Augmentation of the responsiveness to stimuli following the presentation of a salient stimulus

Sensitization is a type of non*associative learning. The sensitizing stimulus is usually strong or noxious. Sensi-tization contrasts with another type of nonassociative learning, "habituation, in which there is a "generalized diminution of response following the presentation of a weak or monotonous stimulus. If the response is already habituated, the effect of the sensitizing experience is termed 'dishabituation'. Thus, whether the "subject is said to undergo sensitization or dishabitua-tion, depends on what we know about its history.

Sensitization is a lingering manifestation of arousal. Another manifestation of arousal is the 'investigatory' or 'orienting reflex', which is an immediate, complex somatic and sensory response to an unexpected stimulus (Pavlov 1927; Sokolov 1963&; "attention). Sensitiza-tion complements the behavioural adaptation to the "surprising situation by transiently decreasing the threshold to further stimuli. The phylogenetic value of sensitization is rather straightforward: 'An earthworm that has just avoided being eaten by a blackbird that has taken a peck at it, is indeed well advised to respond with a considerably lowered threshold to similar stimuli, because it is almost certain that the bird will still be nearby for the next few seconds' (Lorenz 1981).

The ability of a salient stimulus to alter the subsequent response to other stimuli was systematically investigated already by Pavlov. He reported that after "experimental extinction of a "classically conditioned response, a strong or novel stimulus temporarily restored the original response (Pavlov 1927). Later,

Grether (1938) reported that unpaired presentation of unconditioned and conditioned stimuli could result in conditioned response. This was termed 'pseudocondi-tioning'. Whereas pseudoconditioning can be described as nonassociative classical conditioning, sensitization can be described as nonassociative a conditioning.1

The widespread occurrence and the many expressions of sensitization throughout the phylogenetic spectrum makes it unlikely that a single mechanism will explain it all. Indeed, the investigation of a variety of vertebrates and invertebrates preparations unveils diverse circuit and cellular mechanisms (e.g. Egger

1978; Russo and Ison 1979; Davis et al. 1982; Hawkins et al. 1998). Dishabituation and sensitization, which at a certain stage were suspected to be two manifestations of the same phenomenon, were later found not to be so on the bases of differences in the behavioural parameters, in the "development of the response with age, and in the neuronal mechanisms (Rankin and Carew 1988; Byrne and Kandel 1996; Hawkins et al. 1998).

Among the preparations used to study elementary types of sensitization, a prominent place is reserved to a "simple system, the sea hare, "Aplysia. In Aplysia, sensi-tization of the defensive withdrawal reflexes, achieved

50 mV

5 ms

Sensitizing stimulus

Sensory \\J stimulus SN

Behavioural response

Fig. 59 A simplified scheme depicting the sensitization of the gill and siphon withdrawal reflex in Aplysia at various "levels of analysis. (a) The behavioural response (see also page 16). N, 'naive' Aplysia, withdrawing the gill and siphon in response to a mild touch to the skin; S, the augmented response of subjects sensitized by a shock to the tail. (b) The elementary module of the central circuit that subserves the behaviour. IN, interneuron; MN, motor neuron; SN, sensory neuron. (c) Synaptic facilitation, the correlate and cellular analogue of behavioural sensitization in this system. The lower curve in each case is the action potential (spike) in SN, and the upper curve is the excitatory postsynaptic potential (EPSP) in the follower MN (left-hand curves, pre-training, right-hand curves, post-training). The broadened spike in SN after sensitization training ultimately results in an enhanced response to subsequent action potentials, and therefore in enhanced transmitter released on to the MN. This contributes to the augmentation over time of the behavioural response. (d) Elements of the molecular machinery that underlies short-term synaptic facilitation. The sensitizing stimulus releases facilitatory transmitter(s) (ft) from the IN on to the SN. These modulatory substances, e.g. serotonin, activate several types of receptors (Ri, Rj) on the SN membrane.The receptors in turn activate "intracellular signal transduction cascades. One type of receptor activates the "protein kinase C cascade, which results in enhancement of transmitter release. Another type of receptor activates the cyclic adenosine monophosphate (cAMP) cascade, leading to phosphorylation of potassium channels (gk), which results in spike broadening and enhanced excitability in response to subsequent stimuli to the SN. The cAMP cascade could also trigger memory "consolidation that involves modulation of gene expression and culminates in the long-term memory of sensitization (LTM; see *CREB). In reality, the relative contributions of multiple signal transduction cascades, enhanced excitability and enhanced transmitter release, depend on the history of the SN as well as on the time after the sensitizing experience. Use-dependent alterations in other components of the circuit are not shown for simplicity. (Modified from Abrams, 1985, and Byrne and Kandel, 1996.)

by applying a noxious stimulus to the skin, is based on multiple time- and "context-dependent alterations in the circuits that subserve the behaviour (Trudeau and Castellucci 1993; Byrne and Kandel 1996; T.E. Cohen et al. 1997; Cleary et al. 1998). A significant portion of the sensitization of the behavioural response is explained by presynaptic facilitation in a single type of "synapse. This is the synapse between the sensory neuron, which carries information from the skin, and the motor neuron, which commands the withdrawal response (Figure 5, p. 16, and Figure 59.). Synaptic facilitation is a form of use-dependent synaptic "plasticity that is expressed as an enhancement in the strength of the synaptic connection; as synaptic facilitation was found in Aplysia to correlate with major aspects of behav-ioural sensitization, it was accepted in this "system as a convenient cellular analogue of sensitization.

In the aforementioned sensory-to-motor synapse in Aplysia, a considerable part of the facilitation is induced by a modulatory neuron, which is activated by information about the sensitizing stimulus. This neuron releases modulatory substances, which activate a number of "receptors and their downstream "intracellular signal transduction cascades in the sensory neuron terminal. This culminates in multiple plastic changes, among them enhanced "neurotransmitter release by the sensory neuron on to the motor neuron that controls the withdrawal response. Both short-term sensitization, lasting up to a few hours, and long-term sensitization, lasting more than a day, could be "modelled by short- and long-term synaptic facilitation. Whereas short-term facilitation involves post-translational modifications, long-term facilitation requires modulation of gene expression, "protein synthesis, and morphological changes in the synapse, which are assumed to maintain the facilitation over time in spite of the ongoing molecular turnover ("consolidation). Studies of "classical conditioning in the same preparation have unveiled that facilitation is also a component of this elementary type of associative learning, only that in classical conditioning, the use-dependent enhancement in the synapse is specifically augmented by the "coincidence of the conditioned and the unconditioned stimuli (Abrams 1985). That classical conditioning in this system is an elaboration of sensitization is actually not at all surprising, considering that conditioning is of the a type, involving a pre-existing rather than a new response.

The analysis of sensitization in Aplysia is hence a "classical example of a reductive research programme in the field of memory research. It has focused on identified cellular processes in an identified locus in the neuronal circuit that subserves the behaviour, and has succeeded in partially translating the behavioural phenomenon into cellular phenomena that are accessible to mechanistic analysis ("reduction). This programme has identified molecular devices that could perform functions of "acquisition of cellular information (e.g. serotonin receptors), storage (e.g. protein kinases), and readout, or "retrieval, of such information (e.g. potassium channels, components of the transmitter release machinery). A sizeable part of what is so far known about the molecular and cellular mechanisms of short- and long-term memory, is derived from the cellular analysis of short- and long-term facilitation in Aplysia. Hence, whoever wishes to understand the "zeitgeist in molecular neurobiology cannot afford to disregard sensitization in Aplysia.

Sensitization, although only a primitive form of learning, is of great importance in human behaviour. It can be demonstrated already in the neonate (Lipsitt 1990). Later throughout life, sensitization comes to contribute to a plethora of normal as well as pathological responses. Long-term sensitization was proposed as a model for phobia and generalized anxiety disorder (Marks 1987). Furthermore, 'stress sensitization', which is the augmentation by stress experience of the stress response upon re-exposure to a stressor (e.g. Nissenbaum et al. 1991), was invoked to explain why phobias and neurotic rituals relapse after trauma (Marks 1987; Marks and Tobena 1990).

Selected associations: Context, Generalization, Habituation, Surprise, Taxonomy

1in a conditioning the conditioned response is intensification of pre-existing response to the conditioned stimulus; see 'classical conditioning.

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