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A book by
William H. Calvin
The Throwing Madonna
Essays on the Brain
Copyright 1983, 1991 by William H. Calvin.

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Scanned, OCR'ed, and webbed -- but NOT proofread (14 Jan 97)


Aplysia, the Hare of the Ocean

But the cortex is an enormous haystack and we are more likely to find our needles in some smaller bundle.
J. Z. YOUNG, Programs of the Brain

This sea-slug [Aplysia] is about five inches long; and is of a dirty-yellowish colour, veined with purple.... It feeds on the delicate seaweeds.... This slug, when disturbed, emits a very fine purplish-red fluid, which stains the water for the space of a foot around.

CHARLES DARWIN, Voyage of the Beagle

It can look like an underwater bunny, munching happily upon some underwater greenery, with ears standing up waving in the water. But the ears are not for hearing. They are rhinophores, and they taste the water. And at closer look, this animal is more akin to an overgrown garden slug than to an undersized garden rabbit. It is Aplysia, the "sea hare." Sometimes described as a shell-less snail, it too is a gastropod mollusc, seagoing edition (pronounced, in case you're wondering, ah-plea-see-ah).
      But unlike its shelled relatives, it will never wind up as a culinary delight substituting for the European snails known familiarly as escargots. It doesn't need a shell for protection: the secret of Aplysia's success is that it tastes bad. Even sea anemones, which will eat anything, spit out Aplysia. In fact, its major known predator is the neurobiologist, who can be seen wading around in the intertidal waters off southern California, in the Gulf of Mexico, or in the Mediterranean searching for a prized specimen amongst the seaweed with the dedication of a truffle hound. Most of the Aplysia familiar to neurobiologists eat a different species of seaweed than the ones Darwin saw in St. Jago in 1832, and consequently have far more purple than yellowish color. You are what you eat.
      If cows are sometimes uncharitably described as machines for turning grass into beefsteak, so Aplysia might be said to turn seaweed into knowledge about the brain. Its remarkable facility in this regard is hardly due to being especially smart, or athletic (stupid and sluglike are the descriptions that more often come to mind), or being adapted to a strange environment (it has not yet seen fit to crawl ashore in southern California). It became popular with neurobiologists because its nerve cells were so pretty. True, they are often pigmented a bright orange, hardly what one might expect for invertebrate gray matter (and in a purple-colored animal, at that). But the beauty of the Aplysia's nerve cells lies more in their size than in their color: they are often ten to fifty times larger than the cells of mammalian brains. And neurobiologists, whose attempts to stick glass pipettes into them are sometimes reminiscent of spearing apples floating in a barrel, appreciate an easier target (neurobiology was revolutionized in 1936 when J. Z. Young discovered a nerve fiber in the squid more than 1 millimeter in diameter).
      Yet much the same appreciation could be made of neurons in other snails, and indeed Helix species have also earned an honored place on the neurobiologist's workbench (and, once the nerve cells have been removed and garlic added, upon a student's dinner table). What is so nice about Aplysia is the familiarity with which one can get to know its nerve cells as individuals. The cell named R2 is the biggest. There is only one per animal. It always lives on the right side of the abdominal ganglion. Its membrane beats electrically, producing a familiar "R2-like" sound (provided, of course, that one listens in by inserting a glass pipette into the cell and hooking it up to a hi-fi system). The shape of R2 isn't always the same from one animal to the next, but there is no mistaking that forked branching pattern or that wrinkled membrane. When the neurobiologist can get to know a cell so well, it becomes an "identified" cell and is added to the map of the Aplysia nervous system which adorns the office wall of many a neurobiologist.
      Accustomed as we are to a society of unique individuals with their own names, this may not seem special--until you try "identifying" the nerve cells in a fancier brain. There are only two identified nerve cells in the fish brain, and none yet in higher an~mals. In Aplysia, there are almost a hundred identified cells-- still only a small fraction of the total number of Aplysia nerve cells, but an especially useful subset. Some of them are sensory cells, detecting a touch or water current, conveying electrical impulses from the skin into a ganglion of many hundreds of nerve cells where decisions are made. Some of the identified neurons are the motor neurons in the ganglia which send electrical impulses out to a muscle, causing contraction and movement. But some neurons are simply decision-makers, interneurons with no branches coming or going from the skin and muscles. So sensory neurons deliver impulses to interneurons and motor neurons; interneurons affect the motor neurons and modify the messages sent by the sensory neuron endings upon the motor neurons. As more and more of these interneurons have become identified, neurobiologists have been able to figure out some of the basis for learning and memory in these animals.
      One cannot expect an Aplysia to memorize a list of telephone numbers, so learning experiments tend to focus upon simple behaviors and how they come to be modified. If you touch an Aplysia anywhere near its gill, it withdraws and folds a flap of skin over the gill for protection. Touchy beast. But repeated attempts to touch its gill result in less vigorous withdrawals: the beast gets used to the stimulus--or as the technical term goes, it "habituates." Wouldn't it be nice, some neurobiologists mused in the late 1960s, to find the mechanism that altered within the nerve cells and caused this weakened response?
      That started a long detective story. Maybe the sensory neuron was the culprit, giving a weaker response to the repeated stimuli? So a fine glass needle called a microelectrode was inserted inside a sensory neuron to measure the electrical responses. They didn't change with repeated stimuli.
      Maybe the motor neuron or the muscle was giving less response to a standard stimulus from the sensory neuron? So the microelectrode was inserted into the motor neuron and an electrical current passed which mimicked the current produced by the initial sensory barrage. Every few minutes, the intracellular current mimicked a standard sensory barrage. The muscle contraction that moved the gill was examined to see if it was becoming weaker. Not notably, sorry.
      Well, if it isn't the sensory neuron's barrage or the motor neuron's responsiveness that alters, what is left? The sensory neuron makes direct connection to the motor neuron, but it is possible to alter the strength of the connection. This connection site, called a synapse, uses chemical processes in a manner that the remainder of the cell avoids (most of the rest of the cell runs on electricity, pure and simple). When the electrical nerve impulse arrives from the sensory endings in the skin, it allows some calcium to enter the nerve terminals. That causes a chemical substance to be released (called a neurotransmitter; it is a simple molecule). That neurotransmitter spreads through the bodily fluids a very short distance to the motor neuron and opens up some channels through its membrane, which causes its voltage to increase. If that seems complicated, it is. Indeed, it offers all sorts of opportunities for nature to modify the system to produce learning. But, as it happens, only the first part of it is important for our story (if you yearn for more, start by reading Chapter 9 of Inside the Brain). [1997 note: it's out of print, try Chapter 6 of Conversations with Neil's Brain].
      So next our neurobiological detectives tried examining the size of the barrage in the sensory neuron as observed from inside the motor neuron. And, while it hadn't changed as viewed from inside the sensory neuron, it was getting smaller and smaller when viewed from inside the motor neuron. The synapse was changing its strength. But how?
      The easiest possibility is that less neurotransmitter was being released from the terminals of the sensory neuron. Because the space in between neurons is so small and hard to locate, this could not be tested directly--but a series of more indirect measurements suggested that there probably was indeed less release. So maybe it was just fatigue in the release mechanisim, or maybe supplies of neurotransmitter ran short?
      No, because the usual amount of release can be instantly restored by a simple maneuver: just deliver an electric shock to the head end or the tail end of the animal, far away from the gill, and the gill-withdrawal reflex will get much bigger. And how does that work? What neural pathway from head or tail manages to affect the terminals of the gill sensory neuron ending upon the gill motor neuron, so that they again release a lot of neurotransmitter? Fans of English murder mysteries may even recognize this involved plot.
      To make a long story short, the culprit is serotonin or something related to it. Serotonin is a common neurotransmitter even in human brains where, among other things, it regulates sleep and wakefulness. And mood: serotonin imbalances are thought to be involved in severe depressions. Neural pathways from the Aplysia head or tail seem to release some serotonin somewhere near the synapse connecting the gill sensory neuron and the gill motor neuron, and that somehow serves to increase the neurotransmitter release and hence augment motor neuron responses and produce a more vigorous gill withdrawal.
      The details of the augmentation pathway are even becoming obvious. Serotonin (1) affects the synthesis of cyclic AMP (2), another Umessenger molecule" acting inside the neuron. Which in turn activates a protein kinase (3). It closes down a channel through the membrane used by potassium ions (4). That prolongs the next nerve impulse (5) in the terminal (potassium flows limit the impulse duration, so less is more), which allows more calcium to enter the terminal (6) and release more neurotransmitter (7). All clear? Even if it isn't, perhaps you will understand the power of the reductionist scientific approach which dissects the mechanism into its seven (so far) component pieces. That is how you come to understand how nature can modify systems such as these to produce learning and memory. Even the potential mechanisms which, it turned out, were not used in Aplysia learning (such as cyclic AMP effects directly upon calcium channels) may prove useful in analyzing other systems: once you learn how to eliminate the possibility in one animal, you often have the tools to check out other animals. It seems likely that some of the other potential mechanisms are used elsewhere. It will surprise no neurobiologist if those Aplysia results aid the study of human learning--and learning disorders.
      But, you may say, surely habituation is a trivially simple kind of memory. Simpler even than Pavlov's dogs salivating to the bell alone, without food present. Can we perhaps get the Aplysia to respond to a Pavlovian paradigm, where we pair an innocuous stimulus with a more meaningful stimulus--and get an augmented response next time to the innocuous stimulus alone? Yes indeed, though it took a decade to learn how to do the experiment the right way.
      Take two different sensory neurons leading from the gill to a gill motor neuron. Each produces a standard-size response in the quiet animal. Now shock the tail--but lightly, not so strongly that it greatly augments the gill-withdrawal reflex as before (or increases synaptic strengths generally, which is called "sensitization"). This is what prevented the following experiments from being done for a decade, until someone tried turning the shock strength way down. Like Pavlov pairing food with a bell, the researchers tried pairing the mild tail shock with a sensory barrage in one of the two sensory neurons. For us to say that associative learning took place, the tail shock would have to affect only that one sensory neuron whose activity coincided with the tail shock, not other sensory neurons generally.
      And it worked. If the tail shock was given shortly after the sensory barrage, things changed for hours thereafter: succeeding sensory barrages in that one cell would produce much larger responses. That demonstrates a short-term memory of the impulse which is "developed" by the tail shock to cause a more long-lasting change. The synapse became far stronger. Indeed, even without further conditioning, the strength of the synaptic connection grew for many hours after the first pairing, suggesting that the results may provide a model for the consolidation of long-term memory as well as short-term memories in Aplysia.
      And surprise: If the tail shock occurred before the sensory neuron's impulse arrived, nothing much happened. As they say, time has an arrow: Only sensory barrages preceding the noxious tail shock served to prime things so that subsequent gill withdrawals were augmented. There was something about the aftermath of the impulse in the terminal of only that one sensory cell which primed it to respond to the (presumably serotoninmediated) message from the tail shock. The other sensory neuron, not itself activated before the tail shock but only at other random times, was modified only a small amount (i.e., there was thus a little nonspecific sensitization from the tail shock).
      It is indeed a long way from such Aplysia learning to explaining associative conditioning in Pavlovian dogs, much less to memorizing telephone numbers. But at each stage of our analysis of human brains, we have typically found that simpler animals share the same phenomena. The nerve impulses that I record from human brains look just like those I record from lobsters (well, almost--I can tell them apart, but I'm an expert on irrelevant small details). They typically share the same underlying basic mechanisms: the same neurotransmitters, the same calcium channels, the same modular neural circuits (such as seen in the withdrawal reflex), and so on. And the same biophysical principles apply all up the scale.
      Serotonin-augmented synapses in Aplysia may well be a model for one kind of human learning. It may someday even help explain some of the characteristic features of depressive mental illness (several of the leading neurobiological researchers in the invertebrate area are indeed trained psychiatrists). It is the research laboratories of one of those physiological psychiatrists, Eric R. Kandel, at Columbia University, which has been the focus of much of the Aplysia learning work just mentioned, with Tom Abrams, Bob Hawkins, and Tom Carew being particularly responsible for this latest breakthrough in paired conditioning. But there are many invertebrate researchers scattered around the U.S., Canada, and Europe (indeed, Ken Lukowiak's lab in Calgary and John Byrne's lab in Houston reported complementary results at the same time). It is this vigorously interacting community of workers that has made this field of neurobiology one of the most exciting areas of our research into how brains modify themselves.
      But some credit must go to the "stupid slug" for having become such an accessible haystack.

The Throwing Madonna:
Essays on the Brain
(McGraw-Hill 1983, Bantam 1991) is a group of 17 essays: The Throwing Madonna; The Lovable Cat: Mimicry Strikes Again; Woman the Toolmaker? Did Throwing Stones Lead to Bigger Brains? The Ratchets of Social Evolution; The Computer as Metaphor in Neurobiology; Last Year in Jerusalem; Computing Without Nerve Impulses; Aplysia, the Hare of the Ocean; Left Brain, Right Brain: Science or the New Phrenology? What to Do About Tic Douloureux; The Woodrow Wilson Story; Thinking Clearly About Schizophrenia; Of Cancer Pain, Magic Bullets, and Humor; Linguistics and the Brain's Buffer; Probing Language Cortex: The Second Wave; and The Creation Myth, Updated: A Scenario for Humankind. Note that my throwing theory for language origins (last 3 essays) has nothing to do with the title essay: THE THROWING MADONNA is a parody (involving maternal heartbeat sounds!) on the typically-male theories of handedness.
Many libraries have it (try the OCLC on-line listing, which cryptically shows the libraries that own a copy), and used bookstores may have either the 1983 or the 1991 edition.

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