Conditioned Cue Preference Research Articles

Cooperation and competition between the dorsal hippocampus and lateral amygdala in spatial discrimination learning

The conditioned cue preference (CCP) was used to study how rats discriminate between adjacent arms on a radial maze. Chai and White (Behav Neurosci 2004, 118:770-784) showed that an intact dorsal hippocampus is required to learn this discrimination and that an amygdala-based conditioned approach response that produces an equal tendency to enter both arms is simultaneously acquired. In the present experiments, rats were preexposed to the maze with no food and trained by alternately confining them at the ends of two adjacent arms, one that contained food and one that did not. When given a choice between these arms with no food present, the rats spent more time on their food-paired arms, suggesting they had learned to discriminate their locations. Temporary inactivation of the dorsal hippocampus with muscimol during confinement on the food-paired arm had no effect on the discrimination, but inactivation while on the no-food arm impaired it. This pattern of effects was reversed in rats with amygdala lesions (inactivation on the food-paired arm impaired, but inactivation on the no-food arm had no effect on the discrimination), showing that hippocampus-based and amygdala-based learning interact to influence the behavior of normal rats in this situation. The dorsal hippocampus learns about locations that contain food and about locations that do not contain food. The amygdala-based tendency to enter the food-paired arm cooperates with hippocampus-based foraging for food on the food-paired, but the amygdala-based tendency to enter the no-food arm competes with hippocampus-based learning about the absence of food on that arm.

Complementary roles for the amygdala and hippocampus during different phases of appetitive information processing

Evidence collected from rodent models of memory storage suggests that rapid forms of learning engage the involvement of multiple brain regions each of which may participate in a different component of information processing. The present study used temporary inactivation of the amygdala and hippocampus during different phases of information processing on a one-trial appetitive-conditioning task to examine how these two regions might participate in the storage of appetitive memories. Male Long Evans rats were chronically implanted into the amygdala or dorsal hippocampus and food deprived. Rats were trained on a radial maze conditioned cue preference task where training occurred in one 40-min session and testing took place 24 h later. The amygdala or hippocampus was inactivated separately with muscimol (50 ng/μl) injected immediately before or after training, or immediately before testing. Saline-injected rats displayed a conditioned preference by spending more time in the arm that previously contained food than in the arm that did not contain food. Muscimol injected into the amygdala before training or testing blocked the conditioned preference. Muscimol injected into the hippocampus immediately after training blocked the conditioned preference. These results suggest that the processing of memories may require multiple contributions from separate brain systems for at least short-term (24 h) storage. The resulting output from each system may converge on a similar downstream target to influence behavior.

Learning the morphine conditioned cue preference: Cue configuration determines effects of lesions

The morphine conditioned cue preference was investigated using two different apparatus configurations. In one configuration, with a clear Plexiglas partition separating the drug-paired and unpaired compartments, rats could see the cues in both compartments while in either one. In the other configuration, with an opaque wood partition separating the two compartments, rats could see the cues in only one compartment at a time. The experiment had three phases: a session of pre-exposure to the entire apparatus; four 2-day training trials during each of which rats received pairings of 5 mg/Kg morphine sulphate with one compartment and saline with the other (compartments and order counterbalanced), and a test session in which the undrugged rats moved freely between the compartments while the time spent in each was measured. Four groups of rats were trained using the opaque partition in all three phases. Normal rats and rats with amygdala or nucleus accumbens lesions exhibited preferences for their morphine-paired compartments; rats with fimbria-fornix lesions had no preferences. Four additional groups were trained using the clear partition during pre-exposure, the opaque partition during training and the clear partition during testing. Normal rats and rats with fimbria-fornix lesions exhibited preferences, rats with amygdala or nucleus accumbens lesions had no preferences. This interaction between lesioned structures and the apparatus configuration is accounted for by the idea that different types of learning produced the preference for morphine-paired cues in the two apparatus configurations. Each type was learned in a different memory system and so was impaired by different lesions. These findings contribute to understanding the nature of the learning processes that produce the morphine CCP.

Inactivation of the dorsal hippocampus does not affect learning during exploration of a novel environment

The conditioned cue preference (CCP) task was used to study the ability of rats to discriminate between spatial locations. Food-deprived rats explored an eight-arm radial maze with no food present (pre-exposure). On subsequent days, they were alternately confined in one arm of the maze with food and in another arm with no food (training), followed by a preference test with no food present, to determine if they had learned to discriminate between the two arm locations. No injections were given during the two latter phases. With adjacent radial maze arms, rats given three 10-min pre-exposure sessions and four food-pairing trials exhibited a preference for their food-paired arms; rats not pre-exposed did not exhibit this preference. Rats pre-exposed 30 min after dorsal hippocampus injections of muscimol exhibited the preference. With widely separated maze arms, rats given two training trials with no pre-exposure exhibited a preference for the food-paired arm; rats that were given one pre-exposure session did not. Rats pre-exposed 30 min after dorsal hippocampus injections of muscimol did not exhibit the preference. The same intrahippocampal muscimol injections that failed to affect the influence of pre-exposure on CCP learning with both arm configurations impaired win-shift performance, a standard test of spatial learning. These findings suggest that a functional dorsal hippocampus is not required for the (incidental or latent) learning that occurs during unreinforced exploration of a novel environment. The information acquired during this activity subsequently produces a latent learning effect if it is used to discriminate between two ambiguous locations (adjacent arms) or a latent inhibition--like effect if it is used to discriminate between two unambiguous locations (separated maze arms).

Effects of persistent cocaine self-administration on amygdala-dependent and dorsal striatum-dependent learning in rats

The influence of persistent cocaine self-administration on learning and memory has never been evaluated. Our objective was to isolate the effects of contingently administered cocaine from those of its general pharmacological or non-contingent actions on multiple memory system functioning. A triad design was used to yoke passive cocaine and saline administration to the behavior of rats who were actively self-administering cocaine. Following 4 weeks of cocaine or saline exposure in 2-h sessions, six triads were tested in the amygdala-dependent conditioned cue preference task and dorsal striatum-dependent win-stay task in an eight-arm radial maze environment. Drug or saline sessions continued throughout task testing. Throughout task testing, rats actively and passively exposed to cocaine sustained a total daily intake of approximately 15 mg/kg. During the conditioned cue preference task, saline-exposed rats showed robust conditioned preference for a Froot Loops-paired cue. Rats actively and passively exposed to cocaine showed no evidence of conditioning despite normal exploration in the maze during preference testing. For the win-stay task, no significant differences were found among the three groups in terms of the number of sessions to acquire the task or task accuracy at criterion. Rats actively or passively exposed to cocaine, however, completed sessions more quickly than saline-exposed rats at criterion. These findings suggest that contingent and non-contingent cocaine administration similarly disrupt stimulus-reward functions of the amygdala, but do not disrupt stimulus-response functions of the dorsal striatum. This dissociation may relate to differences in the rate by which dopamine is cleared from these tissues following cocaine exposure or possibly to cocaine-induced devaluation of natural rewards, which influences stimulus-reward learning, but not stimulus-response learning.

Hippocampal memory system function and the regulation of cocaine self-administration behavior in rats

There is considerable interest in elucidating neurocognitive mechanisms of cocaine addiction. This report focuses on the hippocampal memory system. Using food reward, two cognitive tasks were examined after lidocaine inactivation of the dorsal (dSUB) or ventral (vSUB) subiculum, the primary hippocampal output regions in rats. These tasks were conducted to first identify functionally relevant stereotaxic coordinates within the hippocampal memory system, in order to then examine its role in regulating drug-seeking and drug-taking behavior studied under a contextually discriminable FI 5-min(FR5:S) second-order schedule of cocaine and brief stimulus delivery. Inactivation of the dSUB and vSUB with 10 μg lidocaine impaired hippocampal-dependent win-shift performance. Amygdalar-dependant conditioned cue preference, used as a test for behavioral specificity of lidocaine, was not affected following inactivation of either site. Inactivation of the dSUB with 100 μg lidocaine significantly reduced drug-seeking and drug-taking behavior studied during the cocaine self-administration maintenance phase. Following extinction, inactivation of neither the dSUB nor vSUB influenced reinstatement of drug-seeking behavior induced by drug-paired cues presented alone or with a cocaine priming injection. The impairments in win-shift performance are consistent with the spatial processing functions of the dSUB and vSUB, and the reduction in drug-taking behavior is consistent with the non-spatial temporal processing functions of the dSUB. The lack of an effect of dSUB and vSUB inactivation on reinstatement of drug-seeking behavior may relate to the fact that the contextual associations with cocaine were well-practiced at the time of cue reinstatement testing, and therefore, drug-seeking behavior was likely regulated by nonhippocampal-dependent mechanisms.

Involuntary, unreinforced (pure) spatial learning is impaired by fimbria-fornix but not by dorsal hippocampus lesions.

Pure spatial learning occurs when rats acquire information about an environment while exploring it in the absence of reinforcers. We previously reported that voluntary, unreinforced exploration of a radial maze retards subsequent reinforced conditioned cue preference (CCP) learning in the same maze. In the present experiment, we examined the effects of involuntary, unreinforced pre-exposure to a radial maze. During pre-exposure, rats were moved by an experimenter between the ends of two arms of a radial maze five times in 30 min. This form of pre-exposure retarded CCP learning, whereas rats that were not pre-exposed and rats that were pre-exposed to a maze in a different room displayed normal CCP learning. These findings suggest that some information specific to the maze environment was acquired during involuntary unreinforced pre-exposure to it. In experiment 2, the retardation of reinforced CCP learning by involuntary unreinforced pre-exposure was eliminated by fimbria-fornix lesions made before pre-exposure but was unaffected by fimbria-fornix lesions made after pre-exposure but before training. Large neurotoxic lesions of the dorsal hippocampus made before pre-exposure had no effect on the retardation of CCP learning, but the rats with these lesions were impaired on a standard test of reinforced spatial learning in a water maze. The lesion effects in experiment 2 are similar to those previously reported for voluntary exploration and suggest that pure spatial learning may occur during both voluntary exploration of and involuntary exposure to an environment in the absence of reinforcers. Pure spatial learning can apparently occur with exposure to two different locations within an environment, but the rats do not have to move between the locations voluntarily. An intact fimbria-fornix is required for acquisition but not expression of this form of learning. The hippocampus is not involved in this form of learning.

Reinforcer devaluation abolishes conditioned cue preference: evidence for stimulus-stimulus associations.

In the conditioned cue preference (CCP) task, the subject is presented with a cue paired with food reward, resulting in a preference for the paired cue when allowed to choose later. To clarify the learning involved, the authors devalued the reinforcer after training by inducing a taste aversion to the food. In five 30-min sessions, rats were confined in 1 arm of a radial arm maze and presented with food. These reinforced sessions alternated with 5 unreinforced sessions in a nonadjacent arm. Devaluation was then accomplished in 1 group by inducing taste aversion; controls received either saline or unpaired lithium chloride treatment. When tested later, both the saline group and the unpaired group preferred the previously reinforced arm, but the devalued group showed aversion to it. Thus, CCP is mediated by the stimulus-reinforcer association; when the reinforcer is devalued, the preference is also abolished.

Cognitive task performance after lidocaine-induced inactivation of different sites within the basolateral amygdala and dorsal striatum.

To determine whether discrete components of amygdaloid and striatal memory systems could interact to guide behavior in a radial arm maze, conditioned cue preference (CCP) and win-stay accuracy were examined after lidocaine inactivation of either the rostral (rBLA) or caudal (cBLA) basolateral amygdala, the lateral (lDST) or medial (mDST) dorsal striatum, or a control site in rats. CCP expression was blocked only after rBLA or cBLA inactivation. lDST inactivation prevented attainment of criteria win-stay performance, whereas rBLA and mDST inactivation delayed it. Control site inactivation did not influence performance in either task. These findings suggest that the amygdala works independently of other memory systems to regulate learned responses in the CCP task, the rBLA may work cooperatively with the lDST to guide behavior in the win-stay task, and the mDST is less critical than the lDST for attaining criteria performance in the win-stay task.

Dorsal hippocampal function in unreinforced spatial learning.

This study examined learning about the spatial environment by rats during a single 10 min period of exploration on an eight-arm radial maze. Because no specific behaviors were learned during this procedure, the existence of learned spatial information was inferred from its retarding effect on subsequent conditioned cue preference (CCP) learning on the same maze. Previous experiments have shown that this form of spatial learning, measured in this way, requires an intact fimbriafornix and functional N-methyl-D-aspartate receptors. However, in the present experiments, large neurotoxic lesions of the dorsal hippocampus that impaired win-shift learning failed to eliminate the retarding effect of exploration on CCP learning. This result was obtained in three independent replications. These findings fail to confirm the hypothesis that the hippocampus is involved in spatial learning when that learning occurs in the absence of reinforcers and does not produce any specific learned behaviors. Previous work showed that this form of "pure" spatial learning requires an intact fimbria-fornix for acquisition but not for expression; the present findings suggest that the hippocampus is not required for either of these processes. The fimbria-fornix may interact with other temporal lobe structures in mediating this form of learning. The function of the hippocampus may be limited in some way to situations that involve reinforcers and/or situations in which specific behaviors are learned.

Neurotoxic Lesions of the Dorsomedial Thalamus Impair the Acquisition But Not the Performance of Delayed Matching to Place by Rats: a Deficit in Shifting Response Rules

This study examined the acquisition of a T-maze matching to place task by rats with neurotoxic lesions of the thalamic nucleus medialis dorsalis. This test of spatial working memory also entails learning a task rule that is contrary to the animals' innate preference. The rats next performed the same matching task over different retention delays. Finally, they were trained on a reversal of the task rule, i.e., to nonmatch to place. Although the lesions produced a clear acquisition impairment on the matching task, there was no evidence of a loss of working memory. A series of control tasks found no appreciable effect on a conditioned cue preference task or on open field activity. The pattern of results shows that medialis dorsalis lesions lead to a selective increase in perseverative behavior that can retard task acquisition. This perseverative deficit closely resembles that observed after prefrontal damage in rats, strongly indicating dysfunction in a common system.

Effects of NMDA receptor blockade on behaviors differentially affected by fimbria/fornix and amygdala lesions

We studied the effects of MK-801, a noncompetitive NMDA receptor antagonist, on acquisition and expression of the food conditioned cue preference (CCP) in the eight-arm radial maze. In this task, food-deprived rats are confined on alternate days in one arm of a radial maze with food and in another arm with no food. After several such training trials, they are given a choice between the two arms, both of which are empty. Normal rats spend more time in the arm that formerly contained food. We previously showed that this CCP is eliminated by lesions of the lateral nucleus of the amygdala. A single 10-min session of preexposure to the maze with no food retards acquisition of the CCP. This retardation is eliminated by fornix lesions, suggesting that hippocampus-based learning about the environment during the preexposure session suppresses subsequent amygdala-based CCP learning. In the present experiment, rats that received MK-801 before a preexposure session exhibited CCPs comparable to those for animals that had not experienced preexposure. We attribute this effect to the prevention of hippocampus-based learning during the preexposure due to NMDA receptor blockade. In other groups of rats, MK-801 given before the training trials or before the test trial eliminated the CCP in rats that had not received preexposure to the maze. The prevention of both acquisition and expression of the amygdala-based food CCP by MK-801 may distinguish the memory-related function of NMDA receptors in the amygdala from that of similar receptors in the hippocampus.

Information acquired by the hippocampus interferes with acquisition of the amygdala‐based conditioned‐cue preference in the rat

White and McDonald (1993, Behav Brain Res 55:269-281) previously reported that animals with amygdala lesions failed to acquire a conditioned-cue preference (CCP) based on spatial cues, but that animals with fornix lesions exhibited larger CCPs of this type than normal animals. The present experiments focused on the hippocampal interference with amygdala-based CCP learning inferred from this finding. In experiment 1 we tested the hypothesis that this interference was due to the acquisition of information about the maze and its environment during a 10 min period of free exploration of the maze before the start of CCP training, hitherto given to all animals in these experiments. Normal animals that were not preexposed to the maze and animals that were preexposed to a similar maze in a different room both exhibited larger CCPs than animals that were preexposed to the same maze in the same room as CCP training and testing. This suggests that normal animals acquire context-specific information during the preexposure period and that this may be the cause of the hippocampus-based interference with the amygdala-mediated CCP. In experiment 2 we attempted to determine if the information thought to be acquired by the hippocampal memory system interferes with acquisition or expression of the CCP. As previously demonstrated, animals that received fornix lesions before preexposure (i.e., before the start of the experiment) exhibited larger than normal CCPs. Animals that received fornix lesions after preexposure but before CCP training and animals that received fornix lesions after CCP training but before testing both exhibited normal CCPs.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine conditioned cue preference and the neurobiology of drug-seeking

This brief review draws a parallel between the drug-seeking behavior of humans addicted to amphetamine and the preference exhibited by animals for a place in which they have previously experienced the pharmacological effects of the same drug. Anatomical and pharmacological analyses suggest that nucleus accumbens dopamine receptor activation is necessary for the development of this preference. Through connections that synapse in ventral pallidum, a neural representation of accumbens dopamine receptor activation may reach the lateral nucleus of the amygdala where it could become associated with representations of existing environmental cues that also reach the lateral nucleus from cerebral cortex. When these conditioned cues are encountered on future occasions, activation of the amygdala-based association may reach either nucleus accumbens or ventral tegmental area. This neural activation either produces an excess of accumbens dopamine release or acts in synergy with a tonic level of dopamine release to cause the animal to approach and maintain contact with the conditioned cues.

A triple dissociation of memory systems: hippocampus, amygdala, and dorsal striatum.

This study investigated the respective roles of the hippocampus, the amygdala, and the dorsal striatum in learning and memory. A standard set of experimental conditions for studying the effects of lesions to the three brain areas using an 8-arm radial maze was used: a win-shift version, a conditioned cue preference (CCP) version, and a win-stay version. Damage to the hippocampal system impaired acquisition of the win-shift task but not the CCP or win-stay tasks. Damage to the lateral amygdala impaired acquisition of the CCP task but not the win-shift or win-stay tasks. Damage to the dorsal striatum impaired acquisition of the win-stay task but not the win-shift or CCP tasks. These results are consistent with the hypothesis that the mammalian brain may be capable of acquiring different kinds of information with different, more-or-less independent neural systems. A neural system that includes the hippocampus may acquire information about the relationships among stimuli and events. A neural system that includes the amygdala may mediate the rapid acquisition of behaviors based on biologically significant events with affective properties. A neural system that includes the dorsal striatum may mediate the formation of reinforced stimulus-response associations.