Operant Delayed Alternation Task Research Articles

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.

Testosterone impairs the acquisition of an operant delayed alternation task in male rats

The current study examined the effects of gonadectomy (GDX) and subsequent testosterone treatment of male Long-Evans rats on an operant variable delay spatial alternation task (DSA). Gonadally-intact rats (intact-B), GDX rats receiving implants that delivered a physiological level of testosterone (GDX-T), and GDX rats receiving blank implants (GDX-B) were tested for 25 sessions on a DSA task with variable inter-trial delays ranging from 0 to 18 s. Acquisition of the DSA task was found to be enhanced following GDX in a time and delay dependent manner. Both the GDX-T and the intact-B rats had lower performance accuracies across delays initially, relative to GDX-B rats, and this deficit persisted into subsequent testing sessions at longer delays. The GDX-T and intact-B rats also had a tendency to commit more perseverative errors during the early testing sessions, with both groups persisting in pressing a lever which had not been associated with reinforcement for at least two consecutive trials. However, both the GDX-T and intact-B groups were able to achieve performance accuracy similar to that of the GDX-B rats by the final sessions of testing. Overall, these results suggest that castration of adult male rats enhances their acquisition of an operant DSA task.

Overexpression of α3/α5/β4 nicotinic receptor subunits modifies impulsive-like behavior

Recent studies have revealed that sequence variants in genes encoding the α3/α5/β4 nicotinic acetylcholine receptor subunits are associated with nicotine dependence. In this study, we evaluated two specific aspects of executive functioning related to drug addiction (impulsivity and working memory) in transgenic mice over expressing α3/α5/β4 nicotinic receptor subunits. Impulsivity and working memory were evaluated in an operant delayed alternation task, where mice must inhibit responding between 2 and 8s in order to receive food reinforcement. Working memory was also evaluated in a spontaneous alternation task in an open field. Transgenic mice showed less impulsive-like behavior than wild-type controls, and this behavioral phenotype was related to the number of copies of the transgene. Thus, transgenic Line 22 (16–28 copies) showed a more pronounced phenotype than Line 30 (4–5 copies). Overexpression of these subunits in Line 22 reduced spontaneous alternation behavior suggesting deficits in working memory processing in this particular paradigm. These results reveal the involvement of α3/α5/β4 nicotinic receptor subunits in working memory and impulsivity, two behavioral traits directly related to the vulnerability to develop nicotine dependence.

A29 Frontostriatal pathology in the (C57BL/6J) YAC128 mouse uncovered by the operant delayed alternation task

BackgroundTo determine the suitability of a mouse line for the trailing of therapeutic interventions, it is necessary to identify behavioural abnormalities that reflect disease relevant pathology. In Huntington's disease (HD),...

Effects of the AMPA receptor modulator S 18986 on measures of cognition and oxidative stress in aged rats

Development of cognitive-enhancing drugs that delay or halt mild cognitive impairment progression to Alzheimer's disease would be of great benefit. The aim of this study was to examine the ability of (S)-2,3-dihydro-[3,4]-cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide (S 18986), a positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, to improve behavioral performance and alleviate age-related deficits in oxidative stress status in the prelimbic cortex and hippocampus. Daily administration of S 18986 (0.1, 0.3, and 1.0 mg/kg) or vehicle was given to separate groups of male rats starting at 12 months of age. Additionally, daily vehicle administration was given to a group of rats starting at 3 months of age. Four months after initiation of drug administration, rats were trained and tested in an operant-delayed alternation task and a reinforcer devaluation task. Upon completion of testing, oxidative stress status was assessed in the prelimbic cortex and hippocampus. S 18986 dose-dependently altered responses in the reinforcer devaluation task such that aged rats came to resemble young rats. There were no age or drug effects in the operant-delayed alternation task. Levels of the lipid peroxidation product 4-hydroxy-nonenal (HNE) were increased, and Cu/Zn-superoxide dismutase (SOD) levels were decreased in prelimbic cortex in aged rats, changes that were reversed by S 18986. Similarly, age-related increases in hippocampal HNE levels were prevented by S 18986. Positive modulation of AMPA receptor activity may be a therapeutic approach to halt or slow progression of mild cognitive impairment via improvement in oxidative stress status in the hippocampus and prelimbic cortex.

Specific role of the posterior dorsal hippocampus–prefrontal cortex in short‐term working memory

Working memory in rats involves neural projections from the hippocampus (HP) to the prefrontal cortex (PFC), based on delayed task experiments in a radial-arm maze, in which the time span of working memory is longer than seconds. To determine whether the HP-PFC pathway is involved in short-term (on the order of seconds) working memory function, we lesioned the PFC and/or HP, and measured performance in an operant delayed alternation task. The posterior dorsal (pdHP) and ventral HP (vHP) were assessed separately. The bilateral PFC and bilateral pdHP ibotenate lesions produced significant working memory deficits, but the vHP lesion did not. Unilateral pdHP lesions combined with a PFC lesion in the opposite hemisphere reproduced the effects of bilaterally symmetrical lesions. By contrast, unilateral lesions of the pdHP combined with a PFC lesion in the same hemisphere had no effect on delayed alternation. These results indicate that the pdHP-PFC pathway is essential for working memory on the order of seconds in rats, and suggest that the pdHP and vHP pathways to the PFC play different behavioral roles.

Striatal grafts alleviate bilateral striatal lesion deficits in operant delayed alternation in the rat

In order to assess the capacity of striatal grafts to alleviate cognitive deficits of the frontal type that arise following bilateral striatal lesions, control, lesion and grafted rats were tested in an operant test of delayed alternation. Bilateral striatal lesions induced a marked impairment in choice accuracy, and signal detection analysis indicated that the lesion animals were reliably impaired on both parametric and non-parametric indices of discriminative sensitivity but not of response bias. The impairment was apparent at all intertrial interval delays, including the very shortest, suggesting the deficit is one of frontal-type executive function rather than of short-term memory. The grafted animals exhibited a significant alleviation of the deficit, again apparent at all delays. Histological analyses indicated good graft survival, and injections of a dextran amine anterograde tracer bilaterally into the host prefrontal cortex indicated reformation of extensive projections into the grafted tissues. Since performance of the operant delayed alternation task is dependent upon the integrity of corticostriatal connections, which is disrupted bilaterally by the lesions and restored to the grafts in the transplanted animals, the results corroborate the hypothesis that striatal grafts can alleviate complex cognitive functions of the frontal type by a mechanism that involves functional integration of the grafted neurons into the neural circuits of the host brain.

Role of 5-HT6 receptors in memory formation.

Mice lacking the 5-HT(6) receptor presented neither gross anatomical or behavioral abnormalities nor obvious changes in microscopic brain morphology, and their performance in rotarod, open field and novel object testing paradigms revealed no differences compared with wild-type animals. Nevertheless, an association between the 5-HT(6) receptor polymorphism C267T and Alzheimer's disease has been reported. Interestingly, the 5-HT(6) antisense oligonucleotide decreased 5-HT(6) gene expression and enhanced spatial learning acquisition in the water maze. Similarly, injection of the 5-HT(6) receptor antagonist Ro-04-6790 improved learning consolidation in an autoshaping task, while mCPP, scopolamine and dizocilpine decreased performance. The effect induced by scopolamine or dizocilpine, but not that induced by mCPP, was completely or partially reversed by Ro-04-6790. Ro-04-6790 did not modify the 8-OH-DPAT facilitatory effects on learning consolidation. Since Ro-04-6790 facilitatory effect was unaffected by 5-HT(1A), 5-HT(2A/2B/2C), 5-HT(3), 5-HT(4) or 5-HT(7) receptor blockade, the facilitatory effect induced by Ro-04-6790 involved specifically 5-HT6 receptors. Similarly, the 5-HT(6) receptor antagonist SB-271046 improved retention in the water maze and produced a significant performance improvement in aged rats in an operant-delayed alternation task. A series of Ro-04-6790 analogues that penetrate the brain and specifically bind to 5-HT(6) receptors reversed scopolamine-induced retention deficit in a passive avoidance learning test. Collectively, these data provide further support to the notion that 5-HT systems, via 5-HT(6) receptors, also play a significant role in memory formation under normal and dysfunctional memory conditions.

Medial prefrontal and neostriatal lesions disrupt performance in an operant delayed alternation task in rats

An operant version of the classical delayed alternation task is presented and applied to evaluate the effects of bilateral prefrontal and striatal lesions in rats. Retractable levers in a conventional operant chamber control discrete trial opportunities for making sequential choice responses to the two sides, and the rats are required to maintain repeated nose poke responses to a central panel during the delay interval, which is randomly varied. The operant task provides measures of the speed and accuracy of response alternation and side bias; analysis at different delay intervals provides an index of the memory demands of accurate performance; and analysis of accuracy depending on the response on preceding trials provides measures of proactive interference and perseveration. Following pretraining in the task contingencies, both striatal and prefrontal lesions induced profound deficits in task accuracy, with no change in side bias and only small changes in movement times. The deficit in the prefrontal lesion group recovered more rapidly, neither group showed any change in sensitivity to proactive interference, while the rats with striatal lesions alone exhibited an increased tendency to perseverate incorrect responses on either side. We conclude that the operant delayed alternation task should assist analysis of fronto-striatal function in rats as well as be useful for the analysis of strategies for fronto-striatal repair.

Facilitating effects of SR 57746A on short‐term memory in an operant delayed alternation task in aged rats

AbstractThe effects of SR 57746A during acquisition and on stabilized performance of a delayed alternation task in a Skinner Box (Model E 10.10, Coulbourn Instruments, Lehigh Valley, PA) were investigated in aged rats (22–26 months old). Test sessions consisted of repeated trials during which animals were first presented with a single lever (left or right) followed several seconds later by two levers. A press on the lever opposite to that presented previously (delayed alternation) was rewarded. The number of correct responses and the reaction times to the one‐ and two‐lever presentations were recorded. SR 57746A (0.3 and 3 mg/kg p.o.) was first evaluated during the acquisition of the delayed alternation, given before each of 10 daily acquisition sessions to different groups of aged animals. The imposed delay was 5 sec. Afterward, training continued without drug until asymptotic performance was reached. Rats were then given repeated drug test sessions during which different intervals (5, 10, and 20 sec) were presented in a random order. During this phase, both young and aged animals received all the different treatments (SR 57746A at 0.3, 1, and 3 mg/kg and vehicle p.o.). Aged animals showed clear deficits during both acquisition and stabilized performance phases. SR 57746A, particularly at the highest dose tested (3 mg/kg p.o.), clearly increased response accuracy of aged animals both during acquisition of the delayed alternation and during stabilized performance. In the latter phase, the facilitation of response accuracy was observed only in conditions (10 sec retention delay) where aged animals showed a deficit compared with young animals. SR 57746A did not affect response accuracy during stabilized performance in young animals at any delay. The drug‐induced increase in response accuracy in aged animals occurred at a dose of SR 57746A (3 mg/kg p.o.) that lengthened reaction times, particularly simple reaction times, during both acquisition and stabilized performance and also lengthened reaction times in young animals during the stabilized performance phase. These results suggest that SR 57746A specifically attenuates age‐related short‐term memory impairment in rats. © 1995 Wiley‐Liss, Inc.

Effects of neonatal mediodorsal thalamic lesions on structure and function of the rat prefrontal cortex

The morphological and behavioral effects of neonatal electrothermal lesions of the mediodorsal thalamus on the development of the prefrontal cortex were studied. Lesions of the mediodorsal nucleus (MDT), inflicted on the day of birth, caused no significant changes in prefrontal architecture on day 35. On the other hand, a significant decrease in cortical width (4.7–7.7%) was observed at some places within the lateral and supragenual parts of the prefrontal cortex. However, these local decreases in cortical width were not reflected by a significant decrease of the total volume of the particular prefrontal subareas. In adulthood, rats with neonatal MDT lesions were exposed to an operant delayed alternation task, which is known to depend upon the integrity of the prefrontal cortex, in order to investigate the behavioral consequences of the lesions for prefrontal functioning. The lesions did not impair the rats abilities to learn the spatial delayed alternation task. Neonatally lesioned and control rats scored equally. Given the relatively mild effects of MDT lesioning, thalamic fibers do not seem to play a crucial role, at least not during the postnatal period of prefrontal cortical development. It is discussed whether or not this is a specific characteristic of agranular association cortex, in which the termination of thalamic and cortical afferents overlap in layer III.