marcello_mercado

The behaviour of synapses can be modified

Cellular mechanisms of learning

by Erik Kandel

At the end of the 19th century Ramón y Cajal introduced the principle of connection specificity, according to which, during development, a neuron will form connections only with certain neurons and not with others. Kupfermann, Castellucci, and I saw in the circuitry of the gill-withdrawal reflex of Aplysia this remarkable regularity of connections that Cajal referred to and we saw, in exquisite detail, that specific identified cells made invariant connections to one another. But this invariant organization of neurons posed deep questions. How could we reconcile hardwired circuits in the nervous system and the specificity of connections with the animal's capability for learning? Once acquired, where or how is learned information retained in the nervous system?

One solution was proposed by Ramón y Cajal in his Croonian Lecture to the Royal Society of London in 1894 when he suggested that "... mental exercise facilitates a greater development of the protoplasmic apparatus and of the nervous collaterals in the part of the brain in use. In this way, pre-existing connections between groups of cells could be reinforced by multiplication of the terminal branches of protoplasmic appendices and nervous collaterals."

This remarkably prescient idea was by no means generally accepted. On the contrary, different theories of learning at various times held the attention of neural scientists. Two decades after Ramón y Cajal's proposal, the physiologist Alexander Forbes suggested that memory is sustained not by changes in synaptic strength of the sort suggested by Ramón y Cajal, but by dynamic changes resulting from reverberating activity within a closed loop of self-exciting neurons. This idea was elaborated by Ramón y Cajal's student, Rafael Lorente de Nó, who found in his own and in Ramón y Cajal's analyses of neural circuitry neurons that were interconnected in closed pathways and could thereby sustain reverberatory activity, thus providing a dynamic mechanism for information storage. In his influential book The Organization of Behavior (1949), D.O. Hebb proposed that a "coincident activity" initiated the growth of new synaptic connections as part of long-term memory storage. But for short-term memory, Hebb invoked a reverberatory circuit:

"To account for permanence, some structural change seems necessary, but structural growth presumably would require an appreciable time. If some way can be found of supposing that a reverberatory trace might cooperate with the structural change, and carry the memory until the growth change is made, we should be able to recognize the theoretical value of the trace, which is an activity only without having to ascribe all memory to it. The conception of a transient, unstable reverberatory trace is therefore useful. It is possible to suppose also some more permanent structural change reinforces it."

Similarly, in The Mammalian Cerebral Cortex, an influential book of 1958, B. Deslisle Burns challenged the relevance of synaptic plasticity to memory.

"The mechanisms of synaptic facilitation which have been offered as candidates for an explanation of memory ... have proven disappointing. Before any of them can be accepted as the cellular changes accompanying conditioned reflex formation, one would have to extend considerably the scale of time on which they have been observed to operate. The persistent failure of synaptic facilitation to explain memory makes one wonder whether neurophysiologists have not been looking for the wrong kind of mechanisms."

Indeed, some scholars even minimized the importance of specific neuronal connections in the brain, advocating instead mechanisms of learning that were partially or even totally independent of "pre-established" conduction pathways. This view was held by Wolfgang Kohler and the famous Gestalt psychologists, and subsequently by the neurophysiologists Ross Adey and Frank Morrell. Thus, in 1965, Adey wrote:

"No neuron in natural or artificial isolation from other neurons has been shown capable of storing information in the usual notion of memory. ... In particular, the possibility exists that extraneuronal compartments may participate importantly in the modulation of the wave process that characterize the intracellular records, and that these wave processes may rank at least equivalently with neuronal firing in the transaction of information and even more importantly in its deposition and recall."

Finally, there were memory macromolecular notions advocated by Holger Hyden, based upon his finding of changes in the nucleotide composition of RNA. He proposed that learning gave rise to a specific pattern of instructional neural activity that altered the stability of RNA molecules, so that one base can exchange for another. In this way, new RNA molecules are formed with new base sequences that are specific to the instructing pattern of neural activity induced by learning. Hyden's hypothesis thus implied that the patterns of stimulation activated by learning could introduce changes in RNA.

We were now therefore in a position to test experimentally which, if any, of these ideas had merit. Using the gill-withdrawal reflex, we quickly established that memory in the Aplysia nervous system is not represented in self-exciting loops of neurons but in changes in synaptic strength. We found that all three simple forms of learning - habituation, sensitization, and classical conditioning - lead to changes in the synaptic strength of specific sensory pathways, and that these changes parallel the time course of the memory process. These findings, which had been fully anticipated by our earlier studies of analogs of learning, gave rise to one of the major themes in our thinking about the molecular mechanisms of memory storage. Even though the anatomical connections between neurons develop according to a definite plan, the strength and effectiveness of those connections is not fully determined developmentally and can be altered by experience.

We therefore concluded the third of our 1970 series of consecutive papers in Science on the cellular mechanisms of learning with the following comments:

"... the data indicate that habituation and dishabituation (sensitization) both involve a change in the functional effectiveness of previously existing excitatory connections. Thus, at least in the simple cases, it seems unnecessary to explain the behavioral modifications by invoking electrical and chemical fields or a unique statistical distribution in a neural aggregate. The capability for behavioral modification seems to be built directly into the neural architecture of the behavioral reflex.

Finally, these studies strengthen the assumption ... that a prerequisite for studying behavioral modification is the analysis of the wiring diagram underlying the behavior. We have, indeed, found that once the wiring diagram of the behavior is known, the analysis of its modification becomes greatly simplified. Thus, although this analysis pertains to only relatively simple and short-term behavioral modifications, a similar approach may perhaps also be applied to more complex as well as longer lasting learning processes."

 

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En busca de la memoria de Eric KANDEL

La comprensión de la mente humana en términos biológicos se ha transformado en la tarea científica fundamental del siglo XXI. Queremos entender la biología de la percepción, el aprendizaje, la memoria, el pensamiento, la conciencia, y también los límites del libre albedrío. Hace apenas unas décadas era inconcebible que los biólogos estuvieran en condiciones de analizar estos procesos mentales. Hasta mediados del siglo XX, era imposible contemplar con seriedad la posibilidad de que la mente, el conjunto de procesos más complejo del universo, pudiera revelar sus secretos más recónditos en el análisis biológico y, menos aún, en el nivel molecular.

Los espectaculares progresos de la biología en los últimos cincuenta años nos permiten plantearnos hoy esos interrogantes. En 1953, James Watson y Francis Crick descubrieron la estructura del ADN y, con ello, revolucionaron la biología y aportaron un marco intelectual para entender cómo la información contenida en los genes controla el funcionamiento de la célula. Se comprendió entonces cómo están regulados los genes, cómo producen las proteínas que determinan el funcionamiento de las células y cómo el desarrollo habilita y bloquea genes y proteínas para establecer el plan general de un organismo. Una vez producidos estos avances extraordinarios, la biología pasó a ocupar un lugar de privilegio en la constelación de las ciencias, junto con la física y la química.

Con conocimientos flamantes y una nueva confianza, los biólogos volvieron su atención a la meta más alta: la comprensión biológica de la mente humana, empresa en pleno desarrollo hoy aunque alguna vez fue tildada de precientífica. En realidad, cuando los historiadores contemplan la travesía intelectual de los últimos dos decenios del siglo XX, subrayan probablemente con sorpresa que las iluminaciones más valiosas sobre la mente no surgieron de las disciplinas que tradicionalmente se ocupaban de ella -la filosofía, la psicología o el psicoanálisis- sino de su combinación con la biología del cerebro, síntesis que cobró impulso en los últimos años con los espectaculares avances producidos en la biología molecular. Ha surgido así una nueva ciencia de la mente que recurre a la poderosa biología molecular para estudiar los misterios de la vida que aún se nos ocultan. Cinco principios son el fundamento de esta ciencia mixta. En primer lugar, no cabe separar la mente del cerebro. El cerebro es un órgano biológico complejo que tiene una enorme capacidad de cómputo y construye nuestras experiencias sensibles, regula nuestros pensamientos y emociones y controla nuestras acciones. No sólo se encarga del comportamiento motor relativamente simple que desarrollamos para correr o comer, sino de complejos actos que reputamos como la quintaesencia de lo humano: pensar, hablar y crear obras de arte. Desde esta perspectiva, la mente es un conjunto de operaciones que lleva a cabo el cerebro, así como caminar es un conjunto de operaciones que llevan a cabo las piernas, con la salvedad de que se trata de algo radicalmente más complejo. En segundo lugar, en cada función mental -desde el reflejo más simple hasta las actividades creativas como el lenguaje, la música y el arte- intervienen circuitos neurales especializados de distintas regiones cerebrales. Por esa razón, es preferible hablar de la "biología mental" para referirnos al conjunto de operaciones mentales que llevan a cabo esos circuitos neurales especializados, en lugar de hablar de la "biología de la mente", expresión que sugiere que todas las operaciones mentales se desenvuelven en un lugar preciso y entrañan un emplazamiento cerebral único. En tercer lugar, todos esos circuitos están constituidos por las mismas unidades elementales de señalización, las células nerviosas. En cuarto lugar, los circuitos neurales utilizan moléculas específicas para transmitir señales en el interior de las células nerviosas y también entre dos células distintas. Por último, esas moléculas específicas que constituyen el sistema de señales se han conservado a lo largo de millones de años de evolución. Algunas de ellas ya estaban presentes en las células de nuestros antepasados más remotos y pueden hallarse hoy en nuestros parientes más lejanos y primitivos desde el punto de vista evolutivo: los organismos unicelulares como las bacterias y las levaduras, y los organismos multicelulares simples como los gusanos, las moscas y los caracoles.

Para organizar sus andanzas en su medio ambiente, estas criaturas utilizan las mismas moléculas que empleamos nosotros para gobernar nuestra vida cotidiana y adaptarnos al nuestro. Así, la nueva ciencia de la mente no sólo nos ilumina sobre nuestro propio funcionamiento -cómo percibimos, aprendemos, recordamos, sentimos y actuamos- sino que, además, nos sitúa en perspectiva en el contexto de la evolución biológica. Nos permite comprender que la mente humana evolucionó a partir de las moléculas que utilizaban nuestros antepasados más humildes y que los mecanismos moleculares que regulan los diversos procesos biológicos también se aplican a nuestra vida mental. En razón de las implicaciones que tiene la biología mental para el bienestar individual y social, el consenso general de la comunidad científica indica que en el siglo XXI esa disciplina ocupará un lugar de preeminencia similar al que la biología del gen tuvo en el siglo XX.

 

15.9.06 00:36