Click for printer friendely version of this HowTo A digression: the biological basis of memory and learning Eric Kandel and his laboratory [11,12,13] used the sea snail (aplysia) to demonstrate the mechanisms that implement neuronal learning. Exploring the siphon withdrawal reflex1.1, they found that learning was activity-dependent. That is, training (repeated stimuli) that occurs frequently appeared to result in more reliable learning than infrequent stimulation. Since memory is not magic, then there must be a change within a cell or within a network of cells that reflects the learned or memorized element. Our guess is that short term memory is probably the result of intracellular accumulation of calcium1.2, Ca, associated with repeated training episodes. Long term memory probably reflects structural changes, either an amplification or attenuation of expression of a cellular signal receptor or channel. If short term memory is the result of the accumulation of intracellular Ca, then there must be some means for controlling this accumulation. An action potential1.3 of some duration is generated each time a cell is excited by a suprathreshold stimulus. The action potential represents the competition between inward (depolarizing) and outward (repolarizing) currents and its duration reflects the magnitude of the net inward or net outward current (net current = inward - outward). An inward sodium ion, Na$^{+}$, current flowing through sodium channels is usually responsible for initially depolarizing a neuron and generating an action potential. An outward K current is usually responsible for restoring the charge balanace that is altered by the influx of Na. Because calcium channels are open at potentials more positive than the sodium channel activation potential, they are open during a large portion of the action potential. The length of time the calcium channels remain open is determined by the duration of the action potential, which in turn is determined by the amplitude of the repolarizing potassium current(s). Large K$^{+}$ currents will rapidly repolarize the cell while small K$^{+}$ currents will prolong the duration of the action potential. Consequently, the calcium influx can be controlled by altering the the availability of potassium channels. Some potassium channels are activated by intracellular second messengers. These receptor-linked channels are sensitive to extracellular neurotransmitters (ACh, serotonin, GABA, dopamine) and provide a way of communicating extracellular events (presence of a neurotransmitter in the vacinity of a membrane-bound receptor) to an intracellular process (generating an action potential). When the time between training episodes (activation of a channel or activation of a receptor) is greater than the time required to restore the balance of intracellular agents reflecting short term meory, then there will be no accumulation and thus no learning. Its easy to understand why rereading a poem 1/year is less likely to result in memorizing the poem than rereading it 1/hour. If, on the other hand, the time between training episodes is less than the restoration time of the intracellular Ca, then the intracellular [Ca] will increase until a threshold is reached (my guess). The protein expression machinery is probably activated when this threshold is exceeded - resulting in either expressing something new, or amplifying/attenuating the expression of existing cellular component, for example, a receptor, such that the cell will have a permanently increased sensitivity to a circulating neurotransmitter. We speculate that short term memory reflects accumulation of something while long term memory reflects a structural change in the cell or cellular network. Given this view, its interesting to look at forgetting and unlearning. The less something is used, the more likely it will be forgotten. On the other hand, something that is frequently used will be reinforced. To unlearn a frequently used habit thus requires significant expenditure of effort - either to reverse the structural changes or to disable the structrual changes. If someone want's a great research project - we suggest exploring the molecular process of forgetting - to complement Kandel's work on remembering. This model suggests a main idea: Repetition is essential for most types of learning. We'll simply state that Repetition is the first law of learning! Click for printer friendely version of this HowTo

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