Periodic Reporting for period 4 - MEME (Memory Engram Maintenance and Expression)
Reporting period: 2021-08-01 to 2023-01-31
How is information stored in the brain? This research project uses cutting edge technologies to mechanistically describe the construction of a memory. The ultimate goal is to reveal how information is encoded in the brain of an individual.
Memory is crucial to everyday life and allows us to adapt to our changing environment. Diseases of memory range from disorders of transience, e.g. Alzheimer’s disease, to disorders of persistence, e.g. post-traumatic stress disorder. As we know so little about memory function in health, it is essential that we achieve a fundamental knowledge of memory in order to understand and treat disorders of memory such as Alzheimer’s disease, drug addiction, and general cognitive decline in the ageing population. More fundamentally, to explain how brain leads to mind, we need to understand how information is coded in the brain. Memory provides a window into tracking the substrate of information, because when we learn something our brains necessarily change to assimilate information and store a memory. Understanding the nature of the particular change or plasticity that represents a memory is a crucial first step to investigating how it is coded.
The physical site of a specific memory in the brain, the memory engram, was originally hypothesized to be encoded in the learning-induced persistent changes of specific brain cells that retain information and are subsequently reactivated during remembering. Until recently neuroscience has investigated memory engrams indirectly. Traditional experimental approaches have focused on investigating the role of brain regions, circuits, and molecules in the capacity of memory formation in general. In contrast, comparatively few studies have investigated how specific memory engrams are stored in the brain. Engram cell-labeling technology has revolutionized the way memory can be studied, allowing us to test long-standing but unproven theories of memory storage. Using the promoters of immediate-early genes, sparse populations of neurons that are active during the time window of a learning episode can be labelled, observed, and manipulated. It has been established that sub-populations of neurons active during a defined training window are both sufficient and necessary for retrieval of targeted memories, and therefore are involved in the storage of specific memories in the brain. However, we do not currently know how they are contributing to storing specific information. This project will address how specific memories are stored in the brain as collections of memory engram cells. The mechanism for the induction of memory engram labeling will be investigated. The biological mechanism of memory formation (learning) will also be probed, in order to delineate how and why a specific subpopulation of brain cells are assigned to a given memory engram. Lastly, the mechanisms of memory updating will be investigated by studying how memory engrams can be linked.
Memory is crucial to everyday life and allows us to adapt to our changing environment. Diseases of memory range from disorders of transience, e.g. Alzheimer’s disease, to disorders of persistence, e.g. post-traumatic stress disorder. As we know so little about memory function in health, it is essential that we achieve a fundamental knowledge of memory in order to understand and treat disorders of memory such as Alzheimer’s disease, drug addiction, and general cognitive decline in the ageing population. More fundamentally, to explain how brain leads to mind, we need to understand how information is coded in the brain. Memory provides a window into tracking the substrate of information, because when we learn something our brains necessarily change to assimilate information and store a memory. Understanding the nature of the particular change or plasticity that represents a memory is a crucial first step to investigating how it is coded.
The physical site of a specific memory in the brain, the memory engram, was originally hypothesized to be encoded in the learning-induced persistent changes of specific brain cells that retain information and are subsequently reactivated during remembering. Until recently neuroscience has investigated memory engrams indirectly. Traditional experimental approaches have focused on investigating the role of brain regions, circuits, and molecules in the capacity of memory formation in general. In contrast, comparatively few studies have investigated how specific memory engrams are stored in the brain. Engram cell-labeling technology has revolutionized the way memory can be studied, allowing us to test long-standing but unproven theories of memory storage. Using the promoters of immediate-early genes, sparse populations of neurons that are active during the time window of a learning episode can be labelled, observed, and manipulated. It has been established that sub-populations of neurons active during a defined training window are both sufficient and necessary for retrieval of targeted memories, and therefore are involved in the storage of specific memories in the brain. However, we do not currently know how they are contributing to storing specific information. This project will address how specific memories are stored in the brain as collections of memory engram cells. The mechanism for the induction of memory engram labeling will be investigated. The biological mechanism of memory formation (learning) will also be probed, in order to delineate how and why a specific subpopulation of brain cells are assigned to a given memory engram. Lastly, the mechanisms of memory updating will be investigated by studying how memory engrams can be linked.
Towards deliver of MEME, substantial progress has been made. A research group has been initiated and developed at Trinity College Dublin. The Principal Investigator and two full time Postdoctoral Research Associates are being employed on this project. These core three investigators have created a research laboratory environment that allows for integrative neuroscience projects to be conducted using extensive behavioral, electrophysiological biochemical, and genetic methodologies. Graduate students have been recruited to this research group within Trinity College Dublin, and are being trained within this environment.
Since creating a functional research group, a number of the scientific objectives MEME have been met. The group have succeeded to label specific engram cell populations and disrupt synaptic connections between them, testing their importance for memory access and memory storage. Furthermore, it has been made possible through the efforts of MEME to label, observe, and manipulate two different memory engram cells populations in awake behaving organisms. Lastly, the research carried out by MEME has lead to the direct observation of engram cell connectivity changes as a consequence of memory updating.
Since creating a functional research group, a number of the scientific objectives MEME have been met. The group have succeeded to label specific engram cell populations and disrupt synaptic connections between them, testing their importance for memory access and memory storage. Furthermore, it has been made possible through the efforts of MEME to label, observe, and manipulate two different memory engram cells populations in awake behaving organisms. Lastly, the research carried out by MEME has lead to the direct observation of engram cell connectivity changes as a consequence of memory updating.
Memory is information that is stored in the brain during learning, and maintained for future recall. Memories of salient experiences can last a lifetime and involve changes to brain structure and function. Research into the biological basis of long-term memory has been influenced by two complementary theories: the memory engram, and synaptic plasticity. In memory engram theory, learning induces persistent changes in a specific group of cells that retain information and are reactivated upon appropriate recall conditions. Synaptic plasticity is the broad concept that learning induces the formation and strengthening of synaptic connections between neurons. A comprehensive model of memory storage needs to synthetically incorporate elements from these two orthogonal theories. Key features of information specificity and anatomical localization are accounted for by engram theory, while the mechanisms of memory encoding and maintenance are provided by synaptic plasticity. MEME investigates the mechanistic basis of how engram ensembles store information. This involves an integrative neuroscience program, drawing on diverse methodologies such as behavioral analysis, electrophysiology, molecular and cellular biology, and optogenetics. It investigates the kinds of plasticity accompanying learning, and that are crucial for the formation of engram connectivity patterns and functional memories. Engram technology allows us to identify some of the neurons that contribute to a given memory. Using this technology we can investigate both the behavioral function of engram cells, and their underlying mechanistic biology, in a unitary experimental preparation. The impact of the research proposal will be to provide conceptual advances as to how memory is coded in the brain as information. Plasticity of connectivity between engram cells provides a potential substrate for the robust and persistent storage of a hierarchical memory through a distributed engram circuit. In essence, engram cell connectivity is a synthesis of the original engram concept conceived by Semon and the more popular, orthogonal theory of synaptic plasticity as originated by Hebb. MEME will determine how specific engram cell connectivity patterns form during learning, and whether they code behaviorally relevant information.