Lesions of the rat nucleus basalis magnocellularis disrupt appetitive-to-aversive transfer learning

Rats with selective lesions of the nucleus basalis magnocellularis (NBM) and sham-lesion control animals were tested in an operant appetitive-to-aversive transfer task. We hypothesized that NBM lesions would not affect performance in the appetitive phase, but that performance would be impaired during subsequent transfer to the aversive phase of the task. Additional groups of NBM lesion and control rats were tested in the avoidance condition only, where we hypothesized that NBM lesions would not disrupt performance. These hypotheses were based, on the argument that the NBM is not necessary for simple association learning that does not tax attention. Both the appetitive phase of the transfer task and the avoidance only task depend only on simple associative learning and are argued not to tax attention. Consequently, performance in these tasks was predicted to be spared following NBM lesions. Complex, attention-demanding associative learning, however, is argued to depend on the NBM. Performance, in the aversive phase of the transfer task is both attentionally demanding and associatively more complex than in either the appetitive or aversive tasks alone; thus, avoidance performance in the NBM lesion group was predicted to be impaired following transfer from prior appetitive conditioning. Results supported our hypotheses, with the NBM lesion group acquiring the appetitive response normally, but showing impaired performance following transfer to the aversive conditioning phase of the transfer task. Impairments were not attributable to disrupted avoidance learning per se, as avoidance behavior was normal in the NBM lesion group tested in the avoidance condition only.     

Discrete and Contextual Cue Alterations Eliminate the Instrumental Appetitive-to-Aversive Transfer Impairment in Phenytoin-Treated Rats

We have shown previously that the antiepileptic phenytoin impairs transfer in an instrumental learning task (Banks et al., 1999). The present study examined the effects of contextual alterations on appetitive-to-aversive transfer performance of rats treated with either phenytoin or tang. Adult rats were tested in tone-signaled appetitive and aversive instrumental tasks, where the animal bar-pressed to obtain a food reward (sugar pellet) or to avoid shock. Rats were trained on the appetitive task for 31 days. Beginning on the twenty-first day, rats were gavaged with either phenytoin or tang twice daily. Animals were then transferred to aversive training, with the phenytoin or tang treatment continuing throughout the 25 testing days. For some animals, contextual changes were introduced as they shifted from appetitive to aversive training, while for other animals these changes were not made. Phenytoin-treated rats that were presented with changes in context as they transferred from the appetitive to the aversive task learned the avoidance response to levels substantially higher than drug-treated rats not presented with the contextual changes. These results indicate that phenytoin impairs avoidance learning following transfer from the appetitive task, and that this impairment can be eliminated by introducing changes in context at the point of transfer. In the tang-treated control subjects, on the other hand, there was no improvement in transfer learning performance associated with the changes in contextual cues. This pattern of results suggests that contextual encoding processes in rats being trained in an instrumental appetitive-to-aversive paradigm are dramatically affected by phenytoin.     

Discrete and contextual cue alterations eliminate the instrumental appetitive-to-aversive transfer impairment in phenytoin-treated rats

We have shown previously that the antiepileptic phenytoin impairs transfer in an instrumental learning task (Banks et al., 1999). The present study examined the effects of contextual alterations on appetitive-to-aversive transfer performance of rats treated with either phenytoin or tang. Adult rats were tested in tone-signaled appetitive and aversive instrumental tasks, where the animal bar-pressed to obtain a food reward (sugar pellet) or to avoid shock. Rats were trained on the appetitive task for 31 days. Beginning on the twenty-first day, rats were gavaged with either phenytoin or tang twice daily. Animals were then transferred to aversive training, with the phenytoin or tang treatment continuing throughout the 25 testing days. For some animals, contextual changes were introduced as they shifted from appetitive to aversive training, while for other animals these changes were not made. Phenytoin-treated rats that were presented with changes in context as they transferred from the appetitive to the aversive task learned the avoidance response to levels substantially higher than drug-treated rats not presented with the contextual changes. These results indicate that phenytoin impairs avoidance learning following transfer from the appetitive task, and that this impairment can be eliminated by introducing changes in context at the point of transfer. In the tang-treated control subjects, on the other hand, there was no improvement in transfer learning performance associated with the changes in contextual cues. This pattern of results suggests that contextual encoding processes in rats being trained in an instrumental appetitive-to-aversive paradigm are dramatically affected by phenytoin.     

The effects of estradiol on avoidance learning in ovariectomized adult rats

The present study examined the effects of ovariectomy and subsequent estradiol replacement on learning in young adult rats using a set of instrumental avoidance paradigms differing in the nature and extent of prior experience in the learning context. Thus, one group of animals was placed directly into avoidance learning (AV). A second group was trained on an appetitive task first, and then transferred into the aversive context (AP-AV). The third group was exposed to the training context without any specific appetitive response requirement, and then required to learn an active avoidance response (Context-AV). We found that estradiol (OVX+E) impaired avoidance acquisition in all cases relative ovariectomized controls (OVX). In contrast, while avoidance learning is improved following appetitive training or context exposure in both OVX+E and OVX animals, the OVX+E animals profit to a greater extent from the appetitive or context experience than do the OVX controls. We suggest that this difference may be due to enhanced attentional processes or improved hippocampal processing of contextual factors. Thus, estradiol negatively influences simple associative avoidance learning in ovariectomized rats, but appears to promote positive transfer.     

The Effects of Estradiol on Avoidance Learning in Ovariectomized Adult Rats

The present study examined the effects of ovariectomy and subsequent estradiol replacement on learning in young adult rats using a set of instrumental avoidance paradigms differing in the nature and extent of prior experience in the learning context. Thus, one group of animals was placed directly into avoidance learning (AV). A second group was trained on an appetitive task first, and then transferred into the aversive context (AP-AV). The third group was exposed to the training context without any specific appetitive response requirement, and then required to learn an active avoidance response (Context-AV). We found that estradiol (OVX+E) impaired avoidance acquisition in all cases relative ovariectomized controls (OVX). In contrast, while avoidance learning is improved following appetitive training or context exposure in both OVX+E and OVX animals, the OVX+E animals profit to a greater extent from the appetitive or context experience than do the OVX controls. We suggest that this difference may be due to enhanced attentional processes or improved hippocampal processing of contextual factors. Thus, estradiol negatively influences simple associative avoidance learning in ovariectomized rats, but appears to promote positive transfer.     

Impaired appetitively as well as aversively motivated behaviors and learning in PDE10A-deficient mice suggest a role for striatal signaling in evaluative salience attribution

Phosphodiesterase 10A (PDE10A) hydrolyzes both cAMP and cGMP, and is a key element in the regulation of medium spiny neuron (MSN) activity in the striatum. In the present report, we investigated the effects of targeted disruption of PDE10A on spatial learning and memory as well as aversive and appetitive conditioning in C57BL/6 J mice. Because of its putative role in motivational processes and reward learning, we also determined the expression of the immediate early gene zif268 in striatum and anterior cingulate cortex. Animals showed decreased response rates in scheduled appetitive operant conditioning, as well as impaired aversive conditioning in a passive avoidance task. Morris water maze performance revealed not-motor related spatial learning and memory deficits. Anxiety and social explorative behavior was not affected in PDE10A-deficient mice. Expression of zif268 was increased in striatum and anterior cingulate cortex, which suggests alterations in the neural connections between striatum and anterior cingulate cortex in PDE10A-deficient mice. The changes in behavior and plasticity in these PDE10A-deficient mice were in accordance with the proposed role of striatal MSNs and corticostriatal connections in evaluative salience attribution.     

Transverse patterning reveals a dissociation of simple and configural association learning abilities in rats with 192 IgG-saporin lesions of the nucleus basalis magnocellularis

This experiment tests the hypothesis that the cholinergic nucleus basalis magnocellularis (NBM) is necessary for complex or configural association learning, but not elemental or simple association learning. Male Long-Evans rats with bilateral 192 IgG-saporin lesions of the NBM (n = 12) and sham-operated controls (n = 8) were tested in the transverse patterning problem, which provides a test of both simple and configural association learning. Rats were trained in phases to concurrently solve first one, then two, and finally three different visual discriminations; Problem 1 (A+ vs B- sign) and Problem 2 (B+ vs C-) could be solved using simple associations, whereas solving Problem 3 (C+ vs A-) required the ability to form configural associations. Consistent with our hypothesis, the NBM lesion group solved the simple discriminations in Problems 1 and 2 but showed impaired configural association learning in Problem 3. Additionally, when Problem 2 was introduced, previously high levels of performance on Problem 1 suffered more in the NBM lesion group than in the control group; this finding suggests an impairment in the ability of animals with NBM lesions to divide attention among multiple stimuli or to shift between strategies for solving different problems. Results support our argument that the NBM is critically involved in the acquisition of associative problems requiring a configural solution but not in problems that can be solved using only simple associations. The observed impairments in configural association learning and the apparent loss of cognitive flexibility or capacity are interpreted as reflecting specific attentional impairments resulting from NBM damage.     

Lesions of the intermediate medial hyperstriatum ventrale impair sickness-conditioned learning in day-old chicks.

Lesion studies show that the intermediate medial hyperstriatum ventrale (IMHV), a forebrain visual association area in chicks, is involved in learning and memory for one-trial passive avoidance and imprinting. We examined the effects of IMHV lesions in a one-trial, nongustatory, sickness-conditioned learning task. This task is similar to passive avoidance and imprinting because all three tasks require the chick to remember visual cues in order to respond correctly. However, sickness-conditioned learning differs from imprinting and passive avoidance because it uses sickness as the aversive stimulus and there is a longer conditioned stimulus-unconditioned stimulus interval (30-min delay compared to seconds). Bilateral IMHV lesions given 24 h before training impaired the ability of the chicks to avoid a bead associated with sickness produced by lithium chloride injection, as did pretraining unilateral left or right IMHV lesions. Post-training IMHV lesions given 1 h after training did not impair avoidance of the test bead in the sickness-conditioned learning task. However, lesioned chicks showed generalized avoidance of all test beads. The pretraining lesion results are similar to those found in imprinting and passive avoidance learning; however, the effects of unilateral IMHV lesions differed. Post-training lesion effects are similar to those found in passive avoidance learning. We propose that both left and right IMHV are necessary for sickness-conditioned learning and that post-training IMHV lesions impair the ability of the chick to learn or remember the association between the color of the bead and the aversive consequences of LiCl injection.     

Stimulus selection in passive avoidance learning and retention: weanling, periadolescent, and young adult rats

Periadolescent rats exhibit a number of behavioral differences in comparison with younger or older animals. For instance, periadolescents tend to show enhanced acquisition of simple active avoidance tasks, but impaired acquisition of more complex appetitive and aversive discriminations. In this experiment, rats were trained on a simple passive avoidance task at one of three ages, as weanlings (25 days), periadolescents (35 days), or young adults (45 days). Training occurred in the presence of both a redundant discriminative stimulus and a specified, redundant contextual stimulus. The periadolescents did not differ from either younger or older rats in rate of learning the passive avoidance task. The retention performance of these animals was then tested following a change in either, neither, or both of the redundant cues. When a measure of performance that controls for baseline activity was used, it was observed that periadolescents were not disrupted by a change in the redundant discriminative stimulus, a cue change that clearly disrupted performance in 25- and 45-day-old animals, and tended to be more disrupted by the contextual change than younger or older rats. It is hypothesized that the alterations in performance exhibited by periadolescents may be related to an ontogenetic alteration in stimulus selection modulated by the catecholaminergic systems.     

Asymmetrical effects of Pavlovian excitatory and inhibitory aversive transfer on Pavlovian appetitive responding and acquisition

Predictions of a theory of Pavlovian motivational transfer, which incorporates principles of both the theory of reciprocal inhibition and the Rescorla-Wagner model, were tested in several Pavlovian aversive to Pavlovian appetitive transfer tasks. As predicted, the presence of a signal for an aversive event, conditioned stimulus (AV CS+), reliably suppressed performance of appetitive conditioned responses (CRs) whether imposed during acquisition or on independently established responding. Acquisition of appetitive responding to a novel CS reinforced in compound with an AV CS+, however, was enhanced (“superconditioning”). This observation suggests that the effects of a discrepancy between expectation and actual outcome on a conditioning trial are influenced by the affective value of both the expectation and the reinforcer. These transfer effects were not symmetrical for an inhibitory aversive stimulus (AV CS?). An AV CS? did not enhance appetitive responding compared to a random control condition, nor did the AV CS? reduce (i.e., block) appetitive conditioning to a novel CS when appetitive reinforcement occurred in the presence of the AV CS?. Comparison of the two shock-exposed conditions with a naive control condition suggests that previous results that were apparently consistent with inhibitory aversive enhancement and blocking of appetitive conditioning may have been due to aversive context conditioning.     

Appetitive and aversive olfactory learning induce similar generalization rates in the honey bee

Appetitive and aversive learning drive an animal toward or away from stimuli predicting reinforcement, respectively. The specificity of these memories may vary due to differences in cost–benefit relationships associated with appetitive and aversive contexts. As a consequence, generalization performances may differ after appetitive and aversive training. Here, we determined whether honey bees show different rates of olfactory generalization following appetitive olfactory conditioning of the proboscis extension response, or aversive olfactory conditioning of the sting extension response. In both cases, we performed differential conditioning, which improves discrimination learning between a reinforced odor (CS+) and a non-reinforced odor (CS?) and evaluated generalization to two novel odors whose similarity to the CS+ and the CS? was different. We show, given the same level of discriminatory performance, that rates of generalization are similar between the two conditioning protocols and discuss the possible causes for this phenomenon.     

Fatty acid amide hydrolase (FAAH) knockout mice exhibit enhanced acquisition of an aversive, but not of an appetitive, Barnes maze task

It is well established that genetic deletion or pharmacological inhibition of the CB₁ receptor disrupts extinction learning in aversive conditioning tasks, but not in appetitive tasks. Consistent with these findings is that genetic deletion or pharmacological inhibition of fatty acid amide hydrolase (FAAH), the primary catabolic enzyme of the endogenous cannabinoid anandamide (AEA), accelerates acquisition as well as extinction in aversive conditioning tasks. However, it is unknown whether FAAH blockade will affect acquisition in an appetitive conditioning task. Therefore, in the present study, we assessed FAAH (−/−) and (+/+) mice in appetitive and aversive Barnes maze conditioning procedures. Here we report that FAAH (−/−) mice displayed accelerated acquisition rates in an aversively-motivated, but not in the appetitively-motivated, Barnes maze task. The CB₁ receptor antagonist, rimonabant attenuated enhanced acquisition in the aversive procedure, consistent with the idea that elevated AEA levels mediate this apparent nootropic effect. These findings support the hypothesis that stimulation of the endocannabinoid system enhances learned behavior in aversive, but not appetitive, conditioning paradigms.     

Nitric oxide is involved in appetitive but not aversive olfactory learning in the land mollusk Limax valentianus

The land slug Limax performs both aversive and appetitive olfactory learning, and we investigated neurotransmitters involved in each type of learning. Slugs were conditioned by presenting a vegetable juice (appetitive conditioning) or a mixture of vegetable juice and quinidine (aversive conditioning), and the latency to reach the juice became shorter (appetitive conditioning) or longer (aversive conditioning) after conditioning. L-NAME injected either before conditioning or testing blocked the reduction in latency in appetitive conditioning but had no significant effects in aversive conditioning. 5,7-dihydroxytryptamine had no significant effects in appetitive conditioning. These results suggest different mechanisms for appetitive and aversive learning.     

Timing at the Start of Associative Learning

Some theories of associative learning imply that time plays a fundamental role in the acquisition process. Consistent with these theories, this paper presents evidence that the time from the onset of a conditioned stimulus (CS) until presentation of the unconditioned stimulus (US) is learned very rapidly at the start of training. We report two autoshaping studies and a study on aversive conditioning in goldfish in which we examine timing at the start of conditioning. We also review data from a number of other conditioning preparations, including fear-potentiated startle, appetitive conditioning in rats, and eyeblink conditioning in rabbits, that report conditioned response (CR) timing early in training. Acquisition speed and the very first expressions of conditioned responding often show sensitivity to the time of US presentation. In instances where temporal control is slowly expressed, it is likely due to performance factors, not to slow learning about time. In fact, the learning about time may be a necessary condition for associative learning.     

Differential involvement of the central amygdala in appetitive versus aversive learning

Understanding the function of the distinct amygdaloid nuclei in learning comprises a major challenge. In the two studies described herein, we used c-Fos immunolabeling to compare the engagement of various nuclei of the amygdala in appetitive and aversive instrumental training procedures. In the first experiment, rats that had already acquired a bar-pressing response to a partial food reinforcement were further trained to learn that an acoustic stimulus signaled either continuous food reinforcement (appetitive training) or a footshock (aversive training). The first training session of the presentation of the acoustic stimulus resulted in significant increases of c-Fos immunolabeling throughout the amygdala; however, the pattern of activation of the nuclei of the amygdala differed according to the valence of motivation. The medial part of the central amygdala (CE) responded, surprisingly, to the appetitive conditioning selectively. The second experiment was designed to extend the aversive versus appetitive conditioning to mice, trained either for place preference or place avoidance in an automated learning system (INTELLICAGE). Again, much more intense c-Fos expression was observed in the medial part of the CE after the appetitive training as compared to the aversive training. These data, obtained in two species and by means of novel experimental approaches balancing appetitive versus aversive conditioning, support the hypothesis that the central nucleus of the amygdala is particularly involved in appetitively motivated learning processes.     

Can a shuttlebox computer analog be used to condition human avoidance behavior?

Freedman (1990) introduced a computer analog of the shuttlebox paradigm and presented results to show that this analog could be used for studying human avoidance conditioning. In the present study, a first experimental phase was conducted to test how the fact that the tone was considered aversive in the instructions and the intensity of this tone affect avoidance behavior. In a transfer-of-control test phase, it was tested as to whether the warning stimulus presented as a cue to the aversive stimulus had acquired either aversive or informative quality. An effect of instructions was observed for both levels of the auditive stimulus, and a stimulus effect was found for those groups that were given the instructions that described the tone as aversive. In the case of subjects who in the first phase achieved a certain learning criterion, it was recorded how often they in the second phase selected a condition in which the warning signal of the first phase was not presented. No transfer of control was observed. Thus, no positive evidence was found indicating that Freedman’s computer analog could be used for studying human avoidance conditioning.     

Dissociating Basal Forebrain and Medial Temporal Amnesic Syndromes: Insights from Classical Conditioning

In humans, anterograde amnesia can result from damage to the medial temporal (MT) lobes (including hippocampus), as well as to other brain areas such as basal forebrain. Results from animal classical conditioning studies suggest that there may be qualitative differences in the memory impairment following MT vs. basal forebrain damage. Specifically, delay eyeblink conditioning is spared after MT damage in animals and humans, but impaired in animals with basal forebrain damage. Recently, we have likewise shown delay eyeblink conditioning impairment in humans with amnesia following anterior communicating artery (ACoA) aneurysm rupture, which damages the basal forebrain. Another associative learning task, a computer-based concurrent visual discrimination, also appears to be spared in MT amnesia while ACoA amnesics are slower to learn the discriminations. Conversely, animal and computational models suggest that, even though MT amnesics may learn quickly, they may learn qualitatively differently from controls, and these differences may result in impaired transfer when familiar information is presented in novel combinations. Our initial data suggests such a two-phase learning and transfer task may provide a double dissociation between MT amnesics (spared initial learning but impaired transfer) and ACoA amnesics (slow initial learning but spared transfer). Together, these emerging data suggest that there are subtle but dissociable differences in the amnesic syndrome following damage to the MT lobes vs. basal forebrain, and that these differences may be most visible in non-declarative tasks such as eyeblink classical conditioning and simple associative learning.     

Dissociating basal forebrain and medial temporal amnesic syndromes: Insights from classical conditioning

In humans, anterograde amnesia can result from damage to the medical temporal (MT) lobes (including hippocampus), as well as to other brain areas such as basal forebrain. Results from animal classical conditioning studies suggest that there may be qualitative differences in the memory impairment following MT vs. basal forebrain damage. Specifically, delay eyeblink conditioning is spared after MT damage in animals and humans, but impaired in animals with basal forebrain damage. Recently, we have likewise shown delay eyeblink conditioning impairment in humans with amnesia following anterior communicating artery (ACoA) aneurysm rupture, which damages the basal forebrain. Another associative learning task, a computer-based concurrent visual discrimination, also appears to be spared in MT amnesia while ACoA amnesics are slower to learn the discriminations. Conversely, animal and computational models suggest that, even though MT amnesics may learn quickly, they may learn qualitatively differently from controls, and these differences may result in impaired transfer when familiar information is presented in novel combinations. Our initial data suggests such a two-phase learning and transfer task may provide a double dissociation between MT amnesics (spared initial learning but impaired transfer) and ACoA amnesics (slow initial learning but spared transfer). Together, these merging data suggest that there are subtle but dissociable differences in the amnesic syndrome following damage to the MT lobes vs. basal forebrain, and that these differences may be most visible in non-declarative tasks such as eyeblink classical conditioning and simple associative learning.     

Social anxiety and cognitive expectancy of aversive outcome in avoidance conditioning

Fear conditioning studies have shown that social anxiety is associated with enhanced expectancy of aversive outcome. However, the relation between cognitive expectancy and social anxiety has never been tested in avoidance conditioning paradigms. We compared 48 low (LSA) and high socially anxious individuals (HSA) on subjective expectancy of aversive outcome during an avoidance conditioning task. Displays of neutral faces were coupled with an aversive outcome (US): a shout and a shock. Participants could avoid the US by pressing a correct button from a button box. First, HSA showed higher US expectancy than LSA during the initial phase of avoidance conditioning, supporting the view that socially anxious individuals have an expectancy bias when social situations are ambiguous. Second, when the avoidance response became unavailable, LSA showed lower US expectancy than HSA, suggesting that low socially anxious individuals are prone to a positive bias when perceived threat is high. A lack of such positive bias in socially anxious individuals may lead to higher susceptibility to safety behavior interpretations. Together, these findings support the role of cognitive processes in avoidance conditioning and underscore the relevance to encounter avoidance learning when studying social anxiety.     

Differential endocannabinoid regulation of extinction in appetitive and aversive Barnes maze tasks

CB 1 receptor-compromised animals show profound deficits in extinguishing learned behavior from aversive conditioning tasks, but display normal extinction learning in appetitive operant tasks. However, it is difficult to discern whether the differential involvement of the endogenous cannabinoid system on extinction results from the hedonics or the required responses associated with the disparate tasks. Here, we report that the CB 1 receptor antagonist rimonabant disrupts extinction learning in an aversive, but not in an appetitive, Barnes maze conditioning task. Accordingly, these results provide compelling support for the hypothesis that the endogenous cannabinoid system plays a necessary role in the extinction of aversively motivated behaviors but is expendable for appetitively motivated behaviors.