Dissociations between medial prefrontal cortical subregions in the modulation of learning and action

The medial prefrontal cortex (mPFC) has been implicated in various attentional functions. This experiment examined the involvement of mPFC subregions in the allocation of attention in learning and action as a function of the predictive accuracy of cues. Rats with dorsal (encompassing anterior cingulate, prelimbic, and infralimbic cortices) or ventral (encompassing mainly infralimbic and dorsopeduncular cortices and tenia tecta) mPFC lesions were trained in a multiple-choice discrimination task in which operant nosepoke responses to some visual cues were consistently (100%) reinforced (CRF) with food, whereas responses to other visual cues were partially (50%) reinforced (PRF). In challenge tests designed to assess attention in the control of action, responding was directed more to CRF cues than to PRF cues in sham and dorsal mPFC-lesioned rats, but ventral mPFC-lesioned rats showed similar levels of responding to both CRF and PRF cues. Nevertheless, when given a choice between simultaneously presented CRF and PRF cues in a cue competition test, all groups responded more to CRF cues. In a subsequent Pavlovian overshadowing phase designed to assess attention in the acquisition of new learning, previously trained CRF cues overshadowed conditioning to novel auditory cues more than did PRF cues in dorsal mPFC-lesioned rats, whereas the opposite pattern was observed in sham and ventral mPFC-lesioned rats. These results suggest a dissociation within the mPFC in the use of reinforcement prediction information to allocate attention for new learning and for the control of action.     

Prefrontal cortical mechanisms underlying delayed alternation in mice

The prefrontal cortex (PFC) has been implicated in the maintenance of task-relevant information during goal-directed behavior. Using a combination of lesions, local inactivation, and optogenetics, we investigated the functional role of the medial prefrontal cortex (mPFC) in mice with a novel operant delayed alternation task. Task difficulty was manipulated by changing the duration of the delay between two sequential actions. In experiment 1, we showed that excitotoxic lesions of the mPFC impaired acquisition of delayed alternation with long delays (16 s), whereas lesions of the dorsal hippocampus and ventral striatum, areas connected with the PFC, did not produce any deficits. Lesions of dorsal hippocampus, however, significantly impaired reversal learning when the rule was changed from alternation to repetition. In experiment 2, we showed that local infusions of muscimol (an agonist of the GABA(A) receptor) into mPFC impaired performance even when the animal was well trained, suggesting that the mPFC is critical not only for acquisition but also for successful performance. In experiment 3, to examine the mechanisms underlying the role of GABAergic inhibition, we used Cre-inducible Channelrhodopsin-2 to activate parvalbumin (PV)-expressing GABAergic interneurons in the mPFC of PV-Cre transgenic mice as they performed the task. Using whole cell patch-clamp recording, we demonstrated that activation of PV-expressing interneurons in vitro with blue light in brain slices reliably produced spiking and inhibited nearby pyramidal projection neurons. With similar stimulation parameters, in vivo stimulation significantly impaired delayed alternation performance. Together these results demonstrate a critical role for the mPFC in the acquisition and performance of the delayed alternation task.     

Olfactory repeated discrimination reversal in rats: effects of chlordiazepoxide, dizocilpine, and morphine

Effects of a benzodiazepine (chlordiazepoxide), an N-methyl-D-aspartate receptor antagonist (dizocilpine), and an opiate agonist (morphine) were studied with a procedure designed to assess effects of drugs and other manipulations on nonspatial learning in rats. In each session, rats were exposed to 2 different 2-choice odor-discrimination problems with food reinforcement for correct responses. One problem (performance discrimination) remained the same throughout the study. That is, 1 odor was always correct (S+) and the other was never correct (S-). For the other problem (reversal discrimination), stimuli changed every session. Six different odors were used to program the reversal discrimination; on any given session, S+ was a stimulus that had served as S- the last time it had appeared, S- was a stimulus that had been S+ on its last appearance. Thus, in each session, learning a discrimination reversal could be studied along with the performance of a comparable, but previously learned, discrimination. Chlordiazepoxide interfered with reversal learning at doses that had no effect on the performance discrimination. Morphine and dizocilpine also impaired reversal learning but only at doses that also affected performance of the well-learned performance discrimination.     

Working and reference memory in seizure-prone and seizure-resistant rats: impact of amygdala kindling

In rat selectively bred for different amygdala kindling rates (Fast vs. Slow), comorbid differences in learning were detected. Here, performance was tested in a delayed alternation task before, during, and after kindling. Although similar reference memory was evident, Fast rats showed working memory deficits with increasing delays between information and choice trials. Further, seizures shortly before learning disrupted both reference and working memory in Fast, but not Slow, rats. Weeks after kindling, progressive delays further disrupted Fast rats, but only longer delays disrupted Slow rats. Clearly relevant to individual differences in human epilepsy, a temporal lobe, seizure-prone genetic background in rats provides poorer original learning and easier disruption of new learning by recent and past seizures than a seizure-resistant background.     

Neonatal lesions of the ventral hippocampus in rats lead to prefrontal cognitive deficits at two maturational stages

This experiment assessed the effect of neonatal ventral hippocampus lesions in rats, a heuristic approach to model schizophrenia, on continuous delayed alternation and conditional discrimination learning performance before and after complete cerebral maturation. Delays (0, 5, 15, and 30 s) were introduced in the tasks to help dissociate between a hippocampal and a prefrontal cortex dysfunction. At postnatal day (PND) 6 or 7, rats received bilateral microinjections of ibotenic acid or phosphate-buffered saline in the ventral hippocampus. From PND 26 to PND 35, rats were tested on the alternation task in a T-maze; from PND 47 to PND 85, the same rats were tested in the discrimination task where a stimulus and a response location had to be paired. Deficits in ventral hippocampus-lesioned rats were observed in both tasks whether a delay was introduced before a response or not. Impaired performance regardless of delay length, combined with high rates of perseverative errors, suggested a post-lesional prefrontal cortex dysfunction which persisted from the juvenile stage into adulthood. Premature cognitive impairments could not be predicted on the basis of the neurodevelopmental animal model of schizophrenia. Nevertheless, they appear consistent with accounts of premorbidly compromised memory, both immediate and delayed, in subgroups of schizophrenia patients.     

Prefrontal electroencephalographic activity during the working memory processes involved in a sexually motivated task in male rats

The prefrontal cortex is involved in working memory functions, and several studies using food or drink as rewards have demonstrated that the rat is capable of performing tasks that involve working memory. Sexual activity is another highly-rewarding, motivated behaviour that has proven to be an efficient incentive in classical operant tasks. The objective of this study was to determine whether the functional activity of the medial prefrontal cortex (mPFC) changes in relation to the working memory processes involved in a sexually motivated task performed in male rats. Thus, male Wistar rats implanted in the mPFC were subjected to a nonmatching-to-sample task in a T-maze using sexual interaction as a reinforcer during a 4-day training period. On the basis of their performance during training, the rats were classified as ‘good-learners’ or ‘bad-learners’. Only the good-learner rats showed an increase in the absolute power of the 8–13 Hz band during both the sample and test runs; a finding that could be related to learning of the working memory elements entailed in the task. During the maintenance phase only (i.e., once the rule had been learned well), the good-learner rats also showed an increased correlation of the 8–13 Hz band during the sample run, indicating that a high degree of coupling between the prefrontal cortices is necessary for the processing required to allow the rats to make correct decisions in the maintenance phase. Taken together, these data show that mPFC activity changes in relation to the working memory processes involved in a sexually motivated task in male rats.     

Serial reversal learning of position discrimination in developing rats

The current study established a procedure to evaluate the capability of rats on postnatal days (PND) 21, 26, and 30 to perform a spatial serial reversal task using a T-maze. Training consisted of an acquisition session followed by a series of six reversal sessions. To examine the role of proactive interference in the serial reversal effect, the point of reversal was manipulated so that it occurred at the start of each session (between-sessions) or the midpoint of each session (within-sessions). Performance was initially impaired during the first reversal but improved dramatically across the series. Reversal between-sessions enhanced this serial reversal effect in comparison to reversal within-sessions. Experiment 1 showed that rats of all ages learned the between-sessions serial reversal task at a comparable rate. However, on the within-sessions task, PND21 rats were impaired relative to the PND26 and 30 rats, which did not differ. Experiment 2 revealed that the addition of a tactile cue that is correlated with each phase of reversal eliminated age and task differences in serial reversal performance. These findings suggest that higher-order cognitive processes underlying serial reversal are present during the weanling period, but there is some improvement with age under conditions involving high memory interference and/or difficulty in detecting the transition between reversal phases.     

Hippocampal seizures disrupt working memory performance but not reference memory acquisition

The effect of hippocampal seizures in rats was assessed in two spatial memory tasks: The reference memory task was a simultaneous two-choice discrimination in a T-maze. The working memory task was a delayed conditional discrimination in a radial arm maze. In each task the hippocampus of each rat was stimulated to seizure after the presentation of the information to be remembered. In the reference memory task, hippocampal seizures did not impair acquisition, whether the stimulation was given immediately after or 4 hr after the presentation of the stimuli to be remembered. In the working memory task, hippocampal seizures did impair performance in a group of the same rats. These results support the distinction between a trial-dependent working memory system that requires hippocampal function and a trial-independent memory system that does not depend on hippocampal function.     

The effects of anticholinergic drugs on delayed time discrimination performance in rats.

To investigate the effects of the muscarinic antagonist scopolamine and the nicotinic antagonist mecamylamine on time discrimination and short-term memory, rats were trained on a delayed conditional time discrimination task until performance stabilized. In a two-lever operant chamber, pressing one lever was correct after the presentation of a stimulus light for 2 seconds (SD short); and pressing the other lever was correct after presentation of a stimulus light for 8 seconds (SD long). Scopolamine (0.06 mg, 0.25 mg, and 1.0 mg/kg) attenuated performance in a dose-dependent manner. Furthermore, the drug decreased nose-pokes (an activity necessary to trigger the presentation of the discriminative stimuli and the presentation of the response levers), and increased response delay (time from opportunity to lever press to actual lever press). Performance attenuating effects of mecamylamine in the time discrimination task did not appear unless high doses (8 mg/kg) of the drug were given. With increasing delays between 0 and 8 seconds, animals injected with saline developed a bias towards reporting the occurrence of the SD long, independent of the actual stimulus presented. A reversal of this bias was seen in animals injected with scopolamine; they more often reported the occurrence of the SD short. Our results support a role for muscarinic receptors in discrimination learning, attention, and time estimation.     

The effects of nucleus basalis magnocellularis lesions in Long-Evans hooded rats on two learning set formation tasks, delayed matching-to-sample learning, and open-field activity

Rats with quisqualic acid lesions of the nucleus basalis magnocellularis (nBM) and control rats were compared in discrimination reversal learning set (DRLS) and olfactory discrimination learning set (ODLS) tasks, a delayed matching-to-sample task (DMTS), and open-field activity. Evidence of learning set formation was seen in control rats but not in nBM-lesioned rats in both the DRLS and ODLS tasks. Better-than-chance performances were seen for both groups in DMTS, indicating no impairment after nBM lesions. There were no group differences in open-field activity. These findings suggest that the nBM is important for higher cognitive processing such as "learning to learn" and thus is important for a complex form of reference memory. In addition, perseverational, working memory, and attentional deficits could not explain learning set impairment after nBM lesions.     

Preserved negative patterning and impaired spatial learning in pigeons (Columba livia) with lesions of the hippocampus.

Pigeons (Columba livia) with bilateral electrolytic lesions of the hippocampus and area parahippocampalis were compared with control pigeons on 2 tasks: negative patterning and delayed spatial alternation. Negative patterning demands configural stimulus representations for its successful solution. The only effect of hippocampal lesions on this task was an increased response rate to the rewarded stimuli. On the delayed spatial alternation task, hippocampal birds showed deficits relative to controls. Differences in the results of prior studies on negative patterning appear to be due to different response requirements to the nonreinforced stimuli. These results are consistent with prior work with rats and suggest that the avian hippocampus is essential for spatial memory and response inhibition but is not involved in configural learning.     

Cholinergic blockade effects on spatial integration versus cue discrimination performance

A within-subjects investigation was conducted to determine the effects of central versus peripheral cholinergic blockade in animals tested either on a spatial integration task in which the possibility of rule learning was also available or on a visual discrimination task in which the daily location of food was marked by a distinctive visual stimulus pattern. All testing was conducted on the Maier three-table apparatus. It was found that the only effect of the peripheral cholinergic blockade on the performance of either task group was to produce a decrease in exploratory behavior. In contrast, central cholinergic blockade markedly impaired spatial integration performance; however, it did not impair the ability of animals in rule learning or visual discrimination learning. It was also found that central cholinergic blockade impaired the animal's tendency to enter all tables before reentering a given table during the exploratory phase of the daily session. This finding was interpreted as reflecting an impairment of working memory for spatial information, rather than a general impairment in working memory, and this interpretation was applied to the explanation of the deficit in the spatial integration performance.     

Combined lesions of septum,amygdala, hippocampus,anterior thalamus,mamillary bodies and cingulate and subicular cortex fail to impair the acquisition of complex learning tasks

Summary Previous investigations (Irle and Markowitsch 1982a, 1983, 1984) demonstrated that triple or fourfold lesions within the cat's limbic system fail to produce learning impairments, as opposed to lesions of single or double loci, when tasks of visual reversal, delayed alternation, and active two-way avoidance were used. On the basis of these results, limbic regions of the cat's brain might be considered unessential for intact learning and mnemonic functions. Therefore, in order to obtain indisputable information on the importance of the limbic system for learning and memory, lesions of nearly all limbic core regions of the cat were performed. Ten cats received lesions of seven limbic core regions: the septum, amygdala, anterior thalamus, mamillary bodies, cingulate cortex, subicular cortex, and the hippocampus proper. Nine of these animals were tested postoperatively in the acquisition of a visual reversal task, a spatial alternation and delayed alternation task, and an active two-way avoidance task, and were then compared to the performance levels of ten control animals. The experimental animals turned out to be unimpaired in all tasks tested; the performance scores in the visual reversal and delayed alternation task and — for some experimental animals in the active two-way avoidance task even indicate a slight, though statistically insignificant, facilitation in the learning behavior of these animals. It is assumed that the learning functions underlying the tasks used were taken over by other brain regions, which, prior to massive limbic lesions, may be suppressed or otherwise inhibited. Alternatively, utilization of spared tissue in the damaged limbic regions must be considered as the possible explanation.     

Differential acquisition of a "working memory" task by the Roman strains of rats

Twenty-eight male rats of the Roman strains-fourteen RHA (Roman High Avoidance) and fourteen RLA (Roman Low Avoidance)-were submitted to a positively reinforced task, the delayed reinforced alternation test (DRA), in a T-maze. Performances of RLA rats were significantly better than those of RHA; RLA rats also had higher VTE (vicarious trial and error) and spontaneous alternation (SA) scores. These data confirm the fact that RLA may acquire positively reinforced learning as rapidly, or even more rapidly, than RHA rats, and that the differences in active avoidance behavior between these strains depend more on differential freezing behavior than on learning and memory capacities. Since the delayed reinforced alternation is considered as a working memory test, our results suggest that the Roman strains could be used as a genetic model for the neurobiological study of this form of memory.     

Learning and memory dissociation in rats with lesions to the subthalamic nucleus or to the dorsal striatum

The striatum and the subthalamic nucleus (STN) are the two main cortical inputs to the basal ganglia. Both structures are involved in motor and cognitive functions, particularly executive functions, known to rely mainly on fronto-basal ganglia circuits. The present work investigated the respective role of the dorsal part of the striatum (dST) and the STN by studying their involvement in learning and memory processes in two separate experiments. In a first experiment, rats with lesions to the STN or to the dST were trained in a light-tone discrimination task. When the learning criterion was reached, rats were then trained to the reversed discrimination. In a second experiment, surgery was done when the learning criterion had been reached. Three weeks after surgery, animals were then subjected to two relearning sessions and then to either a reversal learning or a working memory task. When surgery was done before learning, dysfunction of the dorsal striatum induced slight difficulties in acquisition, whereas dysfunction of the STN induced no difficulties during the initial learning but induced a more rapid inhibition of responses to the first lever press following the presentation of the tone during the reversed discrimination. In the second experiment, dST-lesioned rats showed long-term memory deficit in contrast to STN-lesioned rats which showed no difficulties during relearning but deficits in working memory. These results indicate a clear dissociation in cognitive functions in which STN and dorsal striatum are involved, suggesting that the fronto-striatal circuit and the fronto-STN circuit support, at least in part, different cognitive functions.     

Differential ontogeny of working memory and reference memory in the rat

In two experiments we examined the ability of 15-, 21-, and 27-day-old rats to perform two spatial working memory problems (delayed alternation and discrete-trials delayed alternation) and a reference memory problem (position habit) in a T-maze. In the delayed alternation problem, each animal was presented with a series of free-choice trials and was rewarded for regularly alternating responses to the left and right arms of the T-maze. In the discrete-trials delayed alternation problem, each animal was forced to one maze arm and rewarded (forced run) and was then placed back into the start box and given a choice of arms (choice run). The direction of forced runs followed an irregular, counterbalanced series, and animals were rewarded for choosing the alternate maze arm on choice runs. In the position habit problem, animals were rewarded for consistently choosing one of the two arms of the T-maze. Performance on these problems was assessed relative to control conditions in which reward was not contingent on choice behavior. At all ages, rat pups learned to perform the delayed alternation and position habit problems (Experiment 1). However, only 21- and 27-day-old rats were able to learn the discrete-trials delayed alternation problem. The 15-day-olds were unable to learn this task (Experiment 2). The results of these experiments show that reference memory capacity is present by at least 15 days of age in the rat and does not develop further at later ages.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acetyl-1-carnitine. 2: Effects on learning and memory performance of aged rats in simple and complex mazes

Acetyl-1-carnitine (AC) was administered via drinking water for six months to one group (OLD-AC) of male F-344 rats beginning at 16 months of age, while another group (OLD-CON) of rats was given water only during that period. The rats were maintained on this treatment throughout behavioral testing, which began at 22 months of age. Performance of the OLD-AC and OLD-CON rats was compared to that of young control (YG-CON) rats on the following set of tasks: spontaneous alternation in the arms of a T-maze, two-choice simultaneous discrimination in the stem of a T-maze, rewarded alternation in the arms of a T-maze, spatial discrimination and reversal on a circular platform, spatial working memory in the radial 8-arm maze, long-term memory in the 14-unit T-maze, and for preference of the light or dark chamber of a two-compartment box. AC improved the long-term memory performance in the split-stem T-maze and on the circular platform but had no discernable effects on performance of aged rats in the other tasks. Possible reasons for the selectivity of this agent's action on behavior are suggested.     

Serial spatial reversal learning in rats: Comparison of instrumental and automaintenance procedures

Serial reversals of a spatial discrimination were trained in rats under automaintenance conditions, in which food reward occurred regardless of responding. This automaintained reversal learning was compared to instrumental reversal learning in other rats trained under a similar procedure which required responding for reward. In the automaintenance (AU) procedure, rats received food after every retraction of a “positive” response lever (S⁺); retraction of a second, “neutral” lever (S°) was not paired with food delivery. Responses to the S⁺ were elicited at fairly constant rates during daily 100-trial conditioning sessions. Responses to the S° occurred early in each session but rapidly diminished across trials. When the valences of the levers were reversed, responding shifted to the new S⁺ and diminished on the new S°. Criterion for reversal was defined as a discrimination ratio (DR) of at least 90% responding to the S⁺ in two consecutive 10-trial blocks. With repeated reversals, acquisition of criterion performance occurred with increasing rapidity, reaching an asymptote below that required for the original discrimination. A second group of rats was trained on a similar instrumental schedule, in which at least one response to the S⁺ was required for food delivery. Response rates in this instrumental (IN) group were approximately double those of the AU group. However, ratios of S⁺ to S° response rates were similar to those of the AU group, and the serial reversal curves generated were qualitatively similar. Thus rats can show improvement across serial reversals of a spatial discrimination based entirely on pairings of stimulus events (automaintenance), in a manner similar to that observed in instrumental procedures, in which reward is contingent upon correct responding.     

Naltrexone reverses age-induced cognitive deficits in rats

We evaluated young (3-4 months) and aged (22-24 months) male Sprague-Dawley rats in an attentional set-shifting procedure that assessed reversal, intradimensional shift (IDS), and extradimensional shift (EDS) discrimination learning tasks within one test session. These aspects of discrimination learning are sensitive to damage to distinct regions of frontal cortex. Compared to young animals, aged rats were significantly impaired on the EDS task and did not demonstrate significant impairment on the reversal or IDS tasks. The opioid antagonist naltrexone (2mg/kg, ip) was administered to young and aged rats prior to testing to assess possible improvements in aged-related cognitive impairments. Naltrexone (2mg/kg) attenuated the impairments in cognitive function in the EDS task for aged animals, but did not alter any task performance in the younger group. These results suggest that normal aging in rats is associated with impaired medial frontal cortex function as assessed by this attentional set-shifting procedure and opioid mediated mechanisms may represent a therapeutic target for drugs to improve cognitive deficits associated with aging.