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The Biological Mechanism That Gives Life Meaning

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As the title of our program The Unbearable Lightness of Memory suggests, memory is much more than the process by which we recall errands or birthdays. Memory—how information obtained from experience is stored in the brain—is also the mechanism that molds our sense of the world. As Homo sapiens, we inherited a basic neural circuitry for processing information about our environment. This circuitry, laid down by the instructions in our DNA, endows us with instinctual human behaviors as well as innate emotional predispositions and cognitive capabilities. But it is devoid of content. All of the specific information that forms an individual mind is learned and then maintained in memory.

Think of your earliest memory. Even this memory is composed of many more, still earlier memories. If your first memory was a visual image of your mother, specific neurons, maybe hundreds or thousands in the back of your brain that encode visual information, had already been grouped together in a network to represent the image of your mother. This network was and is held together by persistent changes in synapses, the connections between one neuron and another. This group of neurons in your visual area had been linked to other neurons in the emotional circuits of your brain that make you feel the way you do when you see your mother. If you remembered her speaking, the meaning of the words had been laid down in memory, too, in the middle of the left side of your brain (if you are right-handed). This memory also includes a memory of yourself, giving you a sense of self, a concept not so easily localizable, but surely a network of neurons nonetheless, that has been stable over time from this first memory to the present day. So memory is not just a memo-pad for the day’s events, but the record of the richness of every aspect of your life and the biological mechanism that gives it meaning.

So what is the biological mechanism for the persistence of memory? Until recently, neuroscientists could only guess. For a century, most had a static view of how these long-term memories were stored. Long-term memories were assumed to be small changes in the structure of the circuitry of the brain, most likely new synapses that were formed after an experience to strengthen pre-existing connections. Thus there was no reason to look for special “memory stuff” that might be present in these few synapses encoding memories. But in the last five years or so this notion has radically changed to a more dynamic model of memory storage, one in which memories are maintained not by static structure, but by unique, perpetually active molecules.

Each of the participants of our session has challenged the prevailing notions of memory. As the WSF is physics-friendly, one could say my contribution is identifying an “elementary particle” of memory. To the surprise of most neuroscientists raised on the static structural model of memory storage, this elementary particle is much smaller than a synapse. Instead it is an enzyme, a molecule that catalyzes a specific chemical reaction. The chemical reaction that this enzyme (called protein kinase Mzeta or PKMzeta) promotes doubles the strength of the synapses in which the molecules reside, making these specific connections between neurons stronger. But the even more surprising news is that for a memory to be maintained, the chemical reaction mediated by PKMzeta must be continuous. If the reaction is inhibited by a drug, even for an hour or two, the synapses collapse back to their old strength, and memories, even very old ones, fall apart and the brain returns to a “blank slate.” After the drug has washed away, the memories do not return, but new memories can subsequently be relearned and remembered. Thus, memories can be reduced to the persistent action of PKMzeta, or, more precisely, the persistent action of the pattern of PKMzeta that had been formed in some synapses and not others. The content of the memory is defined by this pattern of PKMzeta within the specific function of the neuronal circuit. To date, my colleague André Fenton and I, and many other laboratories have used a variety of techniques in experimental animals to inhibit PKMzeta and have erased spatial memories in the hippocampus, motor memories in the motor cortex, fear memories in the amygdala, and visual memories in the visual cortex.

Conversely, Yadin Dudai and his colleagues and I have recently shown that increasing PKMzeta in a brain circuit prior to learning vastly increases the capacity for forming new long-term memories. Perhaps most remarkably, we showed that increasing PKMzeta even many days after learning boosts the strength of faded memories that were nearly forgotten. Thus old memories can be erased or enhanced by decreasing or increasing the action of a single molecule, demonstrating a much more dynamic mechanism than previous models had predicted.

To some, the thought that the memory of our mothers and even of ourselves can be wiped out by a single dose of a drug is unbearable. But it is important to remember that the reason to study memory is to understand and treat psychiatric and neurological disease, and to gain knowledge of ourselves. The fact that something as stable as our long-term memory has now been shown to be as malleable as a chemical reaction in a test tube creates unique opportunities for addressing disorders of memory, from post-traumatic stress, phantom limb, chronic pain, and the amnesia of Alzheimer’s Disease. It also radically changes our understanding of ourselves.

How many other elementary particles of memory are there and do they interact? Eric Kandel’s lab has discovered a self-perpetuating prion-like molecule that may work together with PKMzeta to maintain memory. My WSF colleagues Dan Schacter and Liz Phelps have found that old memories can be distorted and manipulated at the cognitive and the emotional levels. Can these “top-down” levels of analysis interact with molecules, or do principles of memory function emerge that cannot be reduced to enzymes? Lynn Nadel and colleagues have theorized that a key area of the brain for memory, the hippocampus, acts as a “cognitive map.” What happens to the map when memories are erased? I look forward to discussing these and many others issues on June 3.

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