Regulated Intron Removal Integrates Motivational State and Experience

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Memory persistence depends on internal state and experience saliency.
• The molecular mechanisms linking experience, internal state, and memory duration are unknown.
• Long-lasting memory in Drosophila requires a specific aggregated state of the Orb2A protein.

Purpose of the Study:

• To elucidate the molecular mechanisms by which experience and internal state influence long-term memory duration.
• To identify the regulatory factors controlling Orb2A protein levels for memory persistence.

Main Methods:

• Analysis of Orb2A mRNA splicing in adult fly brains.
• Genetic screening to identify factors involved in Orb2A mRNA processing.
• Investigating the role of the pasilla gene in memory formation.
• Site-directed mutagenesis to assess the impact of altered Pasilla binding on memory.

Main Results:

• Drosophila Orb2A mRNA exists in an unspliced, non-protein-coding form in the adult brain.
• Experience and internal state converge to transiently increase spliced, protein-coding Orb2A mRNA.
• The pasilla gene (fly Nova-1/2 ortholog) mediates Orb2A mRNA processing.
• A specific intronic mutation reducing Pasilla binding and intron removal impairs long-term memory.

Conclusions:

• Pasilla-mediated processing of unspliced Orb2A mRNA is crucial for long-term memory.
• This processing integrates external experience and internal state to regulate Orb2A protein abundance.
• The findings reveal a molecular mechanism for controlling memory duration based on internal and external cues.