HABITUATION AND SENSITIZATION IN VERTEBRATES

When a ringing bell is presented to a cat, it may evoke a turning of the head toward the sound source. If that same stimulus is repeated over and over again, the probability and magnitude of this orienting response decrease. This phenomenon is called habituation. If a mouse now runs in front of the cat and then the bell is rung again, the cat may reorient to the bell. This phenomenon is called dishabituation. By recording electrical activity in the first central synapse in the auditory system or using another stimulus that elicits an orienting response of the same size, it can be shown that habituation cannot be explained by either sensory adaptation or muscle fatigue (Thompson and Spencer, 1966). Thus, even though the original response no longer occurs, the stimulus still evokes the same electrical activity in early auditory structures as it did before and the original response can be fully elicited by a different stimulus or the same stimulus following dishabituation (e.g., the bell after the mouse ran by). Hence, the decrement in response strength must result from a synaptic change somewhere within the nervous system, and this change is specific to the stimulus that was presented repetitively.

Habituation has been the subject of a great deal of empirical investigation because practically every organism displays habituation, even those with very primitive nervous systems (Harris, 1943). In reviewing this literature, Thompson and Spencer (1966, pp. 18-19) enumerated nine parametric features of habituation and dishabituation that can be seen in a variety of organisms:

1. Given that a particular stimulus elicits a response, repeated applications of the stimulus result in decreased response (habituation). The decrease is usually a negative exponential function of the number of stimulus presentations.
2. If the stimulus is withheld, the response tends to recover over time (spontaneous recovery).
3. If repeated series of habituation training and spontaneous recovery are given, habituation becomes successively more rapid (this might be called potentiation of habituation).
4. Other things being equal, the more rapid the frequency of stimulation, the more rapid and/or more pronounced is habituation.
5. The weaker the stimulus, the more rapid and/or more pronounced is habituation. Strong stimuli may yield no significant habituation.
6. The effects of habituation training may proceed beyond the zero or asymptotic response level (i.e., additional habituation training given after the response has disappeared or reached asymptote will result in slower recovery).
7. Habituation of response to a given stimulus exhibits stimulus generalization to other stimuli.
8. Presentation of another (usually strong) stimulus results in recovery of the habituated response (dishabituation).
9. Upon repeated application of the dishabituatory stimulus, the amount of dishabituation produced habituates (this might be called habituation of dishabituation).

Thompson and Spencer's extremely influential review gave investigators working in diverse areas an explicit operational definition of habituation against which to test plasticity (change in response output with experience) in their particular preparations. In addition, it led to the general belief that habituation might be mediated by a single, fundamental mechanism inherent to most organisms across the phylogenetic scale.

Other experiments indicated, however, that the way in which one interrogates an animal can determine these parametric relationships. For example, the probability or amplitude of response is generally larger, the higher the intensity of the eliciting stimulus. It is not surprising, therefore, that it takes longer to reach a low level of response with intense, as opposed to weak, stimulus intensities. However, if the effects of prior exposure to strong and weak stimuli are subsequently evaluated, when all animals are tested with a common stimulus intensity, the magnitude of response change is actually greater following strong, as opposed to weak, stimuli (Davis and Wagner, 1968). Similarly, the probability of response is generally lower the shorter the interval from an immediately prior stimulus. This leads to a rapid rate of response decrement when stimuli are presented at short, rather than long, interstimulus intervals. However, when animals are subsequently tested under conditions where the interstimulus interval is identical for all animals, prior exposure with long interstimulus intervals actually produces a greater decrease in response strength (Davis, 1970). On the one hand, habituation (i.e., the change in response during stimulus repetition) seems to be greater with weak stimuli presented at short intervals (Thompson and Spencer, 1966); but on the other hand, habituation (i.e., the change in response strength following stimulus repetition) seems to be greater with strong stimuli presented at long intervals (Davis, 1970; Davis and Wagner, 1968).

These disparities illustrate how the term habituation has been used to denote the empirical observation of response decrement with stimulus repetition as well as a theoretical construct to describe the underlying process that accounts for the observed response decrement. However, the two terms may not be isomorphic, so that it is just as necessary to apply a distinction between performance and learning within the study of habituation as it is with other forms of learning such as classical and instrumental conditioning.

The Dual-Process Theory of Habituation

On the basis of the observation that dishabituation appeared to result from a facilitating effect superimposed on the habituation process (Humphrey, 1933; Sharpless and Jasper, 1956; Thompson and Spencer, 1966) and of some unusual results when stimulus intensity was used to study habituation (Davis and Wagner, 1969), Groves and Thompson (1970) proposed that novel and especially intense stimuli activate two hypothetical processes: habituation, which decreases response strength; and sensitization, which increases response strength. The final response output is then the net result of these two opposing influences. With strong stimuli, the underlying habituation process may be masked by a competing sensitization process that tends to decrease the rate of response decrement during stimulus repetition. However, because sensitization may not last as long as habituation, subsequent test sessions may be used to evaluate the effects of prior habituation, somewhat less contaminated by sensitization (e.g., Davis, 1972). The Groves and Thompson dual-process theory received wide empirical support and provided a fundamental theoretical base upon which to study the neural mechanisms of response change during iterative stimulus presentation, in both invertebrates and simple mammalian systems.

Mechanisms of Habituation and Sensitization in Vertebrates

Because of the ubiquity of habituation, many believe it is the simplest form of learning. The most definitive analysis of the cellular mechanisms of habituation and sensitization has been done in invertebrates. In vertebrates, the cellular mechanisms of habituation and sensitization are poorly understood. In broad terms, habituation could be mediated by some neural process intrinsic to the neural pathway in the reflex circuit under study or by activation of other neural circuits extrinsic to, but impinging on, the reflex pathway. Much of the literature on humans has assumed the latter mechanism, probably because of the influential theory of E. N. Sokolov (1960), who proposed a brain comparator process whereby higher brain centers form a neuronal model of incoming stimuli and actively inhibit response output when subsequent stimuli match the neuronal model.

Many animal experiments have attempted to prevent habituation by making lesions of brain areas extrinsic to the reflex circuits under study, or by giving drugs that might prevent these systems from inhibiting the reflex pathway. On balance, however, there are very few behavioral experiments that clearly show that habituation within a single test session is actually prevented by lesions or drugs. When effects are reported, they generally result from a change in overall response levels that does not affect the slope of response decrement (provided the manipulations do not push the initial response levels to the ceiling or floor of the response scale and that measures such as percent decrement or trials to criterion, which depend heavily on changes in overall response level, are not used). Moreover, when effects on the slope of the response decrement curve are found, it is not clear whether this is due to a change in the underlying process of habituation or of sensitization. It has thus been extremely difficult to study in whole organisms how various manipulations affect the process of habituation, since the change in behavioral output may well be the product of two underlying processes, which cannot be distinguished with a single measure.

Habituation and Sensitization in the Spinal Cord

As illustrated by the landmark studies of Spencer, Thompson, and Neilson (1966a, 1966b), the most definitive work on the mechanism of habituation and sensitization in vertebrates has been done in the spinal cord, because this is one of the few places where the underlying neural circuitry of the reflexes being studied is reasonably well understood. Habituation and sensitization have been investigated in centrally projecting sensory fibers and in the interneurons and motoneurons to which they project. The reflexes most studied include the monosynaptic stretch reflex, the oligosynaptic plantar cushion reflex (Egger, 1978; Egger, Bishop, and Cone, 1976), the poly-synaptic flexion reflex in the cat (Mendell, 1984); and the lateral column-motoneuron pathway in the frog (Farel, Glanzman, and Thompson, 1973). Mammalian monosynaptic stretch reflexes (activated by primary afferents from muscle spindles that project directly to motoneurons) typically do not demonstrate marked habituation or sensitization, in contrast to reflexes involving interneurons, which typically do. Current evidence indicates that habituation and sensitization are mediated by synaptic changes intrinsic to interneurons within the reflex pathways being studied (depression or facilitation of transmitter release). To date, there is no direct evidence that interneuronal networks extrinsic to the reflex pathway account for habituation and sensitization by actively inhibiting or facilitating transmission (Mendell, 1984), although such mechanisms cannot be entirely ruled out.

Habituation and Sensitization of the Startle Reflex

In complex mammalian systems habituation and sensitization of the acoustic startle reflex have been studied by eliciting startlelike responses at different points along the neural pathway believed to mediate the very-short-latency (eight milliseconds) startle reflex in rats, with a high level of background noise used to sensitize startle (Davis et al., 1982). Startle elicited by electrical stimulation in the early part of the pathway was increased by the noise but then decreased with repeated elicitations. Startle elicited by stimulation of the part of the pathway that projected directly to the spinal cord was also increased by noise but did not decrease with stimulus repetition. In humans, the R1 component of the eyeblink reflex (latency = ten milliseconds), elicited by electrical stimulation of the facial nerve, which is mediated by a disynaptic circuit, shows a net increase in response amplitude with stimulus repetition. However, the R2 component (latency = twenty-five to forty milliseconds) elicited by the same stimulus, which involves a polysynaptic pathway, shows a net decrease in response strength (Sanes and Ison, 1983). Taken together, the data suggest that sensitization tends to act on the motor side of reflex arcs, whereas habituation tends to act on earlier parts of the circuitry. This suggestion is consistent with data from Thompson and Spencer (1966) on spinal preparations.

The best evidence for extrinsic control of habituation and sensitization has been gathered by looking at between-session or long-term habituation of the startle reflex. Leaton and Supple (1986) have shown that lesions of the cerebellar vermis, which is not part of the acoustic startle pathway, significantly attenuate the decrease in startle amplitude seen across daily test sessions without affecting the rate of response decrement within test sessions. This blockade of long-term habituation was observed with two different stimulus intensities and cannot be explained by ceiling or floor effects caused by the cerebellar lesions. This effect has been replicated when the lesion was made before habituation training, but not when the lesion was made afterward (Lopiano, DeSperati, and Montarolo, 1990). Hence, the cerebellar vermis appears to be necessary for the acquisition but not the retention of long-term habituation. In contrast, lesions of the mesencephalic reticular formation, which again is not itself part of the acoustic startle pathway, block both the acquisition (Jordan and Leaton, 1982) and the expression (Jordan, 1989) of long-term habituation. In other studies Borszcz, Cranney, and Leaton (1989) have shown that loud startle stimuli produce sensitization that can best be described as fear of the experimental context in which startle is measured. Reintroducing animals into this context produces a good deal of freezing, a reliable index of fear. Fear of the context elevates startle on subsequent test sessions, leading to a reduction in the amount of long-term response decrement. Treatments such as lesions of the ventral central gray matter (Borszcz, Cranney, and Leaton, 1989) that are known to reduce freezing, and treatments such as lesions of the amygdala or drugs such as diazepam, which reduce fear in many situations, facilitate the degree of long-term response decrement, presumably by blocking sensitization and hence allowing long-term habituation to be revealed. Taken together, these data provide some of the best evidence that extrinsic systems may be involved in both long-term habituation and sensitization of the startle reflex elicited by intense auditory stimuli.

Conclusion

Because habituation could be observed at all levels of the phylogenetic scale, there was great hope that its analysis would lead to fundamental insights into the neural mechanisms of learning and memory. Moreover, because habituation was such a basic mechanism, deficits in habituation might allow one to understand complex cognitive disturbances such as schizophrenia or mental retardation. These hopes have stimulated a great deal of research. Curiously, however, insights gained from this experience have not been as profound as anticipated. In the only systems where habituation could be analyzed at the cellular level (e.g., invertebrates and short-term spinal preparations), the decrease in response output seemed to result from a relatively short-term decrease in transmitter release. However, the actual cellular mechanism that mediates this effect is still unknown. Long-term habituation seems to be a more interesting phenomenon with respect to learning and memory, yet it has been much more difficult to study. Theories that seek to account for enduring, long-term habituation (Wagner, 1976) or sensitization (Borszcz, Cranney, and Leaton, 1989) inevitably appeal to an associative process, that of classical conditioning. As a result, research on the neural mechanisms of habituation and sensitization has been largely replaced by research on the neural mechanisms of classical conditioning.

See also:APLYSIA: DEVELOPMENT OF PROCESSES UNDERLYING LEARNING; APLYSIA: MOLECULAR BASIS OF LONG-TERM SENSITIZATION; INVERTEBRATE LEARNING: C. ELEGANS; INVERTEBRATE LEARNING: HABITUATION AND SENSITIZATION IN TRITONIA; ORIENTING REFLEX HABITUATION

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MichaelDavis

M. DavidEgger