The concept of synaptic plasticity has a long history, beginning with the neuroanatomical studies of Santiago Ramón y Cajal at the turn of the nineteenth century. He used a method called the Golgi stain to visualize individual neurons in the brains of humans and other animals (Figure 22-40a). The Golgi stain was developed by the Italian scientist Camillo Golgi, with whom Ramón y Cajal shared the 1906 Nobel Prize in Physiology or Medicine for their work on the structure of the nervous system. While Golgi believed that the brain consisted of an “reticular network,” a large syncytium of interconnected nerve cells, Ramón y Cajal recognized that the brain consisted of individual neurons that interacted with one another at sites of contact—what we now know of as synapses. Ramón y Cajal detected synapses as small dendritic protuberances. These protuberances are the postsynaptic compartments of excitatory synapses, and can be visualized not only with the Golgi stain but also with more modern methods based on genetic expression of fluorescent proteins such as GFP (Figure 22-40b). Based on his histological data, Ramón y Cajal hypothesized that memories were stored in the brain by changing the structure of the neuronal arbor and by changing the structure and number of synapses that formed between neurons. In poetic terms, Ramón y Cajal speculated that: “the cerebral cortex is like a garden full of innumerable trees, the pyramidal cells, which in response to intelligent cultivation can increase the number of their branches…and produce ever more varied flowers and fruit.”

Decades of research have largely validated Ramón y Cajal’s predictions, although memories are now thought to be stored primarily as changes in the synapses (“flowers and fruit”) rather than by changes in dendrites and axons (“branches”). Studies of the gill-withdrawal reflex in the sea slug Aplysia californica provide a classic demonstration of the structural basis of memory storage (Figure 22-41). Aplysia californica is a useful model organism for studying the cell biology of memory because its nervous system is relatively simple and its neurons are very large and identifiable, which means that the same neuron can be identified from one animal to another. These features allowed Nobel laureate Eric Kandel and his colleagues to delineate the neural circuitry underlying specific behaviors in the animal, and to then determine how the synaptic connections between neurons in this circuit changed during memory formation. They focused on a simple reflexive behavior, the siphon gill-withdrawal reflex, in which touching the siphon (a tubelike anatomical structure that water flows through) of the animal leads to a defensive withdrawal of its respiratory organ, the gill. Sensory neurons from the siphon that synapse onto motor neurons to the gill mediate the reflex. Touching the siphon triggers firing of the sensory neuron, which triggers an action potential in the motor neuron, which in turn synapses on the gill muscle and causes it to contract. The reflex can be bidirectionally modified by experience. Repeated touching of the siphon leads to a decrease in the amplitude of the gill-withdrawal reflex, called habituation. In contrast, presentation of a noxious stimulus like delivery of an electric shock to the tail leads to an increase in the amplitude of the gill-withdrawal reflex, called sensitization. Sensitization can be thought of as a form of fear learning. Habituation and sensitization can be transient or long lasting, depending on the strength and duration of the stimulus. Long-lasting forms of habituation and sensitization were found to involve dramatic decreases and increases, respectively, in the number of connections that formed between sensory and motor neurons. In this way, just as Ramón y Cajal predicted, the animal’s experience changed the wiring of its nervous system, thereby encoding a memory and changing the animal’s behavior.

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