101 Theory Drive: A Neuroscientist’s Quest for Memory
Citation (Chicago Style): McDermott, Terry. 101 Theory Drive: A Neuroscientist’s Quest for Memory. Knopf Doubleday Publishing Group, 2010. Kindle edition.
Chapter One – The Talking Cure
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“investigator dependent,”
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is far smaller than the thickness of a human hair, yet it contains many thousands of proteins, acting sometimes in unison, often in opposition, almost always in complicated combinations.
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a process called long-term potentiation (LTP) is the means by which memory is encoded, and if memory is to be long-lasting, then brain cells have to change shape during LTP, and networks of these cells with altered shapes are the underpinning of memory. The details of the biochemical
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Christine Gall,
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ampakines,
Chapter Two – Seeing
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(The latter frequent flier proteins are often referred to as hormones.)
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molecular biology, removing a gene was typically referred to as ablating it; the equivalent term in cognitive psychology was lesioning.
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Potentiation in essence is an increase in the current passing between neurons. It seemed that the only way more current could be passed was to strengthen connections between neurons.
Chapter Three – A Strange Damn Place
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Chapter Four – A New and Specific Hypothesis
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than feeding. This was an enzyme in search of something to do. This, of course, was my point. The double deal you made with the devil: you go to stability, and the technology you’re using to dismantle stability, it goes a little too far, you’re done. I think that’s what goes on in the brain with aging.
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The issue was: did the fundamental activity that caused LTP to persist happen on the axon side of the synapse (the so-called presynaptic side) or on the dendritic spine (the postsynaptic side)?
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range. LTP was strongest when the time between bursts was about 200 milliseconds, equal to the rate of approximately five per second, or five hertz. This rate was remarkably similar to a natural rhythm in the mammalian brain, called theta rhythm, that had been discovered in the mid-1950s and occurs in the hippocampus when an animal is alert and exploring new environments.
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Action potentials are a nearly constant process in an awake brain, firing at a rate of up to seventy times per second, the so-called
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gamma rhythm.
Chapter Five – Exile
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squat. Is [using immature cells] a consensus scientific judgment, or is it Jacques Derrida?
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This ability to customize genes, and thus the activities they dictate, is fundamentally what is meant by genetic engineering, or recombinant genetics.
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Chapter Six – The History of Life on Earth
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If the model was correct, categorization took place inside the brain unconsciously at the neural cellular level. LTP sculpted the world even as it was being experienced. Such a system ought to multiply the storage capacity of the cortex many times, by the mere fact of making the categories.
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because the universe is filled with causal relationships within that time frame? I don’t think so. It’s because you inherited this olfactory system from some shit-ass primate 150 million years ago.
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Linda Palmer,
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Her hypothesis is that the brain, through LTP, generates a feeling of satisfaction when new inputs are made to align with old inputs already clustered and categorized.
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“The images in our mind are extraordinarily rich. We can tell if something is liquid or solid, heavy or light, dead or alive. But the information we work from is poor—a distorted, two-dimensional transmission with entire spots missing. So the mind fills in most of the picture.”
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It would seem to be a de facto molecular explanation for human stereotyping and an insight into the power of narrative on the human imagination. Narrative is a form of categorization, taking a nearly random set of experiences and shaping them into coherence.
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We automatically try to fit our experiences of the world into the shape we’ve already built inside our heads.
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“The rest of the world never understood the idea that LTP research threatens to reduce issues that occupied the boys from Kant to Chomsky,” Lynch said.
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There the neurons controlling respiration are very different. In other words, specialized adapted neurons are archaic. The evolutionarily advanced stuff is random and generalized.
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Carl Cotman
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Ralph Bradshaw,
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The family of drugs currently used to treat depression, for example, was developed as treatment for tuberculosis. People administering the drugs in a tuberculosis sanitarium noticed they weren’t having much effect on the disease but that their patients, while still sick, were a lot happier.
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ampakines.
Chapter Seven – Everything Falls Apart
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They had demonstrated how LTP was initiated and revealed some of the molecular details incorporated in its process. They had arrived at a rough consensus that the defining activity of LTP occurs at the synapses where neurons meet and specifically at the neurons on the postsynaptic side of these junctions. They still did not know many or even most of the details of the chemical interactions that LTP includes. More important, they still did not know for sure what if any changes LTP induces that cause a prolonged, perhaps permanent increase in the amount of current that could pass through a neural circuit. Lynch had proposed in the 1970s that the increase in current could result only from some structural changes within the neurons themselves.
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The larger purpose was to provide a final proof of Lynch’s longstanding hypothesis that LTP was the construction of neural networks underlying memory, made possible by structural changes in the neurons within those networks.
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actin, a structural protein.
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integrins.
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determine whether Lynch was correct in proposing that the whole physical remodeling, the actin polymerization, was the direct result of LTP induction and part of the chain that strengthened connections between neurons, those strengthened connections constituting the underpinning of memory.
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“You know the song, ‘War, what is it good for?’ Well, it turns out war is really good for neurobiology.” World War I, in particular, with its onslaught of new explosive weapons technology—mines, artillery, bombs—and the resultant millions of casualties had been a boon for brain science.
Chapter Eight – A Good Rain
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No one remembers or would want to remember everything. Walk down the block, go to the corner store, buy a cup of coffee, and go home. What of that will you want to remember? Likely very little. There has to be a way to get rid of stuff. Sharp waves—in essence, letting the mind wander—seemed a candidate to erase current experience from memory.
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Some of the inputs encourage LTP; others inhibit it. Such dual-modulated, so-called homeostatic systems are common in mammalian biology. They can fail from either direction—too little incitement or too much inhibition. The brain is a particularly complicated equilibrium machine.
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The brain seemed to have two systems for erasure—excess accumulation of adenosine and sharp waves.
Chapter Nine – A Magic Potion
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lab had for the first time demonstrated, and illustrated, the physical reorganization of cells that occurs in the final stages of long-term potentiation.
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Lynch was convinced that many neurological diseases—Alzheimer’s, Huntington’s, Parkinson’s—are in part caused by the normal wear and tear that accompanies aging. Aging effects combined with specific disease malfunctions, some of them genetic in origin, lead to mental difficulties, memory loss among them, he thought. Because aging is not literally a disease but a normal fact of life, its study is not pursued with the vigor and resources devoted to diseases. Lynch thought ampakines could help ameliorate many brain diseases simply by increasing
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the efficiency of neuron-to-neuron signaling—in effect, compensating for aging. It wouldn’t cure the diseases, but it would relieve some of the most damaging symptoms.
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brain. More cortex, less lizard brain. Try to lift the species out of the puddle of its own crap, and what do you get?”
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I wonder if a great deal of what goes on with the brain is the plasticity mechanism. And that’s what you lose as you age.
Chapter Ten – Triumph and Disaster
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When you experience a sensation in the outside world, perhaps seeing, smelling, or touching something, the sensory organs translate the sensation into an electrical signal that is routed to the brain. There it causes the neurons that receive the electrical stimulus to release chemicals to neighboring neurons. A cascade of chemical events inside those neighboring neurons results in the interior reorganization of spines on the neurons’ dendrites. That reorganization, in turn, strengthens the connection between cells at the synapses. The broader hypothesis is that networks of neurons with strengthened connections constitute the biochemical underpinning of memory.
Chapter Eleven – The Kids
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This is yet one more example of what a bizarre mess human biology is. Memory encoding happens because something is turned off?
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The experiments indicated that Huntington’s, Parkinson’s, mental retardation, and, out of left field, menopause all gave evidence of LTP deficiencies well before any physical symptoms appeared.
Chapter Twelve – The Failure of Science
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The process had been resolved to a largely accepted standard schematic: theta bursts open channels into the neuron; ion influx activates the disassembly of the cell cytoskeleton; it is followed by reassembly, otherwise known as the actin polymerization machinery; the polymerization leads to a shape-change on the dendritic spine, locked in by the integrins; the shape-change makes room for more AMPA receptors at the synapse. The greater number of receptors strengthens the likelihood of synaptic communication.
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that produces it was identified long ago, and it has nothing to do with “brain-derived neurotrophic factor,” or BDNF, otherwise known to Lynch as Big Deal Neurotrophic Factor.
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One analysis has estimated that by 2055 Alzheimer’s will cost Medicare more than $ 1 trillion annually.
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is that the presumed substrate of memory is implicated in so many nonmemory activities. “I now suspect,” he notes, “that many diseases involving memory-cognition defects will ultimately screw up the theta-integrin-BDNF–actin polymerization–shape change–synapse change–LTP process. They come at it from different directions, but at some point mess it up. This
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Haldane: “Theories have four stages of acceptance: (1) this is worthless nonsense; (2) this is an interesting, but perverse point of view; (3) this is true, but quite unimportant; (4) I always said so.”
Chapter Thirteen – “So we come to another one of those jump-off-the-cliff moments”
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tied to oscillations—sharp waves, theta pulses—then the whole idea of learning will have to be broken into two phases—acquisition and shaping—with both under the control of entertaining variables. … The basal-dendrite stuff and mossy-fiber results suggest the brain is breaking up the memory problem and assigning the parts to different anatomical systems. In other words, the idea of continuous uniform memory is a perceptual illusion, something produced by brain.
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was in charge of this process. You might compare it to building a computer operating system. The two best-known designers of operating systems are Apple and Microsoft. Apple’s software is highly praised for its intuitive design and simple elegance. Microsoft, contrarily, is criticized for its bloated, all-things-for-all-people messiness. Its operating systems are routinely decried as kluges, not built from the ground up but patched together out of existing parts, only some of which worked well in their initial iterations. Microsoft doesn’t do this because its software engineers are idiots. Its kluginess owes in large part to the corporate decision to make its operating systems as backward-compatible as is practically possible. Apple, valuing its aesthetics over its customers, often goes back to a clean slate. Sadly for us, we are all PCs. Our operating system was very definitely not built from the
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We now have three signaling phases following TBS [theta burst stimulation]. The first goes from a few seconds to several minutes, the second from 1.5 to 10 minutes, and the third from 7 to maybe 60 minutes. It is very, very weird that you can stack things up across time like this in the tiny volume of a spine head. Step one generates potentiation. Step two assembles the actin filaments. Step three stabilizes them.
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The concepts that we call thought, cognition, consciousness, and memory are obviously related. You can’t have memory without the others preceding it. Gerald Edelman, a Nobel laureate biologist who has devoted the second half of his career to the study of consciousness, has elegantly captured the nature of at least a portion of the relationship by describing consciousness as “the remembered present.”
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“consciousness emerged when continuity of brain operations extended into the many-seconds range,” that is, “when memory became so dense, and interconnected, that the brain noticed that it, the observer-generator, was always absent from the incredibly detailed pictures.”
Selected Bibliography
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Linden, David J. The Accidental Mind: How Brain Evolution Has Given Us Love, Memory, Dreams, and God. Cambridge, Mass.: Belknap Press of Harvard University Press, 2007.