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Drosophila olfactory memory: single genes to complex neural circuits

Key Points

  • Fruit flies can learn to associate olfactory or visual cues with rewarding or punishing reinforcement. Fruitfly memory persists for hours or days, depending on the training protocol. Multiple spaced training trials form long-term memory that can persist for days.

  • Labour-intensive genetic screens and reverse genetic approaches over the last 30 years have identified more than 80 genes that are potentially involved in olfactory memory. These mutants provide a unique entry to the molecular processes that engender memory.

  • Localizing the memory-relevant gene products has primarily highlighted the mushroom body neurons as key neural circuit components of olfactory memory. This analysis also led to the identification of the two dorsal paired medial (DPM) neurons that innervate the mushroom bodies and are crucial for aversive and appetitive odour memory stability.

  • Genetic tools have been developed to precisely control transgene expression in space and time. These tools are essential to determine whether a gene product functions acutely in specific neurons in the adult fly brain as opposed to being required for brain development.

  • Interventionist approaches to stimulate or temporarily block synaptic transmission from genetically defined neurons have transformed studies of memory. These genetic tools permit a fine temporal dissection of the role of defined neurons in memory acquisition, consolidation and retrieval and have heralded a systems-level analysis of memory in the fly brain.

  • Monoamine function distinguishes between aversive and appetitive conditioning: aversive odour memory requires functional dopaminerigic neurons, whereas appetitive odour memory depends on octopamine. Current models posit that mushroom body neurons encode memory by integrating coincident odour information with a reward or punishment signal from the respective monoamine.

  • The fly employs parallel and sequential use of different mushroom body neurons to process memory. These findings suggest that memory processing in the fly is dynamic, and may more closely resemble memory processing in the mammalian brain than previously imagined.

  • Optical recording and physiology from genetically marked neurons in the brain of a live behaving fly has given a new dimension to the analysis of memory, filling the considerable gap between a dysfunctional gene and behavioural memory performance. Coupling these techniques with our large collection of memory defective mutants should further revolutionize our understanding of fly memory.

Abstract

A central goal of neuroscience is to understand how neural circuits encode memory and guide behaviour. Studying simple, genetically tractable organisms, such as Drosophila melanogaster, can illuminate principles of neural circuit organization and function. Early genetic dissection of D. melanogaster olfactory memory focused on individual genes and molecules. These molecular tags subsequently revealed key neural circuits for memory. Recent advances in genetic technology have allowed us to manipulate and observe activity in these circuits, and even individual neurons, in live animals. The studies have transformed D. melanogaster from a useful organism for gene discovery to an ideal model to understand neural circuit function in memory.

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Figure 1: Cartoon Drosophila melanogaster head.
Figure 2: Schematic of the adult fly olfactory system circuit.
Figure 3: Three-dimensional models of the mushroom bodies.
Figure 4: Dorsal paired medial neurons.
Figure 5: Model for aversive olfactory conditioning and DPM neuron-dependent memory processing.

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Acknowledgements

We thank B. Leung for the confocal images used to produce Figures 3 and 4. We also thank V. Budnik, B. Leung and M. Krashes for discussion and comments on the manuscript. We acknowledge the contribution of our colleagues in the field, R. Davis, B. Gerber and M. Heisenberg, in shaping our thought process. We apologize to those authors whose work we were unable to cite due to space limitations. This work was supported by a grant to S.W. from the National Institutes of Health MH09883 and a National Research Service Award MH073311 to A.C.K.

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FURTHER INFORMATION

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Glossary

Conditioned stimulus

A stimulus — odour, in olfactory conditioning — that gains meaning following pairing with an unconditioned stimulus.

Unconditioned stimulus

A stimulus that generates an unlearned behavioural response: the shock or sugar in fly olfactory conditioning.

Long-term memory

Consolidated memory that is formed following multiple spaced training trials and requires new protein synthesis after training.

Short-term memory

A phase of fly memory that lasts a few minutes and is sensitive to anaesthetic disruption.

Middle-term memory

A phase of fly memory that lasts a few hours, is sensitive to anaesthetic disruption and is dependent on the amnesiac gene.

Anaesthesia-resistant memory

Consolidated fly memory that is resistant to anaesthetic disruption, develops during the first 30 minutes after training and is dependent on the radish gene.

Mushroom bodies

Mushroom bodies, or Corpora pedunculata, are paired neural structures in the insect brain that morphologically resemble mushrooms and are required for olfactory memory.

Glomeruli

Morphologically distinguishable areas in the antennal lobe that contain the presynaptic terminals of olfactory sensory neurons that express the same olfactory receptor and dendrites of postsynaptic projection neurons.

Labelled line

A simple one-to-one-to-one neural connectivity model that transfers sensory information from the periphery to deeper layers of the brain via a faithful linear arrangement of connected neurons. Sensory signals are thereby represented as activity in 'labelled lines' in the brain.

Neural ensemble

A population of neurons involved in a particular computational process.

Tethered fly preparation

The fly is alive but immobilized for viewing under the confocal microscope. A window is cut in the head capsule so that the brain can be visualized.

Enhancer-trap

Insertion of a P-element transposon harbouring the GAL4 transcription factor in a region of the genome in which a neighbouring transcriptional enhancer element confers region-specific GAL4 expression.

Calyx

A compartment of the mushroom bodies where the presynaptic projection neurons synapse with the dendrites of the Kenyon cells.

Kenyon cells

The neurons comprising the mushroom bodies.

GAL4/UAS system

A genetic system for controlling the induction of gene expression. An activator line that expresses the yeast transcriptional activator GAL4 gene under the control of a tissue-specific promoter is crossed to an effector line that carries the DNA-binding motif of GAL4 (upstream activating sequence, UAS) fused to the gene of interest. As a result, the progeny of this cross expresses the gene of interest in a region-specific manner.

Neuropil

The interior of the fly brain that is rich in axonal material, synaptic connections and intervening glia. The majority of cell bodies, or perikarya, in the fly brain are located on the periphery in the rind.

Golgi-impregnation

A classic histological staining technique developed in 1873 by Camillo Golgi that allows one to visualize the fine detail of single neurons.

Peduncle

The fasciculated axon bundle or 'stalk' of Kenyon cells between the dendritic calyx and presynaptic compartment in the mushroom body lobes.

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Keene, A., Waddell, S. Drosophila olfactory memory: single genes to complex neural circuits. Nat Rev Neurosci 8, 341–354 (2007). https://doi.org/10.1038/nrn2098

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