How can a temporal sequence of related memories — be explained — at the gene-environment level ?

Memories acquired close together in time often become linked, such that recalling one memory leads to the recall of additional memories. For example, recently while writing a “Memoirs” book for my children and grandkids, I tried to remember the name of my grade-school principal. First, I visualized the small white schoolhouse, then the faces and names of my (grades-1 through -8) grade school teachers, and then seeing the principal’s face in the hallway. After that, I recalled his last name (Thurman), after which I then could even remember his first name and curiously, even his middle initial (Wayne S.)! And then I recalled even a story he told students about serving in the U.S. Navy in the Pacific Theatre during WW2 and being on a burning battleship — as it returned to harbor..!! To recall that sequence of events in reverse order (i.e., going from the battleship to his last name to the white schoolhouse) probably could not have happened.

Real-world past memories seem to be formed in a particular sequence-framework and often are not acquired or recalled in isolation. Time is a key variable in the organization of memories, because events that are experienced close to one another in time are more likely to be meaningfully associated, whereas those that are experienced over a longer time interval are not. How does the brain segregate events that are temporally distinct?; the mechanism is not clear.

Authors [see attached article & editorial] show that, after the formation of a contextual memory, a delayed (12–24 h) increase — in expression of C-C chemokine receptor type-5 [(CCR5), an immune receptor that curiously is well known as a co-receptor for HIV infection!!] — determines the duration of the temporal window for associating or linking that memory with subsequent memories. How on earth did an immune-associated receptor get discovered to be a pivotal factor in a memory-sequence context of thoughts in the brain???

The delayed expression of CCR5 in mouse hippocampal dorsal CA1 neurons results in a decrease in neuronal excitability, which, in turn, negatively regulates neuronal memory allocation, thus decreasing the overlap between dorsal CA1 memory ensembles. Lowering this overlap affects the ability of one memory to trigger the recall of the other, and, therefore, closes the temporal window for memory linking. Authors also show that an age-related increase in the neuronal expression of CCR5, and its protein ligand C-C motif chemokine ligand-5 (CCL5) leads to impairments in memory linking in aged mice, which was shown to be reversed by using a Ccr5(-/-) knockout mouse — with, versus without, treatment by a drug thatis an inhibitor of the CCR5 receptor (this result should have clinical implications: think Alzheimer, other dementias). In summary, the data described in this study provide insights into the molecular and cellular mechanisms that shape the temporal window for memory linking, but also showing the interrelationship of the immune and central nervous systems.

What does this topic have to do with “gene-environment interactions?” Well, the environmental signal (in the example given above) is simply a question, posed as a thought: “What was my grade school principal’s name?” This thought stimulated neurons — in a subset of the central nervous system (CNS) grey matter — which resulted in a cascade of genetic networks leading to neuronal (electrical) activity in the form of a series of time-related memories. Subsequently, this sequence of memories led to the principal’s name, and even a WW2 story about him. The unanticipated surprise was the involvement of the immune system’s CCR5 and its ligand CCL5 in activating this CNS function. More generally, the exploration of brain activity during similar behaviors, but on more-granular or more-continuous timescales, will lead to a better understanding of how memories are organized into sequences, episodes and, ultimately, a chronology. 😊


Nature 2 Jun 2022; 606: 438-152 & News N Views pp 38-39.

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