2024 Theses Doctoral

Genetic strategies to uncover the organizational principles of multiple memories

Stackmann, Michelle

Memories are thought to be stored in neuronal ensembles throughout the brain, or engrams. These ensembles are defined as the neuronal populations active during learning, that undergo lasting cellular changes due to the learning, and are necessary for memory retrieval. Genetic strategies that utilize immediate early genes (IEGs), which are expressed upon cellular stimulation, have been developed to identify engrams. These tools allow for the labeling of the cells active during memory encoding, which can then be compared with those active during retrieval, advancing our knowledge of how single memories are stored in the brain.

Despite these advances, little is known about how multiple memories are encoded and stored in the brain. This limitation is due to the current methods, which restrict our ability to visualize multiple ensembles in the brain. Here, I developed a multiple labeling system, based on the IEG Arc, that allows us to investigate how single and multiple memories are stored in the brain.

In Chapter 2, we first show the validity of using an existing Arc-based labeling system to investigate how fear memory ensembles are modulated by propranolol, a β-adrenergic receptor antagonist. We found that propranolol modulates fear retrieval and decreases the reactivation of fear ensembles in the dorsal dentate gyrus (DG). In Chapter 3, I show the development of a novel, multiple Arc (mArc) labeling system that allows for the tagging of multiple Arc ensembles in the brain. We validated this system by investigating how context, time, and valence influence ensemble reactivation in the DG. We show that similar contextual experiences and experiences occurring close in time are stored in overlapping ensembles. The mArc system provides a powerful approach for investigating how multiple memories are organized in the brain and will be useful for multiple areas of investigation.