Sn

C2. After activation of IN

FIGURE 4 Tail-siphon withdrawal reflex of Aplysia and model of the neural circuit and its plasticity. (A) Dorsal view of Aplysia: (1) relaxed position; (2) stimulus applied to the tail elicits a reflex withdrawal of the tail and siphon. (B) Simplified neural circuit for defensive reflexes in Aplysia. A tactile stimulus to the skin activates the afferent terminals of sensory neurons (SNs). These sensory neurons make monosynaptic connections with motor neurons (MNs) as well as interneurons interposed between the SNs and MNs (not shown). Sensitizing stimuli activate facilitatory interneurons (INs) that release modulatory transmitters, one of which is 5-HT. The modulator leads to an alteration of the properties of the SN. (C) Model of heterosynaptic facilitation of the sensorimotor connection that contributes to short- and long-term sensitization in Aplysia. An action potential in a SN after the sensitizing stimulus (C2) results in greater transmitter release and hence a larger postsynaptic potential in the MN than an action potential prior to the sensitizing stimulus (C1). For short-term sensitization, the enhancement of transmitter release is due, at least in part, to broadening of the action potential and an enhanced flow of Ca2+ into the sensory neuron.

ca neurons. When cAMP binds to the regulatory subunit of cAMP-dependent protein kinase (protein kinase A, or PKA), the catalytic subunit is freed and can add phosphate groups to specific substrate proteins and hence alter their functional properties. One consequence of this protein phosphorylation is an alteration of the properties of membrane channels. Specifically, the increased levels of cAMP lead to a decrease in the S-K+ current (IK,S), a component of the calcium-activated K+ current (IK,Ca) and the delayed K+ current (IK,V). These changes in membrane currents lead to depolarization of the membrane potential, enhanced excitability, and an increase in the duration of the action potential (Fig. 4C). Cyclic AMP also appears to activate a membrane potential and spike-duration-independent process of facilitation, which is represented in Fig. 5 (large open arrow) as the translocation or mobilization of transmitter vesicles from a storage pool to a releasable pool, making more transmitter-containing vesicles available for release with subsequent action potentials in the sensory neuron. These combined effects contribute to the short-term cAMP-dependent enhancement of transmitter release. Serotonin also appears to act through another class of receptors to increase the level of the second-messenger diacylglycerol (DAG). DAG activates protein kinase C (PKC). PKC, like PKA, activates the spike-duration-independent process of facilitation. In addition, a nifedipine-sensitive Ca2+ channel (Ica.Nif) and the delayed K+ channel (IK,V) are regulated by PKC. Thus, the delayed K+ channel (IK,V) is dually regulated by PKC and PKA. The modulation of IK,V makes an important contribution to the increase in duration of the action potential (see Fig. 4C).

The consequences of the activation of these multiple second-messenger systems and modulation of multiple cellular processes occur when test stimuli elicit action potentials in the sensory neuron at various times after the presentation of the sensitizing stimuli (see Fig. 4C). More transmitter is available to be released as a result of the mobilization process, and each action potential is broader, allowing a greater influx of Ca2+ to trigger release of the available transmitter. The combined effects of mobilization and spike broadening lead to enhanced release of transmitter from the sensory neuron and consequently a larger postsynaptic potential in the motor neuron. Larger postsynaptic potentials lead to an enhanced activation of interneurons and motor neurons and thus an enhanced behavioral response (i.e., sensitization).

Long-Term Sensitization

Repeating the sensitizing stimuli over a l.5-hour period leads to the induction of long-term sensitization, the memory of which can persist for days to weeks. Repeated training leads to more prolonged phosphor-ylation and activation of nuclear regulatory proteins by PKA. Such proteins interact with regulatory regions of DNA and lead to increased transcription of RNA and hence increased synthesis of specific proteins. Some of the resulting proteins may be transcription factors that can activate other genes, some of which may be able to maintain their own activation. Some of the newly synthesized proteins initiate the restructuring of the axon arbor. The sensory neuron can then form additional connections with the same postsynaptic target or make new connections with other cells. As with short-term

FIGURE 5 Molecular events in the sensory neuron. 5-HT released from the facilitatory neuron (i.e., Fig. 4B) binds to at least two distinct classes of receptors on the outer surface of the membrane of the sensory neuron, which leads to the transient activation of two intracellular second messengers, DAG and cAMP. These second messengers, acting though their respective protein kinases, affect multiple cellular processes, the combined effects of which lead to enhanced transmitter release when a subsequent action potential is fired in the sensory neuron. Long-term alterations are achieved through regulation of protein synthesis and growth. Positive ( + ) and negative (-) signs indicate enhancement and suppression of cellular processes, respectively (see text for additional details).

FIGURE 5 Molecular events in the sensory neuron. 5-HT released from the facilitatory neuron (i.e., Fig. 4B) binds to at least two distinct classes of receptors on the outer surface of the membrane of the sensory neuron, which leads to the transient activation of two intracellular second messengers, DAG and cAMP. These second messengers, acting though their respective protein kinases, affect multiple cellular processes, the combined effects of which lead to enhanced transmitter release when a subsequent action potential is fired in the sensory neuron. Long-term alterations are achieved through regulation of protein synthesis and growth. Positive ( + ) and negative (-) signs indicate enhancement and suppression of cellular processes, respectively (see text for additional details).

sensitization, the enhanced release of transmitter from existing contacts of sensory neurons onto motor neurons and interneurons underlies the long-term enhanced responses of the animal to test stimuli. However, unique to long-term sensitization are the increases in axonal arborization (see Fig. 5) and synaptic contacts that may contribute to the enhanced activation of follower interneurons and motor neurons.

Mechanisms of Classical Conditioning

Mechanisms of classical conditioning have also been examined in Aplysia. Classical conditioning procedures, like sensitization procedures, lead to a modulation of neuronal membrane currents and an enhancement of synaptic efficacy (for a review, see Lechner and Byrne, 1997). Interestingly, mechanisms of classical conditioning are at least in part an extension of mechanisms in place that mediate sensitization. Thus, it appears that more complex examples of learning use as building blocks mechanisms for simpler forms of learning.

Operant Conditioning

In addition to being a model system that has revealed a detailed understanding of the mechanisms underlying nonassociative learning (i.e., sensitization) and classical conditioning, Aplysia is also a useful model system to investigate the mechanisms underlying operant conditioning (Brembs et al., 2002). In an operant conditioning paradigm, the delivery of a reinforcing stimulus is contingent upon the expression of a designated behavior. In the case of feeding behavior, the operant behavior is ingestive or biting movements and the reinforcement is a stimulus to an afferent nerve which, based on previous work, is a neural pathway enriched in dopamine processes and which signals presence of food in the mouth. Animals are conditioned by delivering a brief stimulus to the nerve each time they display a spontaneous bite. Learning is assessed by measuring the number of spontaneous bites following the conditioning procedure. Animals that had received the operant conditioning procedure displayed a higher number of bites than control animals.

The development of behavioral protocols for operant conditioning allowed for further investigations into the mechanisms underlying the learning. Neural correlates of operant conditioning were found in a single identified neuron involved in the generation of the feeding motor program. The changes consisted of a decreased threshold to elicit a burst of spikes and a decrease in the resting conductance. Both changes would lead to an enhanced probability of generating feeding behavior after conditioning. Of considerable interest was the observation that the effects of behavioral conditioning could be mimicked by pairing activity in the cell isolated in culture with a brief application of dopamine. These data suggest that intrinsic cell-wide plasticity may be one important mechanism underlying this type of learning and that dopamine is a key transmitter mediating the reinforcement. Continued analysis will provide insights into the molecular mechanisms of operant conditioning as well as insights into the mechanistic relationship between operant and classical conditioning.

Long-Term Potentiation

Long-term potentiation (LTP) is a persistent enhancement of synaptic efficacy generally produced as a result of delivering a brief (several-second) high-frequency train (tetanus) of electrical stimuli to an afferent pathway. The great difference between the duration of the tetanus and the duration of the subsequent enhancement is the defining characteristic of LTP. Such long-term synaptic enhancement, lasting at least several hours in in vitro preparations and weeks in intact preparations, has received growing attention because of the possibility that it is related to natural mechanisms of learning and memory. For example, there are "cooperative" and "associative" influences on LTP, and there appear to be a number of similarities between neural changes produced by LTP procedures and neural correlates of associative learning (e.g., Pavlovian conditioning). Long-term potentiation has been observed in many regions of the mammalian central nervous system (CNS), in the peripheral nervous system, and in the CNS and neuromuscular junctions of several invertebrates.

Figure 6A illustrates an experimental arrangement for inducing and analyzing LTP. An intracellular recording is made from a postsynaptic neuron that receives mono-synaptic excitatory inputs from presynaptic neurons. Brief electric shocks delivered to the afferent pathway lead to the initiation of action potentials in the individual axons in the pathway, and these action potentials propagate to the synaptic terminals. (The rationale for stimulating multiple afferents will become clear when the mechanisms for LTP are discussed later.) The release of transmitter from the multiple afferent terminals produces a summated excitatory postsynaptic potential (EPSP) in the postsynaptic cell. Test stimuli are repeatedly delivered (Fig. 6B1) at a low rate that produces stable EPSPs in the postsynaptic cell (Fig. 6B2). After a stable baseline period, a brief high-frequency tetanus is delivered. Subsequent test stimuli produce enhanced EPSPs. The enhancement is associated with at least two temporal domains. There is a large but transient enhancement that represents a phenomenon known as post-tetanic potentiation (PTP). The PTP is followed by a stable and enduring enhancement that persists for

Mechanisms of Learning and Memory

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