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.
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.