Why do some memories fade easily, perhaps within minutes, while others persist over decades?
Is there anything more integral to our ‘sense-of-self’ other than our memories? Things we have seen, stories we have heard, skills we have learned, the past we have lived, and the future we envision for ourselves are ultimately all memories that we acquire, store, and retrieve at our whim. Without our memories, we are sentenced to an eternal present much like the one Leonard from Christopher Nolan’s classic film ‘Momento’ was stuck in.
Our brain is a remarkable dynamic entity. It has the capacity to physically change and adapt every time we read, learn, or remember something. The neurons, also known as nerve cells, continuously communicate with each other and undergo changes at a microscale level. Neurons can strengthen existing connections, tune down weaker connections, and even form new connections. These adaptable alterations are a result of the malleable nature of our nervous system known as ‘neuroplasticity.’ As a result, our temporary, labile memory is transformed into an enduring form. The physical representation of this more stable memory in our brain is defined as an ‘engram’ or a memory trace. Engrams are the basic unit of memory that exist as a web of neurons dispersed across multiple brain regions that are constructed by learning and reactivated by recall.
To attempt to answer this neuroscience conundrum, we have to understand our biology’s complicated relationship with viruses.
Given the vast network of neurons that meander through the brain, why is it that only some neurons, but not others, are recruited into a memory engram? That is, why do some memories fade easily, perhaps within minutes, while others persist over decades? To attempt to answer this neuroscience conundrum, we have to understand our biology’s complicated relationship with viruses.
Viruses are scandalous in the scientific realm. Sitting at the edge of our definition of living things, they are specks of genetic material encapsulated by a protective shell called capsid. Nearly 8% of our genome consists of remnants of ancient viruses that have integrated into our DNA millions of years ago. The majority of these viral remains have been rendered inactive, but some have evolved to give rise to novel functions. One such function is our ability to form memories.
The plasticity in our brain that underlies memory requires the synthesis of certain proteins that can transmit genetic information between neurons. One such protein is activity-regulated cytoskeletal (Arc) protein that plays a critical role in learning and memory formation.
Once neurons are activated in the brain as a result of a stimulus such as reading a book, the Arc gene is switched on. These neurons package genetic instructions to produce Arc protein in spherical structures called vesicles and secrete them. Neighboring neurons take up these secreted vesicles and ramp up the production of Arc protein. The Arc cell-to-cell delivery mechanism is repeated resulting in the formation of a network of activated neurons that are incorporated into an engram. The cellular information is subsequently consolidated as an engram.
Remarkably, viruses, too, behave in a similar fashion by bringing their own genomic material packaged in a spherical capsid to insert in the host cell’s DNA. In fact, when scientists peered down at the microscope, they found that the Arc protein structurally resembled human immunodeficiency virus (HIV), the virus that causes AIDS. The Arc protein even had spikes on its surface that resembled spikes used by the viruses for cell entry. Evolution has modified the viral entry strategy to work to our cognitive benefit.
Overwhelming amount of evidence has elucidated the importance of Arc in memory formation. Deletion of Arc gene in mice resulted in failure to form long-lasting memories. These mice could learn new tasks, but failed to recall them the next day. Scientists also generated mouse models that produced fluorescence whenever the Arc gene was switched on in the brain. The mice were then trained to fear a specific noise (stimulus), and then re-exposed to the same stimulus days later to observe memory re-activation. Re-exposure to the noise stimulus led to memory recall and the formation of engram neurons in the hippocampus, brain’s memory hub, was detected via fluorescence. This indicated that Arc gene was expressed when memory recall occurred.
Arc protein stained in the hippocampus of the brain (image from the Christa K. McIntyre Lab at The University of Texas at Dallas School of Behavioral and Brain Sciences).
There is still much to learn about the Arc protein and the novel form of viral-like cellular communication it participates in. But we can be sure of one thing: understanding the function of Arc in the brain is essential to understand the neural basis of our past, present, and possibly future.
Mahlaqua Noor [2019, Hughes Hall] is a PhD candidate at the Department of Medicine. She investigates how our immune system responds to viruses that cause life-long infections.
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