Latent inhibition of conditioned odor potentiation of startle: a developmental analysis

We conducted a two-part study of age and latent inhibition in the rat. In the first part of the study, rats given odor-shock pairings at 23 or 75 days of age exhibited a potentiated startle response in the presence of the odor the following day. This effect did not occur in rats trained at 16 or 20 days of age. Odor pre-exposure on the day prior to conditioning markedly reduced the odor potentiation of startle effect in 23- and 75-day-old rats but had no effect in 16 and 20-day-olds. In the second part of the study, rats were pre-exposed to the odor at 16 or 20 days of age and then conditioned at 23 days of age. When tested the day after conditioning, these pre-exposed rats exhibited a disruption in the odor potentiation of startle effect. We compare our results with other studies of latent inhibition, and with recent studies on whether conditioned responses are appropriate to the animal's age at training or their age at test.     

Ontogeny of context-specific latent inhibition of conditioned fear: Implications for configural associations theory and hippocampal formation development

Latent inhibition of fear conditioning to an auditory cue, as measured by behavioral freezing, was examined in 18- and 23-day-old rats. In Experiment 1, CS preexposure and conditioning occurred in the same context for some rats but in a different context for other rats, and 24 hr separated CS preexposure and conditioning. The 23-day-old rats showed a context-specific latent inhibition effect, but the 18-day-old rats showed no latent inhibition. In Experiment 2, CS preexposure and conditioning occurred in the same trainining session and both 18- and 23-day-old rats showed latent inhibition. These results were discussed in relation to Wagner's (1976) theory of information processing, hippocampal formation maturation, and function, and Sutherland and Rudy's (1989) configural association theory.©1994 John Wiley & Sons, Inc.     

Cingulate cortical coding of context-dependent latent inhibition

Neuronal activity of the auditory thalamus, amygdala, cingulate cortex, and substantia nigra was recorded during the administration of a behavioral test for latent inhibition (LI) or the retardation of behavioral conditioning because of preexposure of the conditional stimulus (CS). Following CS preexposure, both the preexposed CS and a control CS predicted avoidable footshock. LI occurred as significantly fewer avoidance conditioned avoidance responses after the preexposed CS than after the control CS. Attenuation of neuronal responses to the preexposed CS, or neural LI, occurred in all monitored areas. One group of subjects (Oryctolagus cuniculus) then received context extinction, and additional groups experienced novel context exposure or handling. Context extinction enhanced behavioral responding to the preexposed CS, eliminating LI. Context extinction also eliminated cingulate cortical neural LI by enhancing posterior cingulate cortical responses to the preexposed CS and attenuating anterior cingulate cortical responses to the control CS. Present and past results are interpreted to indicate that LI is (a) a failure of response retrieval and/or expression mediated by interfering CS-context associations and (b) a product of interactions of the posterior cingulate cortex and the hippocampus.     

Latent Inhibition and Conditioning in Rat Strains Which Show Differential Prepulse Inhibition

Latent inhibition (LI) is the retardation of associative conditioning resulting from preexposure of the conditioned stimulus (CS) alone prior to conditioning. Schizophrenic patients show deficient prepulse inhibition (PPI) and, at least acutely, deficient LI as well. We recently found that Brown Norway (BN) rats show a PPI deficit compared to Wistar-Kyoto (WKY) rats. If PPI and LI depend on neural processes with common genetic substrates, then LI should be deficient in BN rats as well. Here, LI of a conditioned taste aversion was examined in BN and WKY rats. One group from each strain was preexposed to a saccharin-flavored solution (CS) the day prior to conditioning. For taste aversion conditioning, these two groups again consumed saccharin and were injected with lithium chloride (unconditioned stimulus) 10 min later. A second group from each strain was not preexposed to the CS and was treated identically during conditioning, while a third group was not conditioned (injected with sodium chloride). To test for taste aversion conditioning, saccharin was offered for 20 min/day for 3 days. Nonconditioned BN and WKY rats consumed equal amounts of saccharin on test days. In both strains, conditioned rats showed a saccharin aversion. However, conditioning was less robust in BN than in WKY rats. WKY rats showed good LI of the conditioned taste aversion in that preexposed WKY rats consumed significantly more saccharin on test days than conditioned, nonpreexposed WKY rats. Preexposed BN rats did not consume significantly more saccharin on test days than conditioned, nonpreexposed BN rats. The previously reported deficiency in PPI in the BN rats was confirmed here 1 week after the taste aversion experiment. These results suggest that BN rats show deficient LI as well as PPI and display poor associative learning, a trait also reported in schizophrenia.     

Disruption of contextual freezing, but not contextual blocking of fear-potentiated startle, after lesions of the dorsal hippocampus

The role of the dorsal hippocampus in contextual fear conditioning was investigated with a contextual blocking paradigm. In Experiment 1, rats were given pairings of a light conditioned stimulus (CS) and footshock after preexposure either to footshock or to the context alone. The group preexposed to footshock showed poorer fear conditioning to the light CS, as measured by the fear-potentiated startle reflex. In Experiment 2, a group preexposed to footshock in the same context showed poorer fear conditioning to the light CS than did a group preexposed to footshock in a different context, indicating contextual blocking of fear-potentiated startle. In Experiment 3, lesions of the dorsal hippocampus had no effect on contextual blocking, even though contextual freezing was disrupted. The sparing of contextual blocking indicated that contextual memory was intact following hippocampal lesions, despite the disruption of contextual freezing.     

Novel factors contributing to the expression of latent inhibition

Behavioral and neural correlates of latent inhibition (LI) during eyeblink conditioning were studied in 2 experiments. In Experiment 1, rabbits (Oryctolagus cuniculus) were conditioned after 8 days of tone conditioned stimulus (CS) presentations or 8 days of context-alone experience. LI was seen in the CS-preexposed rabbits when a relatively intense (5 psi) airpuff unconditioned stimulus was paired with the CS. In Experiment 2, rabbits were given 0, 4, or 8 days of CS preexposures or context-alone experience. Hippocampal activity was monitored from the 8-day CS- or context-exposure rabbits. The LI effect was seen only in rabbits given 4 days of CS preexposure, thus suggesting that LI depended largely on the rate of acquisition in the context-preexposed control group. The neural recordings showed that the hippocampus was sensitive to the relative novelty of the stimuli and the overall context, regardless of whether exposure to stimuli and context promoted LI.     

Lesions to the basolateral amygdala and the orbitofrontal cortex but not to the medial prefrontal cortex produce an abnormally persistent latent inhibition in rats

Repeated nonreinforced preexposure to a stimulus interferes with the establishment of conditioned responding to this stimulus when it is subsequently paired with reinforcement. This stimulus-preexposure effect is known as latent inhibition (LI). Rather remarkably, LI appears to be resistant to the effects of numerous lesions, including the prefrontal cortex (PFC) and the basolateral amygdala (BLA). However, intact behavioral expression of LI following damage to given brain regions does not preclude the possibility that such regions participate in the regulation of LI expression in the intact brain. The present study showed that lesions of the BLA and the orbitofrontal cortex (OFC) but not of the medial PFC (mPFC) led to an abnormally persistent LI which emerged under conditions that disrupted LI in control rats. LI was measured in a thirst motivated conditioned emotional response procedure by comparing suppression of drinking in response to a tone in rats which received 0 (nonpreexposed) or 40 tone presentations (preexposed) followed by either two or five tone-shock pairings. Control rats showed LI with 40 preexposures and two conditioning trials, but raising the number of conditioning trials to five disrupted LI. OFC- and BLA-lesioned rats showed LI under the former condition but in addition persisted in exhibiting LI under the latter condition. Rats with lesion of the mPFC did not show persistent LI. Thus, although LI does not depend on the integrity of BLA and OFC (because it is present in BLA- and OFC- lesioned rats even under conditions disrupting the phenomenon in normal rats), these regions play an important role in the modulation of its expression, more specifically, in the control of the non-expression of LI when the impact of conditioning increases beyond a certain level.     

Postconditioning recovery from the latent inhibition effect in conditioned taste aversion

Two experiments were conducted examining the effects of flavor (CS) preexposure on the retention of conditioned taste aversion. In Experiment 1, rats received preexposure to sucrose solution followed by a sucrose-illness pairing. The expected “latent inhibition” effect was obtained when testing occurred after a two-day but not an eleven-day training-to-test interval. Experiment 2 extended these results by employing five- and twenty-one-day training-to-test interval parameters and provided evidence that the stronger taste aversion displayed by preexposed subjects following long retention intervals is not attributable to differences in training consumption of sucrose solution. This posttraining increase in conditioned taste aversion (CTA) suggests that preexposure blocks expression of memory.     

Peculiarities of Latent Inhibition Formation in SHR Rats in Conditioned Task of Different Complexity

Inhibition of attention to irrelevant stimuli was studied in SHR rats using latent inhibition test. Latent inhibition was formed in two types of conditioned tasks with different levels of complexity and stress. Passive and active avoidance conditioning was preceded by preexposure to conditioned stimulus consisting of 20 and 100 non-reinforced presentations, respectively. Control Wistar rats demonstrated successful formation of latent inhibition in both tasks. SHR rats showed different degree of disruption of latent inhibition depending on the type of behavioral task. We assume that learning defect in these animals in respect to both novel and preexposed conditioned stimuli is associated with the lack of behavioral inhibition.     

The ontogeny of conditioned odor potentiation of startle

During development, conditioned responses usually occur first to olfactory, then to auditory, and finally to visual cues. The authors of the present study report that fear potentiation of startle to an olfactory conditioned stimulus emerges relatively late in development (i.e., at 23 days of age; Experiments 1 and 2). The failure to observe conditioned odor potentiation of startle (OPS) in younger rats was not due to a failure to either acquire or remember the odor-shock association (Experiment 3). Surprisingly, the authors also found that rats trained at 16 but tested at 23 days of age failed to exhibit the OPS effect even though they did exhibit pronounced odor avoidance (Experiment 4). The results are discussed in terms of (a) sensory-specific sequential emergence of learned fear, (b) the neural circuit involved in fear potentiation of startle, and (c) the concept that conditioned responding is appropriate to the animal's age at the time of training rather than its age at testing.     

Familiarity-based stimulus generalization of conditioned suppression in rats is dependent on the perirhinal cortex

We report that bilateral, excitoxic lesions of the perirhinal cortex attenuate rats' familiarity-based stimulus generalization. After surgery, rats were preexposed either to 2 auditory stimuli (A and B) or to only 1 auditory stimulus (B). Following preexposure, all rats received pairings of A and a footshock before assessment of generalized responding (conditioned suppression) to B. Sham rats' generalization was greater when preexposure was to both A and B than when preexposure was to B only. That pattern was abolished in lesioned rats, though no general deficiency was found in other measures of auditory processing. Our findings suggest that the perirhinal cortex is required for rats to encode familiarity as part of stimulus representations.     

Genetic influences on latent inhibition

The present study examined the development of latent inhibition in a number of inbred strains of mice. C57BL/6J, DBA/2J, C3H/Ibg, BALB/cByJ, A/J, CBA/J, 129/SvevTac, 129/SvJ, and AKR/J mice were screened for the development of latent inhibition. The latent inhibition paradigm involved 1 day of either 40 preexposures to the conditioned stimulus (CS) or no preexposure. On the following training day, the CS was twice paired with a shock unconditioned stimulus (US). On a subsequent test day, the strength of the CS-US association was measured. Mice preexposed to the CS should show a weaker CS-US association, which would reflect development of latent inhibition. Significant between-strain differences existed. The 129/Svev, C57BL/6, BALB/cByJ, AKR, and DBA/2 mice developed latent inhibition, but 129/SvJ, CBA, A, and C3H mice did not. Thus, genetic variance contributes to variability in the development of latent inhibition.     

Age-related differences in avoidance behavior in rats following CS preexposure

Weanling and adult rats were exposed to either 0 or 10 conditioned stimulus (CS) presentations prior to 1-way active-avoidance (AA) training. Although CS exposure retarded avoidance acquisition in the adults, it produced no effect in the pups during avoidance learning. Neither adult nor young rats demonstrated preexposure effects in extinction. A general extinction analysis showed that pups had less resistance to extinction than the adults, despite a comparable avoidance learning criterion between age groups. The lack of preexposure influences on performance by the pups was compared to previous findings of response inhibitory deficits in immature rats. The results were considered in light of selective attention interpretations of latent inhibition.     

Reinforcers in infancy: classical conditioning using stroking or intra-oral infusions of milk as UCS

Six-day-old rats received 20 forward pairings of an odor-conditioned stimulus (CS) with one of two unconditioned stimuli (UCS); 1) intra-oral milk infusions or 2) stroking with a sable-hair brush. These UCS's produce a common general response of increased behavioral activity, but different specific behaviors. For each UCS, additional pups received backward pairings of the CS and UCS, random pairings of the CS and UCS, CS only, UCS only, or no stimuli. Four hours later, pups received a two-odor choice test to assess the development of an odor preference and a CS-only test to assess the acquisition of conditioned responding (CR). The results of the two-odor choice test indicated that for both UCS's only forward pairings of the CS and UCS resulted in an odor preference. Similarly, the CS-only test showed that only forward pairings of the CS and either UCS were effective in producing CR's; pups that received forward pairings exhibited increased behavioral activity during presentations of the CS, which is an unconditioned response (UCR) to both UCS's. Only the forward paired CS-milk UCS group exhibited increased mouthing and probing during the CS only test; these are UCR's that occur to milk infusions but infrequently to the stroking UCS. These results demonstrate the development of similar conditioned odor preferences using behaviorally activating UCS's, but CR's which are specific to the form of the UCR.     

Effects of opiate manipulations on latent inhibition in rabbits: sensitivity of the medial septal region to intracranial treatments

The effects of opiate manipulations were examined on latent inhibition of classically conditioned heart rate in rabbits. Animals were exposed to an auditory stimulus that was later used as a conditioned stimulus (CS). Administration of the agonist levorphanol into the medial septal region either preceding or immediately following CS preexposure sessions attenuated latent inhibition of the conditioned response. This effect was observed in animals that showed no change in long-term retention of habituation. Administration of levorphanol into the central nucleus of the amygdala, a sensitive site for opiate manipulations on aversive conditioning tasks, was ineffective. Further analysis of the effect obtained within the septal region revealed pharmacological specificity. The effect of posttraining levorphanol was also time dependent and exhibited neuroanatomical specificity. Posttraining opiate antagonist administration into the medial septum produced a modest augmentation of latent inhibition. The medial septal region appears to provide a site where opiate manipulations alter some aspect of retention for events that occur in the absence of reinforcement.     

Disruption of latent inhibition following systemic administration of parachlorophenylalanine (PCPA).

Rats received either 0 or 30 preexposures to a tone which was later used as a CS in a two-way active avoidance task. Tone preexposure resulted in retarded conditioning in normal animals. This latent inhibition effect, however, was not present in rats treated with parachlorophenylalanine. A second experiment used the combined-cue summation test to verify the fact that stimulus preexposure endowed the tone with latent and not conditioned inhibitory properties. The results were discussed in terms of the role of the serotonergic mesolimbic system in tuning out irrelevant stimuli.     

Effects of conditioned stimulus preexposure on human electrodermal conditioning

Two experiments investigated the effects of conditioned stimulus (CS) preexposure on Pavlovian differential conditioning and extinction of the skin conductance response. In both experiments, half the subjects were exposed to 20 presentations each of the CS+ and CS-, and the other half were exposed to control stimuli. CS duration was 8 sec. The unconditioned stimulus in Experiment 1 (N = 48) was a 1000 Hz tone of 80 dB which signalled a reaction time requirement, and in Experiment 2 (N = 48), it was a 1 sec burst of white noise at 105 dB. The results of Experiment 1 indicated that no-preexposure groups displayed more CS+/CS- differentiation than preexposure groups during acquisition and more resistance to extinction, at least for the first interval anticipatory response. In addition, the results of Experiment 2 indicated that no-preexposure groups displayed more differentiation than preexposure groups in terms of the second interval anticipatory response. These data constitute a demonstration of the latent inhibition effect with human subjects, and imply that there is an intrinsic relationship between the orienting response and the conditioning process.     

Early handling and latent inhibition in the conditioned suppression paradigm

Latent inhibition (LI) is a behavioral paradigm in which repeated exposure to stimuli not followed by meaningful consequences renders these stimuli ineffective for subsequent learning. The development of LI is considered to reflect learning not to attend, to ignore, or tune out irrelevant stimuli. The present study investigated the differences in the development of LI between handled and nonhandled males and females. Infantile handled (days 1-22) and nonhandled, male and female Wistar rats were tested in maturity in the LI paradigm, using a conditioned emotional response (CER) procedure. The procedure consisted of three stages: preexposure, in which the to-be-conditioned stimulus, tone, was presented without being followed by reinforcement; acquisition, in which the preexposed tone was paired with shock; and test, in which LI was indexed by animals' suppression of licking during tone presentation. Handled animals exhibited less conditioned suppression as compared to nonhandled animals. LI was obtained in both the handled and the nonhandled females, but only the handled males showed the LI effect. Nonhandled males failed to develop LI. These results replicate our previous findings on LI in conditioned avoidance in demonstrating that: the effects of handling are evident in learning tasks that do not involve motivational-emotional variables, i.e., learning to ignore irrelevant stimuli; handling differentially affects males and females; the nonhandling procedure has deleterious consequences on adult behavior.     

Conditioning of aversion to an odor paired with peripheral shock in the developing rat

Four experiments examined an apparent inability to associate, or severe deficiency in associating, an odor and a footshock during the first 2 weeks of life in the rat, a cue-to-consequence relationship that had formerly seemed age-dependent. With a particular classical conditioning procedure, however, significiant conditioning occurred on postnatal Days 6 and 10 with relatively few conditioning trials; the procedure employed an odor explicitly unpaired with footshock (CS?), as well as an odor paired with footshock (CS+) (Experiment I). Experiment II assessed the contribution of a CS? exposure in the conditioning of rats 8, 15, or 50 days of age. For 8-day-olds, exposure to both the CS+ and CS? resulted in conditioned aversion to the CS+ after eight but not one conditioning trials, but neither 1 nor eight trials with only a CS+ produced conditioning. For 15- and 50-day-olds, conditioning to the CS+ odor was significant after one trial with, but not without, a specific CS? with eight trials, however, conditioning was significant with or without the specific CS?. It was verified with the 50-day-olds in Experiment III that aversion to the CS+ was conditioned with a single trial only if a CS? had been presented, with a slight trend toward superior conditioning if the CS? preceded rather than followed the CS+ during conditioning. Experiment IV tested the hypothesis that exposure to the distinctive CS? odor sensitzes the animal to the specific properties of the CS+ odor. Fifteen and 50-day-old rats were given one conditioning trial with a CS+ odor that was either unaccompanied by a CS? or that was presented with a CS? odor in the same context as the CS+ or in a different context. For both 15? and 50-day-old rats, conditioning to the CS+ occurred only for animals given the CS? in the same context as the CS+, indicating that the hypothesis should be rejected. The results generally indicate rapid and substantial odor-footshock conditioning in rats as young as 6 days of age, with CS-exposure established as perhaps especially significant for conditioning early in life, but important for rats of all ages tested, from infancy to adulthood.     

Extinction in the developing rat: an examination of renewal effects

In the present series of experiments the context-specificity of extinction was examined from a developmental perspective. For postnatal day (PN) 23 rats, renewal of freezing to an aversive odor conditioned stimulus (CS) was observed when rats were conditioned in Context A, extinguished in Context B, and tested in Context A (i.e., ABA renewal). This effect was not observed in PN16 rats, which is consistent with previous studies suggesting that rats < approximately PN20 are impaired in encoding contextual information [i.e., Carew and Rudy [1991]. Developmental Psychobiology, 24, 191-209]. Subsequent experiments demonstrated that for rats conditioned at PN16 and tested at PN23, contextual regulation of extinction performance depended on the age at which extinction occurred. Specifically, ABA renewal was observed in rats given extinction training at PN22 but not in rats given extinction training at PN17. These latter results show that whether or not context regulates the expression of an ambiguous memory is determined by the animal's age when the memory becomes ambiguous.