Eric Kandel

Another important perspective to consider, in order to continue the description of brain processes was, and continues to be, the investigation of the molecular mechanisms that underlie the workings of the nervous system.

In this aspect, it’s very difficult to forget to mention Eric Kandel, Nobel prize awardee of 2000.

Fig 1. Eric Kandel holding an aplysia.

Following Darwin’s thoughts, Kandel, was able to decipher the inner workings of high brain processes, such as learning and memory, in a meticulous study performed in the Aplysia, a sea snail.

“The difference in mind between man and the higher animals, great as it is, certainly is one of degree and not of kind”

Charles Darwin, 1871

The selection of this sea snail was not coincidental. Kandel understood that it had a convenient quality. It had a quite large, yet traceable number of individual neurons.
This enabled the tracking of the activity of each neuron in isolation, but at the same time, it makes possible to observe the details of the circuits and connections among them.

To start his experiment, he made sure two prerequisites were present. First, Aplysia was susceptible of habituation, sensitization and classical conditioning, and exhibited the gill withdrawal reflex behavior.
And second, Kandel and his group, made sure that this reflex could be modified by the three learning processes mentioned before.

He actually demonstrated, that these particular reflex could be modified in more than one way.
Next step, was to elucidate the complete neuronal circuit involved in the gill withdrawal reflex.

In a semi-intact preparation, the behavioral response of the reflex and the electrical activation of neurons were visible. He could examine physiological changes of the individual neurons on the circuit.

This model, made possible to isolate precise neurons that were modified as a consequence of previous learning, and in this way, recognize the specific characteristics of the modification.
Having this experimental model thought out, he described the habituation phenomenon.
Habituation, looked, in the molecular level, like the consequence of a decrease in the synaptic force of the sensitive neurons to interneurons, reason why, there was less neurotransmitter release.

In the case of sensitization and classical conditioning, the mechanism was the contrary, presynaptic facilitation, more neurotransmitter in the synapsis. There was a reinforce in the synaptic force between neurons and interneurons.

The molecule on charge of this presynaptic facilitation happened to be cAMP (cyclic adenosine monophosphate). Conditioning to stimuli or sensitization causes an increase in the level of cAMP, so there’s more availability to join the regulatory unit of PKA (protein kinase A), that liberates its catalytic unit. This produces a calcium burst, inside the neuron’s terminals. The final consequence is more release of neurotransmitter, an increase in the synapse force.

These two explanations define two important aspects of the learning process, associative and non-associative learning. Kandel recognized a shared molecular mechanism between these two events.

Learning is reversible, Kandel was well aware of this, so he didn’t neglect this feature in his research. Taking in account the retention time of each learnt conduct, he used the categorization applied by psychologists, between Short Term Memory (STM) and Long Term Memory (LTM).

He proved that the physical base of STM is an elevated level of cAMP, and the resulting modifications of the structure of certain proteins and their function. When cAMP begins to disappear, the short term memory starts to vanish.

In the case of LTM, with the multiple stimulation of the conduct, some of the PKA catalytic subunits induced by the typical cascades produced by STM in the interior of the cell’s nuclei, lead to the interaction with transcription factors, especially CREB1 and CREB2. CREB2 is a represor for LTM and CREB1 induces LTM. The central role for PKA is to oposse to the repression by CREB2 and to activate CREB1.

Later studies confirmed this paradigm. In the final steps of the process of LTM formation, a strengthening connection forms, when new synaptic contacts are stablished. This is known as consolidation.

Kandel has demonstrated in his later work that this mechanism in the general aspects, also applies to the mammalian’s hippocampus. It’s a much more complex structure so there’s also more mechanisms, like Hebbian learning, but the base, the involvement of cAMP, is the same.

This impressive work is being followed since then, and the goal of explaining all relevant conducts at a molecular level is one of the biggest challenges for Neuroscientists.

This inaugarated the field of mental biology, in Kandel’s words:

“New mental biology suggests that not only the body, but also the mind and specific molecules intervening in higher cognitive functions – consciousness of oneself and of everybody else, of the past and the future – evolve since the times of our ancestors. Moreover, this new biology postulates that consciousness is a biological process that, at the appropriate time, could be explained in terms of the molecular signaling pathways applied by the nervous cells populations interacting among them.”

In search of memory: the emergence of a new science of mind. Eric Kandel, 2006.


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