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.     

Learning and latent inhibition in old mice.

The inhibitory component of selective attention has been compared in young (7-8 weeks) and older (9-10 months) female mice using the latent inhibition (LI) paradigm. LI consists of retardation in conditioning to a stimulus as a consequence of its prior non-reinforced pre-exposure. In the present work, active avoidance of an electric footshock signaled with a sound was used. Avoidances of the electric footshocks were significantly reduced in old relative to young mice which did not differ regarding pain threshold. This likely results from a slower learning in old mice. LI was significantly present and of the same importance in both young (46%) and old (49%) mice. These results suggest that in 8-9 months-old mice, the learning ability is reduced but the inhibitory component of selective attention is not altered.     

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.     

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.     

The forgetting of stimulus attributes in latent inhibition

Numerous studies have demonstrated that the forgetting of stimulus attributes is a common occurrence; that is, organisms forget the specific characteristics of training stimuli over long retention intervals, while retaining general information of the training stimuli themselves. However, most studies have examined this effect after a learning episode, and there have been virtually no accounts to test whether the forgetting of attributes occurs for stimuli presented prior to training. Therefore, this experiment was designed to test that possibility, and it examined whether the forgetting of stimulus attributes occurred prior to training for the flavor stimulus in a conditioned taste aversion (CTA) procedure. Specifically, a latent inhibition (LI) procedure was used to measure the extent of forgetting for a pre-exposed flavor over short and long retention intervals. The results indicate that rats forgot the specific characteristics of the flavor stimulus (CS) while retaining memory for pre-exposure sessions over a long retention interval. That is, subjects pre-exposed and conditioned with different concentrations of sucrose showed no LI effect with a 1-day delay between pre-exposure and training, but demonstrated a generalized LI with an 8-day delay between pre-exposure and conditioning. This experiment provides further evidence for the robustness of the forgetting of stimulus attributes, and demonstrates that this specific type of forgetting also occurs prior to the learning of a CTA task.     

The effect of antibody on latent pseudorabies virus infection in vitro.

Cytosine arabinoside (Ara C) inhibited the synthesis of pseudorabies virus when Vero cells were infected at a multiplicity of infection of 0.0001-0.05 PFU per cell. On removal of Ara C, infectious virus reappeared after a latent period of 3-5 days. The activation of latent virus was not influenced by elevating the temperature to 40 degrees C at the time of Ara C removal but it was prevented by antiviral antibody. When antiviral IgG was added into the culture fluid of cells either during the incubation with Ara C, or after removal of the inhibitor, the number of infectious centres was reduced to about 10%. The role of antiviral IgG in the maintenance of latency is discussed.     

Amplified migration inhibition effect.

Upon exposure to specific antigen in tissue culture, sensitive lymphocytes released macrophage migration inhibition factor and other lymphokines into the supernatant culture medium. Migration of peritoneal macrophages from nonsensitive animals was inhibited in the presence of such supernatants. However, with previous techniques it was found that an inhibitory effect was present at only low low titers (less than 10(2)). It is therfore of great interest that by increasing cellular density, the total number of cells being kept constant, inhibitory activity can be amplified by a factor as great as 10(10). This amplification was observed only when lymphocytes and macrophages were loosely packed, as by spontaneous sedimentation in a conical test tube. The effect was abolished by dispersing the cell suspension in a flat-bottomed flask or, alternatively, by shaking the test tube so that intimate prolonged intercellular contact was prevented.     

Cytotoxic lesions of the retrohippocampal region attenuate latent inhibition but spare the partial reinforcement extinction effect

 Experiment 1 assessed the effect of cytotoxic retrohippocampal (entorhinal and extra-subicular cortices) lesions on the development of latent inhibition (LI) using an off-the-baseline, between-subjects, conditioned emotional response paradigm. Sham-operated controls and unoperated rats that had been pre-exposed to a light stimulus prior to light-shock pairings showed less conditioned suppression towards the light stimulus than the nonpre-exposed animals, thus demonstrating LI. However, LI was not evident in rats with retrohippocampal lesions. In experiment 2, the same animals were trained to run in an straight runway for food. Half of the animals were trained under a 50% partial reinforcement schedule (i.e. they were rewarded randomly on half of the acquisition trials) and the other half were trained under a continuous reinforcement schedule (i.e. they were rewarded on every acquisition trial). When tested in extinction, animals trained on the partial reinforcement schedule showed greater persistence than animals trained on continuous reinforcement, thus demonstrating the partial reinforcement extinction effect (PREE). Rats with retrohippocampal lesions showed a PREE that was at least as clear as that seen in the sham-operated controls and in the unoperated animals. It is concluded that cytotoxic lesions of the retrohippocampal region selectively led to an abolition of LI, but spared the PREE. The present study thus provided evidence against the hypothesis that LI and the PREE share a common neural substrate. Received: 13 June 1996 / Accepted: 24 December 1996     

Augmentation of latent inhibition by electrical stimulation of hippocampus

The effects of low-level hippocampal stimulation on the development of latent inhibition were investigated employing classical conditioning of the nictitating membrane response of rabbits. Four groups were given either (a) no preexposure of the to-be-CS, (b) preexposure, (c) preexposure overlapped by hippocampal stimulation or (d) preexposure overlapped by cortical stimulation, followed by 300 conditioning trials for each group. After conditioning, the hippocampal group was divided into two groups designated HS-1 and HS-2 by means of a post-hoc test for stimulation effects. Conditioning was found to be retarded in all three preexposured groups, with significantly greater retardation (augmentation of latent inhibition) in Group HS-2. The results support a general conception that the hippocampal stimulation produced its effects through the modulation of sensory input.     

Attenuation of latent inhibition by electrical stimulation of hippocampus

The effects of hippocampal stimulation on the development and expression of latent inhibition were investigated employing classical conditioning of the nictitating membrane response of rabbits. Hippocampal stimulation overlapping conditioned stimulus preexposure produced attenuation of latent inhibition, as did stimulation presented during conditioning after preexposure. However, hippocampal stimulation during conditioning in the absence of preexposure had little effect. The results support the hypotheses that in classical conditioning a major function of the hippocampus is the modulation of sensory input, especially input involved in the learned irrelevance of stimuli.     

Dissociating entorhinal and hippocampal involvement in latent inhibition

This study used anatomical cues to suggest a functional dissociation between the roles of the entorhinal cortex and the hippocampus in learning. The authors proposed that the highly convergent inputs to the entorhinal cortex indicate this region may be particularly important for selecting or compressing information. This hypothesis was tested in rabbits (Oryctolagus cunniculus) trained on an associative learning task that is a common index of stimulus selection. In this task, known as latent inhibition, preexposure to a stimulus (such as a tone) leads to slowed learning when the same tone is subsequently paired with an outcome (such as an airpuff to the eye). As hypothesized, rabbits with neurotoxic lesions of the entorhinal cortex failed to show slowed learning following preexposure (no latent inhibition) and learned the association faster than control rabbits. In contrast, hippocampal-lesioned animals showed normal (slowed) learning.     

Ventral subiculum involvement in latent inhibition context specificity

The subiculum is the main structure linking the hippocampus with several cortical and subcortical areas. In particular, ventral subiculum might act as an interface between the hippocampus, a contextual information processor, and cortical and subcortical processing systems related to motivation, such as the ventral striatum. Electrophysiological studies have shown a relationship between ventral subiculum and ventral striatum, namely a strong influence on mesolimbic system and the activity of dopaminergic neurons in the ventral tegmental area. Dopamine activity in this system has received special attention for its role in the latent inhibition phenomenon. However, the functional relationship between mesolimbic system and this behavioral process remains unclear. Two experiments were performed to analyze the role of ventral subiculum on latent inhibition. The results showed that ventral subiculum is involved in contextual processing that modulates the expression of latent inhibition. These findings are consistent with electrophysiological studies revealing the ventral subiculum as a structure modulating the mesolimbic DA system and DA release in the nucleus accumbens.     

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.     

The effects of radiofrequency lesion or transection of the fimbria-fornix on latent inhibition in the rat.

Latent inhibition consists of a decrement in conditioning to a stimulus as a result of its prior non-reinforced pre-exposure. Based on evidence pointing to the involvement of the hippocampus and the nucleus accumbens in latent inhibition disruption, it has been proposed that latent inhibition depends on the integrity of the subicular input to the nucleus accumbens. Since fibers originating in the subiculum and destined for the nucleus accumbens run through the fimbria-fornix, we assessed the effects of radiofrequency lesion or transection of the fimbria-fornix, on latent inhibition. The effectiveness of both lesions was demonstrated by the total disappearance of acetylcholinesterase staining in the hippocampus and of retrogradely labeled cells in the hippocampus/subiculum following the injection of the retrograde tracer biotin-dextran amine into the shell subregion of the nucleus accumbens. Likewise, in accord with previously documented behavioral effects of lesions to the hippocampus and related structures, both lesions increased spontaneous activity and disrupted performance in Morris water maze, and the radiofrequency lesion facilitated the acquisition of two-way active avoidance. In spite of the above, latent inhibition remained unaffected by both fimbria-fornix lesions, indicating that the critical projections subserving latent inhibition are not those traversing the fimbria-fornix from the hippocampus/subiculum to the nucleus accumbens. The implications of these results for the neural circuitry of latent inhibition and the latent inhibition model of schizophrenia are discussed.     

The chakragati mouse shows deficits in prepulse inhibition of acoustic startle and latent inhibition

The chakragati (ckr) mouse, which was serendipitously created as a result of a transgenic insertional mutation, has been proposed as a model of aspects of schizophrenia. The mice exhibit circling, hyperactivity, reduced social interactions, and enlarged lateral ventricles, which parallel aspects of the pathophysiology of schizophrenia. Deficits in sensorimotor gating and processing of the relevance of stimuli are core features of schizophrenia, which underlie many of the symptoms presented. Measures of prepulse inhibition (PPI) and latent inhibition (LI) can assess sensorimotor gating and processing of relevance in both humans and animal models. We investigated PPI of acoustic startle and LI of aversive conditioning in wild-type, heterozygous, and ckr mice. The ckr mice, which are homozygous for the transgene insertion, but not heterozygous littermates, showed impaired PPI in the absence of any difference in acoustic startle amplitude and showed deficits in LI of conditioning of a light stimulus to footshock, measured as suppression of licking for water in water-restricted mice. Together with the previous evidence for hyperactivity, reduced social interactions, and enlarged lateral ventricles, these data lend further support to the suggestion that the ckr mouse has utility as an animal model of aspects of schizophrenia.     

Rolipram attenuates MK-801-induced deficits in latent inhibition

Latent inhibition is used to examine attention and study cognitive deficits associated with schizophrenia. Research using MK-801, an N-methyl-D-aspartate (NMDA) open channel blocker, implicates glutamate receptors in acquisition of latent inhibition of cued fear conditioning. Evidence suggests an important relationship between NMDA-induced increases in cyclic adenosine monophosphate (cAMP) and learning and memory. The authors examine whether amplification of the cAMP signaling pathway by rolipram, a selective Type 4 cAMP phosphodiesterase inhibitor, reverses MK-801-induced impairments in latent inhibition. One day before training, mice were injected with MK-801, rolipram, MK-801 and rolipram, or vehicle and received 20 preexposures or no preexposures to an auditory conditioned stimulus (CS). Training consisted of 2 CS-footshock unconditioned stimulus pairings. Rolipram attenuated the disruptive effect of MK-801 on latent inhibition, which suggests a role for the cAMP signaling pathway in the task and implicates phosphodiesterase inhibition as a target for treating cognitive impairments associated with schizophrenia.     

Effects of swim stress on latent inhibition using a conditioned taste aversion procedure

Rats were used to examine the effects of inescapable swim stress on latent inhibition using a conditioned taste aversion procedure. Subjects were subjected to inescapable swim after each of three saccharin taste preexposures and saccharin was later paired with LiCl. The ability of swim to influence latent inhibition was assessed on subsequent saccharin test trials. Swim stress significantly attenuated latent inhibition. The implications of these results regarding the effects of swim stress on conditioned taste aversion are discussed.