Learning Memory Lessons From Aplysia

While you are reading this on your computer, there may be many distractions in the background. Your mom may be shouting at someone or your daughter may be receiving her piano lessons. But after you finished reading this, no memory trace of this background remains. They are not registered with your memory. We seem to ignore this 'negative memory' by a process called 'habituation'. We remember by consolidating memories by another process known as 'sensitization'. But what is this that we call memory? Memory helps us to store, retain and retrieve information. To start it all, learning is needed.

Now you might ask why Aplysia out of all animals?

Aplysia californica, called 'sea hare' by the ancient Greeks, is a marine snail which has some resemblance to a rabbit. A hermaphrodite by sexual orientation, Aplysia feeds on marine algae, and often takes the color of the algae that it eats. When threatened, it liberates a colored, irritant compound to blind the attacker, as seen in the left. It was Eric Kandel who used this phenomenon to study how neural transmission occurred through synapses. He was awarded the Nobel Prize in Physiology or Medicine in 2000 for his pioneering work on Aplysia. Aplysia offers a distinct advantage by: 1. eliciting a visible (measurable) response (siphon-mediated gill withdrawal reflex) to a stimulus, that can be studied directly; 2. the response is triggered by several electrical synapses firing simultaneously, exemplifying several output in response to a single input; 3. Smaller number of neurons, about 20,000; 4. BIG neurons. Hence this animal is considered a role model in neurobiology.

The organism can be stimulated by the application of a minor electric shock to one side of the siphon, and the magnitude of response can be measured by a force transducer, a device, usually piezoelectric, which converts mechanical pull in terms of electricity. Applying a more intense shock to the tail, or administration of chemicals into its abdominal ganglion are other ways of stimulating the mollusk. After careful observations, scientists postulated that habituation, sensitization and classical conditioning were responsible for the learning that occurred in Aplysia.

In the picture on the left, you can see a presynaptic neuron on the left side, a postsynaptic neuron on the right and another neuron (facilitator terminal) on top left stimulating the presynaptic neuron. The flow of impulse propagation is from left to right, that is, from presynaptic to postsynaptic neuron. When the presynaptic neuron was stimulated alone, the post-synaptic neuron responded in a ‘what is it’ response. When the stimulus was given repeatedly, then the response of the post-synaptic neuron became less and less. This implies that the post synaptic neuron became as if ‘habituated’. On the other hand, when a noxious stimulus was applied at the ‘facilitator terminal’ at the same time the presynaptic neuron was stimulated, the response became stronger and stronger. They called this ‘sensitization’.

In the case of habituation, it was found that the release of neurotransmitter diminished in the presynaptic neuron, possibly due to progressive inactivation of calcium ion channels. It is the calcium ion channel which allows degranulation and release of neurotransmitters. Thus inactivation means blockage of impulse. Structurally, both the presynaptic vesicle number and size are seen to decrease in habituation.

In sensitization, both the presynaptic vesicle number and size increase. Here the ‘noxious stimulus’ delivered alongside, causes release of serotonin from the facilitator terminal. This chemical, also called 5HT, binds with 5HT receptors in the presynaptic terminal. This is followed by activation of an enzyme known as adenylyl cyclase, which in turn produces cyclic AMP from ATP. cAMP then activates another enzyme, protein kinase A (PKA), which phosphorylates potassium ion (K+) channels. As a result K+ channels get blocked. When an imulsee arrives at the synapse, the membrane gets depolarized, i.e., the inside of the cell becomes positive with respect to the outside. For the cell voltage to return to its normal polarized state, the potassium ions must diffuse out, through K+ channels. But the exit route is blocked now. The action potential remains longer; more Ca++ enters into the presynaptic terminal.

Recent evidence points at the role of post synaptic neurons in habituation, sensitization and classical conditioning. Glanzman et al have proposed that activation of postsynaptic glutamate receptors might play a critical role in mediating long-lasting habituation of gill withdrawal reflex in Aplysia. A whole new range of activity starting at the synaptic knob to the nucleus and thence back to the knob again has been proposed for memory storage.

Short-term memory, which usually lasts for a few minutes, involves covalent bonding of pre-existing proteins leading to alterations in the strength of already existing connections. By contrast, long-term memory requires mitogen activated protein kinase (MAPK), CREB and new mRNA and protein synthesis; in addition to PKA.

MAPK migrates into the nucleus where it phosphorylates cAMP-responsive element binding protein (CREB). This then regulates gene expression, resulting in transcription and translation. Moreover, long-term memory is associated with the growth of new synaptic connections, phosphorylation of post synaptic densities (PSD is like a scaffold on which proteins are assembled) and many other processes. Thus it seems post synaptic mechanisms might have a bigger role than imagined.

So far, we discussed about only one form of memory: implicit or non-associative memory. Declarative or explicit memory consists of semantic (book) and episodic (related with places, memory of events) memory, which are consciously stored. Humans are perhaps, the best or only known subject in this regard. We certainly can't expect Aplysia to speak out.

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References:
Prolonged Habituation of the Gill-Withdrawal Reflex inAplysia Depends on Protein Synthesis, Protein Phosphatase Activity, and Postsynaptic Glutamate Receptors
Youssef Ezzeddine, David L. Glanzman

Molecular Mechanisms of Memory Storage in Aplysia
Robert D. Hawkins, Eric R. Kandel and Craig H. Bailey

C. Bailey, M Chen (1983). Morphological basis of long-term habituation and sensitization in Aplysia Science, 220 (4592), 91-93 DOI: 10.1126/science.6828885