NCBI Bookshelf A service of the National Library of Medicine National Institutes of Health Siegel GJ Agranoff BW Albers RW et al editors Basic Neurochemistry Molecular Cellular and Medical Aspects 6th edition Philadelphia Lippincott Raven 1999 Invertebrate Learning and Memory Bernard W Agranoff Carl W Cotman and Michael D Uhler Correspondence to Bernard W Agranoff Mental Health Research Institute University of Michigan 1103 E Huron Ann Arbor Michigan 48104 1687 Invertebrates offer a number of advantages as model systems for learning and memory Foremost among these advantages is the simplicity of the neuronal networks which are often organized into several discrete ganglia rather than a CNS In addition the genome is typically less complex in invertebrates than in vertebrates so that the number of genes involved in a learning response is likely to be smaller as well Aplysia provides a cellular model of learning and memory Kandel and co workers 13 pioneered the use of the sea snail Aplysia californica as a model system for the study neuronal events associated with learning Aplysia has a relatively simple nervous system consisting of approximately 10 000 neurons many of which are sufficiently large to allow them to be manipulated directly within defined neuronal circuits Three behaviors each of which has adaptive value have been studied in Aplysia habituation sensitization and classical conditioning Habituation describes a learned response in which a decrease is observed in a specific behavioral response after repeated stimulation In Aplysia habituation serves as a rudimentary model that shares some aspects of regulation relevant to learning A snail ordinarily withdraws its gill after gentle tactile stimulation of the siphon Upon repeated stimulation the gill withdrawal reflex diminishes in both magnitude and duration If the habituation experience consists of one training session of relatively few stimulations say less than ten over a short period of time less than 1 hr then the habituation lasts for only a few hours after the training If however four or more individual training sessions are given the habituation response can last for several weeks These two forms of habituation have been interpreted as models of short and long term memory There is a difference in how short term and long term memory are measured in Aplysia experiments and in behavior in vertebrates such as the goldfish In Aplysia short term memory refers to a fleeting memory resulting from few training trials With additional trials memory appears to be more robust and to last longer In experiments with goldfish and rats the same training session is thought to give rise to both a short and long term form of memory Short term memory is formed during the training session while long term memory proceeds by a consolidation process that takes place after the training session In both fish and Aplysia it appears that the short term memory formation does not require ongoing protein synthesis while the long term form does The relatively simple neuronal circuitry involved in habituation of the gill withdrawal reflex is shown in Figure 50 3 Stimulation of a sensory neuron innervating the siphon causes stimulation of motor neurons that innervate the gill muscle As habituation proceeds the number of postsynaptic potentials produced in the motor neuron decreases When completely habituated the motor neuron does not depolarize and there is no gill withdrawal while depolarization of the sensory neuron in response to siphon stimulation is unaffected Kandel and co workers 13 have shown that habituation is the result of a decrease in synaptic efficacy between the sensory neuron and the motor neuron due to altered permeability of the Ca2 required for neurotransmitter release at the presynaptic terminal The Ca2 enters the presynaptic terminal through voltage sensitive Ca2 channels and during habituation Ca2 channels in the presyn aptic terminal become inactivated Although specific mechanisms for this inactivation have been postulated its nature in the synaptic terminal of the sensory neurons is unknown Furthermore since the long term habituation appears to involve protein synthesis the known mechanisms for inactivation of Ca2 channels do not suffice to explain it Figure 50 3 A A simplified diagram of the circuitry involved in sensitization habituation and classical conditioning in Aplysia Sensory neurons motor neurons and facilitating interneurons are indicated Sensory neurons from the mantle shelf B and siphon skin more A second form of learning in Aplysia known as sensitization involves a more complex learning paradigm and depends on a more complicated cellular regulatory mechanism In one type of sensitization experiment a mild tail shock is given to the animal shortly preceding tactile stimulation of the siphon The prior tail shock sensitizes the animal so that the normal gill withdrawal reflex associated with siphon stimulation is increased in magnitude and duration Like habituation sensitization can be either short term or long term in nature depending on the duration and number of training sessions involved The neuronal pathway involved in the tail shock sensitization experiment is schematized in Figure 50 3A Stimulation of sensory neurons in the tail causes generation of an action potential in the specific interneurons that facilitate sensitization These facilitating interneurons form a specific synaptic connection with axons of the sensory neuron that innervate the siphon The synapses of the facilitating interneurons are positioned so that release of neurotransmitter from their axons is targeted to the axons of the sensory neuron forming an axo axonic synapse In tail shock sensitization the facilitating interneurons release serotonin onto the axonal terminals of the sensory neurons Specific serotonin receptors on the sensory axons respond to the serotonin and increase axonal cAMP concentrations Fig 50 3B The elevated cAMP then activates cAMP dependent protein kinase PKA which has multiple substrates in the sensory neuron Initially PKA phosphorylates K channels in the sensory axon The resulting decrease in K influx prolongs the action potential and increases the duration of Ca2 influx through voltage sensitive Ca2 channels The net effect of this phosphorylation event is that more Ca2 flows into the axon and since Ca2 is required for synaptic vesicle fusion with the membrane greater neurotransmitter release is observed when the
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