom bodies are third-order neurons of the olfactory system (Figure 1) and also apparently receive monoaminergic [1Reimensperger, T., Völler, T., Stock, P., Buchner, E., and Fiala, A. (2005). Punishment prediction by dopaminergic neurons in Drosophila. Curr. Biol. November 8 issue.Google Scholar, 3Schwaerzel M. Monastirioti M. Scholz H. Friggi-Grelin F. Birman S. Heisenberg M. Dopamine and octopamine differentiate between aversive and appetitive olfactory memories in Drosophila.J. Neurosci. 2003; 23: 10495-10502PubMed Google Scholar] and putative peptidergic [4Waddell S. Armstrong J.D. Kitamoto T. Kaiser K. Quinn W.G. The amnesiac gene product is expressed in two neurons in the Drosophila brain that are critical for memory.Cell. 2000; 103: 805-813Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar] modulatory input. The current dogma predicts that, during conditioning, the US drives modulatory monoaminergic neurons to release transmitter onto CS pathway neurons and thereby change the synapses of active CS pathway neurons [2Heisenberg M. Mushroom body memoir: from maps to models.Nat. Rev. Neurosci. 2003; 4: 266-275Crossref PubMed Scopus (874) Google Scholar]. An important recent paper [3Schwaerzel M. Monastirioti M. Scholz H. Friggi-Grelin F. Birman S. Heisenberg M. Dopamine and octopamine differentiate between aversive and appetitive olfactory memories in Drosophila.J. Neurosci. 2003; 23: 10495-10502PubMed Google Scholar] reported that blocking dopaminergic neuron output during acquisition in Drosophila perturbed shock-reinforced memory but left sugar reinforced memory unaffected. Furthermore, compromised octopaminergic signaling reduced reward learning and left punished memory intact. It was proposed that dopaminergic neurons convey a punitive US in flies — contrasting with their established rewarding role in mammals — while octopaminergic neurons convey a rewarding US. An alternative explanation would be that the monoamines are not instructive cues and instead establish levels of brain activity that are conducive to, and necessary for, learning with these different stimuli. How might one examine whether dopaminergic neurons convey the US in aversive conditioning? It would be a good start to show that dopaminergic neurons respond to US and not CS presentation. Reimensperger et al. [1Reimensperger, T., Völler, T., Stock, P., Buchner, E., and Fiala, A. (2005). Punishment prediction by dopaminergic neurons in Drosophila. Curr. Biol. November 8 issue.Google Scholar] have now reported experiments that suggest dopaminergic neurons preferentially respond to a US. Recently investigators have imaged intact living flies under the microscope and watched signaling events unfold in the brain [5Fiala A. Spall T. Diegelmann S. Eisermann B. Sachse S. Devaud J.M. Buchner E. Galizia C.G. Genetically expressed cameleon in Drosophila melanogaster is used to visualize olfactory information in projection neurons.Curr. Biol. 2002; 12: 1877-1884Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar, 6Ng M. Roorda R.D. Lima S.Q. Zemelman B.V. Morcillo P. Miesenboeck G. Transmission of olfactory information between three populations of neurons in the antennal lobe of the fly.Neuron. 2002; 36: 463-474Abstract Full Text Full Text PDF PubMed Scopus (361) Google Scholar, 7Wang J.W. Wong A.M. Flores J. Vosshall L.B. Axel R. Two-photon calcium imaging reveals an odor-evoked map of activity in the fly brain.Cell. 2003; 112: 271-282Abstract Full Text Full Text PDF PubMed Scopus (596) Google Scholar, 8Wang Y. Guo H.F. Pologruto T.A. Hannan F. Hakker I. Svoboda K. Zhong Y. Stereotyped odor-evoked activity in the mushroom body of Drosophila revealed by green fluorescent protein- based Ca2+ imaging.J. Neurosci. 2004; 24: 6507-6514Crossref PubMed Scopus (154) Google Scholar], even as the animal learns [9Yu D. Ponomarev A. Davis R.L. Altered representation of the spatial code for odors after olfactory classical conditioning.Neuron. 2004; 42: 437-449Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar, 10Yu, D., Keene, A.C., Srivatsan, A., Waddell, S., and Davis, R.L. (2005). Drosophila DPM neurons form a delayed and branch-specific memory trace after olfactory classical conditioning. Cell, in press.Google Scholar]. The Fiala group [5Fiala A. Spall T. Diegelmann S. Eisermann B. Sachse S. Devaud J.M. Buchner E. Galizia C.G. Genetically expressed cameleon in Drosophila melanogaster is used to visualize olfactory information in projection neurons.Curr. Biol. 2002; 12: 1877-1884Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar] developed some of this technology and in their new study [1Reimensperger, T., Völler, T., Stock, P., Buchner, E., and Fiala, A. (2005). Punishment prediction by dopaminergic neurons in Drosophila. Curr. Biol. November 8 issue.Google Scholar] they expressed a genetically encoded reporter of intracellular Ca2+ (Cameleon 2.1) in dopaminergic neurons and imaged the dopaminergic neuron processes that innervate the mushroom bodies, through a window cut in the fly head cuticle (Figure 1). They report for the first time that mushroom-body-projecting dopaminergic neurons respond strongly to shock presentation but weakly to a moderate concentration of odor. As a control they show that projection neurons, part of the canonical olfactory pathway, respond strongly to the same odor presentation but not to shock (although this contradicts a previous report [9Yu D. Ponomarev A. Davis R.L. Altered representation of the spatial code for odors after olfactory classical conditioning.Neuron. 2004; 42: 437-449Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar] of shock activation of projection neurons using a different reporter gene). These new data [1Reimensperger, T., Völler, T., Stock, P., Buchner, E., and Fiala, A. (2005). Punishment prediction by dopaminergic neurons in Drosophila. Curr. Biol. November 8 issue.Google Scholar] are thus consistent with the idea that dopaminergic neurons confer punitive US information to the mushroom bodies. It is notable that dopaminergic neurons are widespread in the brain and that it is not known whether mushroom body-projecting dopaminergic neurons are critical for olfactory conditioning. Furthermore, the identity of the shock-responsive neurons that drive dopaminergic neurons is a mystery and it will be important to establish whether dopaminergic neurons specifically respond to electric shock or more generally to all punitive stimuli and whether dopaminergic neurons are not responsive to rewarding stimuli, such as sugar. Mammalian dopaminergic neurons respond to an unexpected reward, but after training with cue-reward pairing they respond more strongly to the predictive cue than to the reward [11Schultz W. Getting formal with dopamine and reward.Neuron. 2002; 36: 241-263Abstract Full Text Full Text PDF PubMed Scopus (1804) Google Scholar]. Reimensperger et al. [1Reimensperger, T., Völler, T., Stock, P., Buchner, E., and Fiala, A. (2005). Punishment prediction by dopaminergic neurons in Drosophila. Curr. Biol. November 8 issue.Google Scholar] therefore looked for a conditioned response in fly dopaminergic neurons. They conditioned flies under the microscope by pairing one odor with shock (CS+) and one odor without shock (CS–). Following training they exposed the flies consecutively to either the CS+ odor or CS– odor and monitored the evoked response in dopaminergic neurons. Surprisingly, the CS+ evoked response in dopaminergic neurons was prolonged following training whereas the CS– response remained unchanged. Therefore the dopaminergic neurons could be considered to have a memory trace and the authors suggest that the dopaminergic neurons acquire the ability to predict punishment. There are several interesting points raised by these data and conclusions. Firstly, the CS+ response is prolonged and the different response is only apparent when the odor stimulus is withdrawn. What does this mean for the animal? If dopaminergic neurons instruct the fly to run away from pending doom, the fly would be expected to respond immediately and preferentially to the CS+ while the odor was present. Furthermore, if dopaminergic neurons are instructing the fly, blocking their output specifically during retrieval should abolish display of memory. This can easily be tested using the available genetic tools and behavioral assays. Reimensperger et al. [1Reimensperger, T., Völler, T., Stock, P., Buchner, E., and Fiala, A. (2005). Punishment prediction by dopaminergic neurons in Drosophila. Curr. Biol. November 8 issue.Google Scholar] also propose the existence of a positive feedback loop between mushroom body neurons and dopaminergic neurons during the course of CS-US association. However, data from three independent labs do not support the importance of this proposed circuit. Mushroom body output is dispensable during acquisition and storage but is required for memory retrieval [12Dubnau J. Grady L. Kitamoto T. Tully T. Disruption of neurotransmission in Drosophila mushroom body blocks retrieval but not acquisition of memory.Nature. 2001; 411: 476-480Crossref PubMed Scopus (317) Google Scholar, 13McGuire S.E. Le P.T. Davis R.L. The role of Drosophila mushroom body signaling in olfactory memory.Science. 2001; 293: 1330-1333Crossref PubMed Scopus (320) Google Scholar, 14Schwaerzel M. Heisenberg M. Zars T. Extinction antagonizes olfactory memory at the subcellular level.Neuron. 2002; 35: 951-960Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar] whereas dopaminergic neuron output is required during acquisition [3Schwaerzel M. Monastirioti M. Scholz H. Friggi-Grelin F. Birman S. Heisenberg M. Dopamine and octopamine differentiate between aversive and appetitive olfactory memories in Drosophila.J. Neurosci. 2003; 23: 10495-10502PubMed Google Scholar]. If dopaminergic neurons predict punishment, do octopaminergic neurons predict reward? A tantalizing glimpse comes from a classic electrophysiological study in the honeybee [15Hammer M. An identified neuron mediates the unconditioned stimulus in associative olfactory learning in honeybees.Nature. 1993; 366: 59-63Crossref PubMed Scopus (491) Google Scholar]. The VUMmx1 neuron is octopaminergic and responds robustly to sugar reward. Following training VUMmx1 responds to the CS+ odor with a prolonged excitation similar to that seen for dopaminergic neurons by Reimensperger et al. [1Reimensperger, T., Völler, T., Stock, P., Buchner, E., and Fiala, A. (2005). Punishment prediction by dopaminergic neurons in Drosophila. Curr. Biol. November 8 issue.Google Scholar]. However, to date the existence of VUM-like neurons has not been reported in Drosophila. The data of Reimensperger et al. [1Reimensperger, T., Völler, T., Stock, P., Buchner, E., and Fiala, A. (2005). Punishment prediction by dopaminergic neurons in Drosophila. Curr. Biol. November 8 issue.Google Scholar] suggest dopaminergic neurons, like projection neurons [9Yu D. Ponomarev A. Davis R.L. Altered representation of the spatial code for odors after olfactory classical conditioning.Neuron. 2004; 42: 437-449Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar] and DPM neurons [4Waddell S. Armstrong J.D. Kitamoto T. Kaiser K. Quinn W.G. The amnesiac gene product is expressed in two neurons in the Drosophila brain that are critical for memory.Cell. 2000; 103: 805-813Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar, 10Yu, D., Keene, A.C., Srivatsan, A., Waddell, S., and Davis, R.L. (2005). Drosophila DPM neurons form a delayed and branch-specific memory trace after olfactory classical conditioning. Cell, in press.Google Scholar], have traces of memory. These data suggest that memory is more distributed across the fly brain than just within the mushroom bodies. However, although functional imaging allows us the enviable luxury of watching events in the fly brain during conditioning, parallel interventionist approaches and behavioral analyses are essential for us to work out which of these observed phenomena are critical for memory [4Waddell S. Armstrong J.D. Kitamoto T. Kaiser K. Quinn W.G. The amnesiac gene product is expressed in two neurons in the Drosophila brain that are critical for memory.Cell. 2000; 103: 805-813Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar, 10Yu, D., Keene, A.C., Srivatsan, A., Waddell, S., and Davis, R.L. (2005). Drosophila DPM neurons form a delayed and branch-specific memory trace after olfactory classical conditioning. Cell, in press.Google Scholar, 16Keene A.C. Stratmann M. Keller A. Perrat P.N. Vosshall L.B. Waddell S. Diverse odor-conditioned memories require uniquely timed dorsal paired medial neuron output.Neuron. 2004; 44: 521-533Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar]. This might be particularly important for dopamine whose pleiotropic influence extends to such complex phenomena as arousal [17Andretic R. van Swinderen B. Greenspan R.J. Dopaminergic modulation of arousal in Drosophila.Curr. Biol. 2005; 15: 1165-1175Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar, 18Kume K. Kume S. Park S.K. Hirsh J. Jackson F.R. Dopamine is a regulator of arousal in the fruit fly.J. Neurosci. 2005; 25: 7377-7384Crossref PubMed Scopus (361) Google Scholar]. Drosophila Memory: Dopamine Signals Punishment?Keene et al.Current BiologyDecember 06, 2005In Brief(Current Biology 15, R932–R934; November 22, 2005) Full-Text PDF Open Archive
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