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Hippocampal mediation of stimulus representation: a computational theory.

The authors propose a computational theory of the hippocampal region's function in mediating stimulus representations. The theory assumes that the hippocampal region develops new stimulus representations that enhance the discriminability of differentially predictive cues while compressing the representation of redundant cues. Other brain regions, including cerebral and cerebellar cortices, are presumed to use these hippocampal representations to recode their own stimulus representations. In the absence of an intact hippocampal region, the theory implies that other brain regions will attempt to learn associations using previously established fixed representations. Instantiated as a connectionist network model, the theory provides a simple and unified interpretation of the functional role of the hippocampal region in a wide range of conditioning paradigms, including stimulus discrimination, reversal learning, stimulus generalization, latent inhibition, sensory preconditioning, and contextual sensitivity. The theory makes novel predictions regarding the effects of hippocampal lesions on easy-hard transfer and compound preexposure. Several prior qualitative characterizations of hippocampal function--including stimulus selection, chunking, cue configuration, and contextual coding--are identified as task-specific special cases derivable from this more general theory. The theory suggests that a profitable direction for future empirical and theoretical research will be the study of learning tasks in which both intact and lesioned animals exhibit similar initial learning behaviors but differ on subsequent transfer and generalization tasks.

Animals↗

Reinstatement of fear to an extinguished conditioned stimulus.

Four experiments are reported which demonstrate the ability of an unconditioned stimulus (UCS) presentation following extinction to partially reinstate the conditioned response. These experiments are interpreted in terms of the strengthening of an extinction-reduced UCS representation. The first two experiments address alternative interpretations in terms of sensitization, reinstating the stimulus conditions of acquisition, conditioning of background cues, and stimulus generalization. Experiment 3 suggests that reinstatement is possible with a UCS qualitatively different from that used in conditioning. Experiment 4 explores an alternative extinction procedure which especially preserves the conditioned stimulus-unconditioned stimulus association while encouraging modification of the UCS representation. The results are discussed both in terms of related empirical phenomena, such as spontaneous recovery and sensory preconditioning, and in relation to the general role of the UCS representation in conditioning.

Acoustic Stimulation↗

Drug-cue conditioning to external stimulus conditions.

Rats were trained to discriminate 0.04 mg/kg fentanyl from saline in a 2-lever procedure, and to discriminate 10 mg/kg pentobarbital from saline in a maze procedure. Stimulus generalization experiments in rats trained in this double discrimination indicate that the internal cues produced by these training drugs can be conditioned to the external stimulus conditions associated with the different discrimination procedures.

Animals↗

Discriminative stimulus properties of the serotonin agonist 1-(3-trifluoromethylphenyl)piperazine (TFMPP).

Using a standard two-lever drug discrimination procedure, twelve rats were trained to discriminate 1.0 mg/kg of the serotonin (5-HT) agonist TFMPP from saline. Once trained, the animals displayed a dose-related decrease in discriminative performance upon administration of lower doses of TFMPP. Tests of stimulus generalization were performed using the purported 5-HT agonist RU-24, 969 and 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM). While TFMPP produced stimulus effects similar to those of RU-24,969, these effects seem to be dissimilar to those of DOM. The results of the present study suggest that the discriminative stimulus effects of TFMPP may involve a 5-HT1-related mechanism.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗

Generalization after intradimensional discrimination training in 2-year-old children.

Two-year-old children received intradimensional discrimination training at initially distant points on a circle-ellipse continuum. This training often did not produce stimulus control by circle-ellipse differences smaller than the original training values. The lack of control did not reflect capacity limitations, however. Good control was established when the children were given further training at nearer points on the continuum. The data confirm results of earlier research on stimulus generalization, extending them to a developing human subject population.

Child, Preschool↗

Generalization of excitation and inhibition after different amounts of training of an avoidance baseline.

After acquisition of a treadle-pressing response maintained by an avoidance contingency, four groups of pigeons received interdimensional discrimination training. For two groups, the positive stimulus was a 1000-Hertz tone correlated with the avoidance schedule and the negative stimulus was noise correlated with extinction. The discriminative stimuli were reversed for the other two groups. For two groups, the test stimuli were presented during extinction without any shocks during the test stimuli, for the other two groups, an unavoidable shock was presented during each test stimulus. Generalization was measured daily during discrimination training by randomly substituting each of six test frequencies for the 1000-Hertz tone. When the 1000-Hertz tone was correlated with the avoidance schedule, the number of responses to it increased and the excitatory gradient became steeper as a function of the amount of training. When the 1000-Hertz tone was associated with extinction, the number of responses to it decreased as a function of days of training and the inhibitory gradient became slightly steeper, provided that responding to the test stimulus was elevated by unavoidable shock. The training effects parallel those obtained with positive reinforcement.

Journal Article↗

New efficient stimuli for evoking frequency-specific auditory steady-state responses.

ASSR is a promising tool for the objective frequency-specific assessment of hearing thresholds in children. The stimulus generally used for ASSR recording (single amplitude-modulated carrier) only activates a small area on the basilar membrane. Therefore, the response amplitude is low. A stimulus with a broader frequency spectrum can be composed by adding several cosines whose frequency intervals comply with the desired stimulus repetition rate. Compensation of the travelling wave delay on the basilar membrane is possible with a stimulus of this type. Through this, a better synchronization of the neural response can be obtained and, as a result, higher response amplitudes can be expected, particularly for low-frequency stimuli. The additional introduction of a frequency offset enables the use of a q-sample test for the response detection, especially important at 500 Hz. The results of investigations carried out on a large group of normally hearing test subjects have confirmed the efficiency of this stimulus design. The new stimuli lead to significantly improved ASSRs with higher SNRs and thus higher detection rates and shorter detection times.

Acoustic Stimulation↗

Pentobarbital-like discriminative stimulus properties of halothane, 1,1,1-trichloroethane, isoamyl nitrite, flurothyl and oxazepam in mice.

Volatile inhalants represent a diverse group of chemicals which pose a public health problem because of their abuse potential and neurobehavioral toxicity. Although relatively little is known about their pharmacology, they share certain pharmacological properties with classic central nervous system depressants. Drug discrimination procedures were used to compare the effects produced by pentobarbital (PB), oxazepam and several inhalants. Mice were trained to discriminate PB from saline injections in a two-lever operant task. Stimulus generalization was examined after 20-min inhalation exposures to halothane (500-8000 ppm), 1,1,1-trichloroethane (500-12000 ppm), isoamyl nitrite (150-1050 ppm), flurothyl (562-1300 ppm) and injections of oxazepam (0.1-20 mg/kg). Halothane, 1,1,1-trichloroethane and oxazepam produced discriminative stimulus effects similar to those produced by PB. Isoamyl nitrite and flurothyl, while decreasing rates of responding, were not consistently generalized from PB. Differences are apparent in the PB-like discriminative effects of inhalants. Toluene, as shown in a previous study, as well as halothane and 1,1,1-trichloroethane have PB-like discriminative effects which are also shared by oxazepam and may be another common effect of central nervous system depressants. Other chemicals, like isoamyl nitrite and flurothyl, are representative of qualitatively different classes of behaviorally active inhalants.

Administration, Inhalation↗

Morphine discrimination in the pigeon using a color tracking procedure.

Pigeons were trained to discriminate 5.0 mg/kg morphine from saline. After morphine, subjects tracked the location of red response keys and after saline, the location of green keys. When stimulus generalization to other drugs was investigated dl-methadone produced morphine-like responding and this response generalization was primarily due to the l-isomer. Pretreatment with 1.0 mg/kg naloxone shifted the morphine generalization curve 10-fold to the right but only shifted the rate suppression curve 3-fold to the right. dl-Cyclazocine generated dose-related increases in responding on the red key location and in 3 of 5 birds, responses after 1.0 mg/kg were indistinguishable from those after morphine training doses. Meperidine did not produce responding on the red keys, nor did diazepam, cocaine, d-amphetamine, phencyclidine or pentobarbital. The discriminative stimulus effects of morphine are thus stereo-selective and pharmacologically specific. Generalization of responding to dl-cyclazocine but not to phencyclidine suggests that the morphine-like discriminative dl-cyclazocine cue was not due to interaction at sigma opiate receptors.

Animals↗

Further characterization of the three-choice morphine, cyclazocine and saline discrimination paradigm: opioids with agonist and antagonist properties.

Rats were trained in a three-choice morphine (3.0 mg/kg), cyclazocine (0.3 mg/kg) and saline discrimination using a discrete-trials avoidance procedure. Behavior was considered to be under stimulus control when an animal reliably completed at least 18 trials of a 20-trial session on the correct lever after s.c. administration of either morphine, cyclazocine or saline. In tests of stimulus generalization, levorphanol produced a dose-related increase in trials completed on the morphine choice lever, whereas its optical enantiomer, dextrorphan, produced predominantly cyclazocine-appropriate responding, indicating that stimulus control of behavior was stereoselective. Ethylketocyclazocine, ketocyclazocine, levallorphan and SKF 10,047 engendered stimulus control of behavior that was unambiguously cyclazocine-like. In contrast, three other opioids with mixed agonist and antagonist properties occasioned responding on both the morphine- and cyclazocine-appropriate choice levers consistent with the mixture of morphine- and cyclazocine-like activity exhibited by these drugs in other procedures in animals and man. The stimulus effects of phencyclidine, a nonopioid compound, were not clearly interpretable within the present experimental context. This three-choice discrimination paradigm provides an approach for studying concurrently the morphine- and cyclazocine-like discriminative stimulus effects of opioids with multiple components of action and may lead to a more precise characterization of the stimulus properties of mixed-acting opioids than has been possible with conventional two-choice discrimination paradigms alone.

Animals↗

Discriminative stimulus properties of the serotonergic agent 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI).

Using a two-lever drug discrimination procedure, six rats were trained to discriminate 0.5 mg/kg of racemic 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) from saline. Once trained, the animals demonstrated a dose-related decrease in discriminative performance upon administration of lower doses of DOI (ED50 = 0.16 mg/kg). DOI-stimulus generalization occurred with the putative 5-HT2 agonist DOM (ED50 = 0.49 mg/kg), but not with the 5-HT1A agonist 8-OH DPAT, or the 5-HT1B agonist TFMPP. Furthermore, the DOI stimulus could be antagonized by pretreatment of the animals with the 5-HT2 antagonist ketanserin. The present results, coupled with the prior demonstration that DOI possesses a significant affinity and selectivity for 5-HT2 binding sites, suggest that the discriminative stimulus effects of DOI may be 5-HT2-mediated.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

Inhaled toluene produces pentobarbital-like discriminative stimulus effects in mice.

The abuse of volatile solvents may be due to their ability to produce an intoxication similar to that produced by classical central nervous system depressants such as the barbiturates and ethanol. To evaluate this hypothesis, mice were trained to discriminate pentobarbital from saline injections in a two-lever operant task. Stimulus generalization was examined following 20-min inhalation exposures to toluene (300-5400 ppm). In 8 of 10 subjects, pentobarbital-lever responding occurred following toluene exposure indicating an overlap in the discriminative stimulus properties of toluene and pentobarbital.

Aerosols↗

Generalization decrement in human contingency learning.

An association between a cue and an outcome will generalize to a similar novel cue to some extent, but not completely. Learning theorists refer to the discrepancy between responding elicited by the original cue and the novel cue as a generalization decrement. Two experiments used a contingency learning task with human participants to compare the size of a generalization decrement between configurations of cues that were altered by adding or subtracting compositional elements. The results suggest that adding elements to a configuration can produce a generalization decrement, but removing elements produces a more robust generalization decrement. Furthermore, the generalization decrement caused by adding elements was not likely to be caused by competing orienting responses. The results are used to contrast Pearce's (1987, 1994) and Wagner's (2003) models of stimulus generalization.

Cues↗

Conditioned social aversion in the male Mongolian gerbil (Meriones unguiculatus).

Adult male Mongolian gerbils formed conditioned social aversions to young male conspecifics. The basic paradigm consisted of pairing a subject with a young animal (test stimulus) for 5 min and then injecting the subject with lithium chloride to produce gastrointestinal distress. When retested 48 hr later, the subject avoided the animal used as a test stimulus, as indicated by significantly decreased investigation time and approach frequency. Through a series of experiments on dose level, delay of toxin injection, and stimulus generalization, it was demonstrated that a dose of .03 ml/g body weight of .15 M LiCl is effective, the injection of the toxin should be given within 15 min of the preliminary social pairing, the social aversion formed is specific to the particular first paired stimulus animal, and isolation between test sessions is necessary for an aversion to develop. This paradigm of conditioned social aversion extends our knowledge of the learned aversion process and demonstrates that this type of learning can be generalized to a social situation by gerbils.

Animals↗

Characterization of the discriminative stimulus effects of centrally administered morphine in the rat.

The discriminative stimulus effects of centrally administered morphine were characterized in rats trained to discriminate 3.0 mg/kg SC morphine from saline in a two-choice discrete-trial avoidance paradigm. The intracerebroventricular (ICV) administration of 0.3-10 micrograms morphine engendered morphine-appropriate responding, morphine administered ICV being nearly 1000 times as potent as morphine administered SC. Cannula implantation itself did not affect the sensitivity of the rats to the discriminative effects of morphine. The onset of the discriminative stimulus effects of ICV morphine was not immediate; stimulus generalization comparable to that produced by 3.0 mg/kg morphine occurred 30-60 min after the injection of 1.0 or 10 micrograms ICV morphine and persisted for 90 and 150 min, respectively. Naltrexone blocked the discriminative stimulus effects of 10 micrograms ICV morphine in a dose-related manner. Complete antagonism of the stimulus effects of this dose of morphine was obtained with 0.01-0.03 mg/kg SC naltrexone. When administered centrally, the relatively lipid insoluble naltrexone methobromide completely antagonized the discriminative effects of 3.0 mg/kg morphine at a median effective dose of 0.3 micrograms. In contrast, when injected systemically at a dose of 1.0 mg/kg (approximately 500 micrograms), naltrexone methobromide failed to block the discriminative stimulus effects of either 10 micrograms ICV morphine or the SC training dose. Thus, periventricular brain sites appear to be involved in mediating the discriminative stimulus effects of morphine in the rat.

Animals↗

Drug effects on the repeated generalization of a visual discrimination acquired under one trial per day conditions.

Six pigeons were trained to respond under concurrent fixed-ratio extinction schedules of food reinforcement (FR 50) on the side keys of a three key chamber. Presence or absence of continuously-flashing, colored lights on the center key signalled which key pecking response (left or right) would be reinforced over the course of an entire experimental session; thus, the lights were analogous to a drug cue in drug-discrimination situations. In test (generalization) sessions of one FR in duration, the percentage of light on the center key was varied from 0 to 100%. During these sessions, saline, lysergic acid diethylamide (LSD; 0.04-0.20 mg/kg) and morphine (3.75 mg/kg) produced orderly, log-linear light generalization gradients, but only LSD shifted the gradient to the right (by approximately 50%). These results demonstrate the potential value of the method for assessing the effects of drugs on both exteroceptive (light) and interoceptive (drug) stimulus control. The method has the additional advantage that the effects of drugs on such control (i.e., on stimulus generalization) are relatively unaffected by corresponding effects on response control (e.g., rate of responding).

Animals↗

Efficient stimuli for recording of the amplitude modulation following response.

Amplitude modulation following response (AMFR) is a promising tool for objective frequency-specific assessment of hearing thresholds in children. The stimulus generally used for AMFR recording (one amplitude-modulated carrier) activates only a small part of the basilar membrane. Therefore, the response amplitude is small. Combined frequency and amplitude modulation is not significantly more effective. A new stimulus is proposed that is composed of several carriers. All carriers are modulated with the same modulation frequency. The signal to noise ratio of the response to the multiple-carrier stimulus is significantly increased compared with the usual one-carrier stimulus. Therefore, response detection near threshold is expected to be improved. AMFR also seems to be well suited to newborn hearing screening. Simultaneous recording of six responses (three AMFRs from each ear) to 1-, 2-, and 4-kHz multiple-carrier stimuli of a 40 dB HL stimulus level is demonstrated in normally-hearing adults. Verification in babies will be necessary.

Adult↗

(-)Ephedrine and caffeine mutually potentiate one another's amphetamine-like stimulus effects.

Using rats trained to discriminate 1 mg/kg of (+)amphetamine (ED50 = 0.4 mg/kg) from saline vehicle in a two-lever drug discrimination procedure, it was shown that (-)ephedrine (ED50 = 4.5 mg/kg), but not (+)ephedrine, substitutes for the (+)AMPH stimulus. It was also shown that caffeine (ED50 = 12.9 mg/kg) can substitute for (+)amphetamine in a dose-related fashion. Doses of (-)ephedrine and caffeine, which produced < or = 1% drug-appropriate responding when administered alone, were able to enhance each other's stimulus effects when administered in combination such that there was a twofold leftward shift in their respective dose-response curves. Furthermore, stimulus generalization occurred when a dose of caffeine that produced saline-appropriate responding when administered alone was administered in combination with (+)ephedrine. It would appear that low doses of (-)ephedrine and caffeine may mutually potentiate one another's stimulus effects in (+)AMPH-trained rats, and that a combination of caffeine and (+)ephedrine result in altered stimulus character when compared to comparable doses of either agent administered alone.

Amphetamine↗