From Engrams to Pathologies of the Brain.

Christine A Denny,Steve Ramirez,Evan Lebois

doi:10.3389/fncir.2017.00023

Abstract

Memories are the experiential threads that tie our past to the present. The biological realization of a memory is termed an engram—the enduring biochemical and physiological processes that enable learning and retrieval. The past decade has witnessed an explosion of engram research that suggests we are closing in on boundary conditions for what qualifies as the physical manifestation of memory. In this review, we provide a brief history of engram research, followed by an overview of the many rodent models available to probe memory with intersectional strategies that have yielded unprecedented spatial and temporal resolution over defined sets of cells. We then discuss the limitations and controversies surrounding engram research and subsequently attempt to reconcile many of these views both with data and by proposing a conceptual shift in the strategies utilized to study memory. We finally bridge this literature with human memory research and disorders of the brain and end by providing an experimental blueprint for future engram studies in mammals. Collectively, we believe that we are in an era of neuroscience where engram research has transitioned from ephemeral and philosophical concepts to provisional, tractable, experimental frameworks for studying the cellular, circuit and behavioral manifestations of memory.

Highlights

We begin with a disclaimer on our interpretation of the state of engram research: we do not know what an engram is fully; we have not found an engram in its entirety; we do not have a complete understanding of the biochemical and physiological parameters underlying engram storage, retrieval and updating
We are as optimistic about the modern state of memory research as we are realistic about the amount of science that remains to be performed before we understand the principles organizing memory
Any logic underpinning memory must take into consideration the dynamic nature of memory across circuits and across time

Summary

INTRODUCTION

We begin with a disclaimer on our interpretation of the state of engram research: we do not know what an engram is fully; we have not found an engram in its entirety; we do not have a complete understanding of the biochemical and physiological parameters underlying engram storage, retrieval and updating. We must embrace that the term engram—like any scientific paradigm or framework still in its infancy—is provisional and subject to change as our understanding of memory improves. This is a good thing: given the early stages of engram research, we welcome the opportunity to falsify, revise and update many of the claims regarding engrams because that necessary process of hypothesis testing is the process of science itself. We provide a conceptual and experimental scaffold for future engram research and to clarify and reconcile many of the recent controversies surrounding a slew of studies claiming to have leverage over such mnemonic processes. While our focus is the mammalian brain and episodic memory, readers are referred elsewhere for excellent reviews focusing on invertebrates (e.g., C. elegans, Drosophila melanogaster) or other types of memories (e.g., motor, perceptual; Martin et al, 2000; Horn et al, 2001; Christian and Thompson, 2003; Weinberger, 2004)

A CENTURY OF MEMORY RESEARCH

A CROSS-SPECIES APPROACH TO ENGRAM RESEARCH

A CONCEPTUAL FRAMEWORK FOR CROSS-SPECIES ENGRAM RESEARCH

A CONVERGENCE OF STIMULATION STRATEGIES

CONCLUSIONS