Discovering Principles of Memory Storage, Retrieval, and Restoration
Abstract
A tremendous amount of research has provided us with an understanding of how experience modifies brain cells to enable memory. The physical manifestation of memory, or an engram, is believed to be stored in the strengthened synaptic connectivity between distributed populations of neurons. Although the activity of cell populations is assumed to underlie the stability of memory, an emerging body of literature suggests that neural activity patterns change over extended timescales, even if a given behavior remains the same—a phenomenon known as representational drift. The work here aims to build on our previously funded AFOSR work on memory by using a state-of-the-art multi-photon microscope to reconcile a fundamental paradox present in biology- how is memory stable when its underlying cellular representations are in constant flux. To understand how memories are stored across neural networks to yield stable behavioral outputs despite the changing nature of their underlying physiology, what is needed now is a technological and conceptual shift in how we view memory. To that end, we will utilize a custom state-of-the-art two-photon microscope to image the activity of memory-bearing cells with unprecedented subcellular resolution in healthy and amnestic animals. Using a combination of our lab s activity-dependent tagging systems to visualize and perturb memory-bearing cells, our proposed experiments will discover generalizable principles of memory storage, retrieval, and restoration. Our general approach will compare activity patterns of memory-bearing cells and non-memory-bearing cells to extract principles governing the experience-dependent modification of cellular activity in vivo. All measures will be correlated with cognitive and behavioral performance by using neuronal modeling approaches developed in the Ramirez laboratory. Specifically, we will gain a deeper understanding of how unstable biology enables stable engrams in awake behaving animals by resolving the real-time dynamics of neural ensembles and dendritic spine activity as they evolve before, during, and after complete cellular turnover (i.e., drift) has occurred. A major technical goal here involves adopting an all-optical approach to record and deliver real-time patterns of sub-cellular compartments of neurons over large spans of times (i.e. weeks). A significant milestone in this regard would be to causally demonstrate that a subset of dendritic spines represents a stable correlate of memory after total population drift has occurred, and even in the presence of amnesia, thereby identifying a physical and molecularly constrained mechanism that enables memory retrieval amidst fluctuating neuronal populations or amnestic states. Our project will revise the most widely adopted theoretical model of memory formation that is based on simple learning rules in excitatory synapses-this model posits that memory involves the stabilization of coactive neuronal ensembles during learning, which are reactivated to drive the recall of previously learned associations. We propose, however, that coactive dendritic spines encode individual memories that are retrieval after drift and-or amnesia has occurred, and that stimulating their activity is sufficient to successfully restore memories in each condition. This intriguing notion shifts our understanding of memory by suggesting that subcellular activity can sample environmental features and incorporate both stable and varying information as patterned activity, all with the biological purpose of continuously updating a population of active cells in reaction to the ever-changing flow of experience. In summary, our project uses novel imaging methods to causally relate how microscopic interactions at the cellular level and macroscopic structures that perform computations across networks enable all phases of memory in the brain.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 14, 2024
- Source ID
- FA95502310754
Entities
People
- Steve Ramirez
Organizations
- Air Force Office of Scientific Research
- Boston University
- United States Air Force