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      Multiple neurons encode CrebB dependent appetitive long-term memory in the mushroom body circuit

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          Lasting changes in gene expression are critical for the formation of long-term memories (LTMs), depending on the conserved CrebB transcriptional activator. While requirement of distinct neurons in defined circuits for different learning and memory phases have been studied in detail, only little is known regarding the gene regulatory changes that occur within these neurons. We here use the fruit fly as powerful model system to study the neural circuits of CrebB-dependent appetitive olfactory LTM. We edited the CrebB locus to create a GFP-tagged CrebB conditional knockout allele, allowing us to generate mutant, post-mitotic neurons with high spatial and temporal precision. Investigating CrebB-dependence within the mushroom body (MB) circuit we show that MB α/β and α’/β’ neurons as well as MBON α3, but not in dopaminergic neurons require CrebB for LTM. Thus, transcriptional memory traces occur in different neurons within the same neural circuit.

          eLife digest

          Our brains can store different types of memories. You may have forgotten what you had for lunch yesterday, but still be able to remember a song from your childhood. Short-term memories and long-term memories form via different mechanisms. To establish long-term memories, the brain must produce new proteins, many of which are common to all members of the animal kingdom. By studying these proteins in organisms such as fruit flies, we can learn more about their role in our own memories.

          Widmer et al. used this approach to explore how a protein called CrebB helps fruit flies to remember for several days that a specific odor is associated with a sugary reward. These odor-reward memories form in a brain region called the mushroom body, which has three lobes. Input neurons supply information about the odor and the reward to the region, while output neurons pass on information to other parts of the fly brain. CrebB regulates the production of new proteins required to form these long-term odor-reward memories: but where exactly does CrebB act during this process?

          Using a gene editing technique called CRISPR, Widmer et al. generated mutant flies. In these insects CrebB could be easily deactivated ‘at will’ in either the entire brain, the whole mushroom body, each of the three lobes or in specific output neurons. The flies were then trained on the odor-reward task, and their memory tested 24 hours later. The results revealed that for the memories to form, CrebB is only required in two of the three lobes of the mushroom body, and in certain output neurons. Future studies can now focus on the cells shown to need CrebB to create long-term memories, and identify the other proteins involved in this process.

          In humans, defects in CrebB are associated with intellectual disability, addiction and depression. The mutant fly created by Widmer et al. could be a useful model in which to investigate how the protein may play a role in these conditions.

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          Most cited references 36

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          The many faces of CREB.

          The transcription factor CREB is best known for its involvement in learning and memory. However, emerging evidence suggests that CREB activity has very different roles--sometimes beneficial, sometimes detrimental--depending on the brain region involved. Induction of CREB in the hippocampus by antidepressant treatments could contribute to their therapeutic efficacy. By contrast, activation of CREB in the nucleus accumbens and several other regions by drugs of abuse or stress mediates certain aspects of drug addiction, and depressive and anxiety-like behaviors. These complexities suggest that strategies that exploit regional differences in upstream factors or that target specific CREB-regulated genes, rather than CREB itself, could make a promising contribution to the treatment of neuropsychiatric conditions.
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            CREB and memory.

            The cAMP responsive element binding protein (CREB) is a nuclear protein that modulates the transcription of genes with cAMP responsive elements in their promoters. Increases in the concentration of either calcium or cAMP can trigger the phosphorylation and activation of CREB. This transcription factor is a component of intracellular signaling events that regulate a wide range of biological functions, from spermatogenesis to circadian rhythms and memory. Here we review the key features of CREB-dependent transcription, as well as the involvement of CREB in memory formation. Evidence from Aplysia, Drosophila, mice, and rats shows that CREB-dependent transcription is required for the cellular events underlying long-term but not short-term memory. While the work in Aplysia and Drosophila only involved CREB function in very simple forms of conditioning, genetic and pharmacological studies in mice and rats demonstrate that CREB is required for a variety of complex forms of memory, including spatial and social learning, thus indicating that CREB may be a universal modulator of processes required for memory formation.
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              Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila.

              Consolidated memory after olfactory learning in Drosophila consists of two components, a cycloheximide-sensitive, long-term memory (LTM) and a cycloheximide-insensitive, anesthesia-resistant memory (ARM). Using an inducible transgene that expresses a dominant negative member of the fly CREB family, LTM was specifically and completely blocked only after induction, while ARM and learning were unaffected. These results suggest that LTM formation requires de novo gene expression probably mediated by CREB family genes.

                Author and article information

                Role: Reviewing Editor
                Role: Senior Editor
                eLife Sciences Publications, Ltd
                22 October 2018
                : 7
                [1 ]deptDepartment of Biology University of Fribourg FribourgSwitzerland
                Brandeis University United States
                National Centre for Biological Sciences, Tata Institute of Fundamental Research India
                Brandeis University United States
                © 2018, Widmer et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                Funded by: FundRef, Bundesbehörden der Schweizerischen Eidgenossenschaft;
                Award ID: SynaptiX
                Award Recipient :
                Funded by: FundRef, Novartis Stiftung für Medizinisch-Biologische Forschung;
                Award ID: 18A017
                Award Recipient :
                Funded by: FundRef, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung;
                Award ID: CRSII5_180316
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Research Article
                Custom metadata
                The transcription factor CrebB mediates long-term memory formation in different neurons within the mushroom body learning circuit, including mushroom body intrinsic and output neurons but not dopaminergic input neurons.

                Life sciences

                long-term memory, creb, learning, d. melanogaster


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