Repeated acquisition of response sequences: The analysis of behavior in transition

doi:10.1016/0149-7634(94)00067-B

Neuroscience & Biobehavioral Reviews

Volume 19, Issue 3, Autumn 1995, Pages 397-406

https://doi.org/10.1016/0149-7634(94)00067-B Get rights and content

Abstract

Repeated acquisition (RA) procedures are behavioral preparations in which subjects are required to learn new response sequences within each experimental session. Such procedures avoid problems inherent in nonRA learning procedures. For example, as the subject masters nonRA tasks, one begins to measure performance of a learned response rather than learning itself. Advantages to using RA procedures include (a) the strength of the within-subjects design, including the ability to establish dose effect curves within individual subjects; (b) the ability to assess learning phenomena over extended periods of time; (c) the ability to use chronic dosing regimens; and 9d) the ability to assess treatments with permanent or long-lasting effects. In addition, analysis of the response patterns committed during acquisition allows for a description of how behavioral strategies may change in response to experimental manipulation. Difficulties include the relatively long training period often preceding attainment of a stable baseline of acquisition. This review examines the history of RA paradigms, with an emphasis on procedural comparisons.

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The variability procedure was selected because of its relevance to behavioral interventions for humans with ASD. The IRA procedure was selected because it is a test of advanced learning that, in humans, is highly correlated with score on IQ tests (Baldwin et al., 2012; Cohn and Paule, 1995). BALB/c mice were of interest because they have been advanced as a model of some aspects of the autism phenotype (Brodkin, 2007).
Behavioral inflexibility is often assessed using reversal learning tasks, which require a relatively low degree of response variability. No studies have assessed sensitivity to reinforcement contingencies that specifically select highly variable response patterns in mice, let alone in models of neurodevelopmental disorders involving limited response variation. Operant variability and incremental repeated acquisition (IRA) were used to assess unique aspects of behavioral variability of two mouse strains: BALB/c, a model of some deficits in ASD, and C57Bl/6. On the operant variability task, BALB/c mice responded more repetitively during adolescence than C57Bl/6 mice when reinforcement did not require variability but responded more variably when reinforcement required variability. During IRA testing in adulthood, both strains acquired an unchanging, performance sequence equally well. Strain differences emerged, however, after novel learning sequences began alternating with the performance sequence: BALB/c mice substantially outperformed C57Bl/6 mice. Using litter-mate controls, it was found that adolescent experience with variability did not affect either learning or performance on the IRA task in adulthood. These findings constrain the use of BALB/c mice as a model of ASD, but once again reveal this strain is highly sensitive to reinforcement contingencies and they are fast and robust learners.
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Postoperative Cognitive Dysfunction (POCD) is a complication that can occur in the elderly after anesthesia and surgery and is characterized by impairments in information processing, memory, and executive function. Currently, it is unclear whether POCD is due to the effects of surgery, anesthesia, or perhaps some interaction between these or other perioperative variables. Studies in rodents suggest that the development of POCD may be related directly to anesthesia-induced neuroactivity. Volatile anesthetics have been shown to increase cellular inflammation and apoptosis within the hippocampus of aged rodents, while producing corresponding impairments in hippocampal-dependent brain functions. However, it is unclear whether volatile anesthetics can affect additional aspects of cognition that do not primarily depend upon the hippocampus. The purpose of this study was to use established operant tests to examine the effects of isoflurane on aspects of behavioral inhibition, learning, and motivation in aged rats. Twenty-one adult Sprague-Dawley rats (11 male, 10 female) were trained to perform fixed consecutive number (FCN), incremental repeated acquisition (IRA), and progressive ratio (PR) tasks for a minimum of 15 months prior to receiving anesthesia. At 23 months of age, rats were exposed to 1.3% isoflurane or medical grade air for 2 h. Initial results revealed that a 2 h exposure to isoflurane had no effect on IRA, FCN, or PR performance. Thus, rats received 3 additional exposures to 1.3% isoflurane or medical grade air: 2, 4 and 6 h exposures with 2 weeks elapsing before exposure two, 3 weeks elapsing between exposures two and three, and 2 weeks elapsing between exposures three and four. These additional exposures had no observable effects on performance of any operant task. These results suggest that single and repeated exposures to isoflurane do not impair the performance of aged rats in tasks designed to measure behavioral inhibition, learning, and motivation. This lack of significant effect suggests that the impairments associated with isoflurane exposure may not generalize to all aspects of cognition, but may be selective to tasks that primarily measure spatial memory processes.
Spatial discrimination reversal and incremental repeated acquisition in adolescent and adult BALB/c mice
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Specifically, the dependent measure progress quotient (PQ), directly related to the number of reinforcers earned at a given chain length, can vary over a dynamic range and serve as an independent, overall measure of performance (Bailey et al., 2010; Johnson et al., 2010). The IRA procedure has been used with a wide variety of species, including rats, mice, pigeons, and non-human primates (Cohn and Paule, 1995) and has garnered extensive use when evaluating acute drug effects and chronic exposure to environmental contaminants (Bailey et al., 2013; Paule and McMillan, 1984). A mastery-based approach allows task difficulty to adjust in real time according to the animal's performance, an approach that has led to the production of very long response chains by mice (Bailey et al., 2010; Johnson et al., 2010).
Adolescence is characterized by neural and behavior development that includes increases in novel experiences and impulsive choice. Experimental rodent models can characterize behavior phenotypes that typify adolescence. The present experiment was designed to characterize differences between adolescent (post-natal day (PND) 34–60) and adult (PND 70–96) BALB/c mice using a response-initiated spatial discrimination reversal (SDR) and incremental repeated acquisition of response chains (IRA) procedures. During SDR, adolescents omitted more trials and were slower to initiate trials than adults, but the age groups did not differ on accuracy and perseveration measures. During IRA, adolescents displayed poorer overall performance (measured by progress quotient), lower accuracy at individual chain links, and completed fewer long response chains (>3 links) than adults. In both procedures (SDR and IRA), the poorer performance of adolescents appeared to be related to the use of a response device that was spatially removed from reinforcer delivery. These results indicate that SDR and IRA performance can be established during the brief rodent adolescent period but that these two age groups’ performances differ. We hypothesize that adolescent behavior is more sensitive than adult behavior to the spatiotemporal distance between response device and location of reinforcer delivery.
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Transgenic mice expressing mutations in tau have yielded essential discoveries for Alzheimer's disease. One of the most commonly used tau mouse models is the tet-off Tg(tauP301L)4510 model that expresses P301L human tau driven by the calcium–calmodulin kinase IIα (CaMKIIα) promoter system. Tau expression in this model is regulatable, allowing for suppression of mutant tau expression until adulthood and prevention of possible developmental alterations resulting from P301L tau expression during development. Here, we compared the effect and sample sizes needed for three learning and memory tasks in mice with adult-onset P301L tau expression. Our findings indicate that the Incremental Repeated Acquisition (IRA) and trace fear conditioning tasks, neither of which have previously been published with these mice, were highly sensitive to P301L tau expression, whereas the Morris water maze, the most commonly used task with this model, was the least sensitive. Memory deficits were observed at a time when tau pathology was subtle and prior to readily detectable neuronal loss. Thus, we provide essential information (effect and sample sizes needed) for establishing experimental designs at a time point when memory deficits are likely to go undetected if inadequate sample sizes are used. Our work also suggests the tet-off Tg4510 model provides a way to avoid mutant tau expression during the perinatal and early postnatal stages, thereby preventing possible developmental alterations unrelated to Alzheimer's disease.
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Adult-onset methylmercury (MeHg) exposure is thought to result primarily in sensory and motor deficits but effects on learning are poorly understood. One mechanism by which chronic MeHg may exert its neurotoxicity is via sustained disruption of intracellular calcium homeostasis, with a consequent increase of intracellular Ca²⁺ ions in vulnerable neurons. A biochemically heterogeneous group of compounds, calcium channel blockers, have been shown in vitro to attenuate MeHg's toxicity. To evaluate the role of calcium antagonism in MeHg toxicity in vivo, adult BALB/c mice were exposed chronically to 0 or 15 ppm of Hg (as MeHg) via drinking water and to nimodipine, a dihydropryidine, L-type Ca²⁺ channel blocker with action in the CNS. Nimodipine was administered orally in diets (0, 20, or 200 ppm, producing approximately 0, 2, or 20 mg/kg/day of nimodipine). An incremental repeated acquisition (IRA) of response chains procedure was used to detect MeHg-induced deficits in learning or motoric function and to evaluate possible neuroprotection by nimodipine. MeHg impaired performance on the IRA task, and this was partially or completely blocked by dietary nimodipine, depending on dose. Measures of learning co-varied with measures of motoric function as indicated by overall response rate. Nimodipine delayed or prevented the behavioral toxicity of MeHg exposure as evidenced by IRA performance; effects on learning seemed secondary to response rate decreases.
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The child was presented with only one six-link response chain to complete during the session. This was randomly chosen based on three criteria: (a) each lever had to be used at least once during each six-link response chain; (b) the first and last levers in a six-link response chain were not the same lever; and (c) no lever was used twice in a row during a six-link response chain (see Cohn and Paule, 1995). Each testing session consisted of five tasks presented in the following order: progressive ratio (10 min), conditioned position responding (5 min), temporal response differentiation (10 min), delayed matching-to-sample (15 min), and IRA (15 min; see Paule et al., 1988 for a description of each task).
The development of valid animal models of learning is especially important since learning is critical for nearly all aspects of human behavior and identifying appropriate surrogates provides additional opportunity to study various aspects of learning. Examining the factors that affect learning is often complicated by the need to administer the same task repeatedly across experimental conditions. Incremental repeated acquisition (IRA) tasks have been used extensively in animal research because they circumvent this problem by requiring a subject to learn different response chains repeatedly across sessions. The present study examined the association of age, sex of the participant, and IQ on the performance of an incremental repeated acquisition task in 837 children, aged 5–13 years. This task required children to learn to press four response levers in a specific sequence that was randomly chosen. Illumination of colored indicator lights signaled position in the required response chain. Initially, for the first link, only one of the four levers was correct: a response to it resulted in the delivery of a monetary reinforcer (5 cents). After mastery of the first link (i.e. three correct presses), the children were presented with a two-link response chain: a different lever had to be pressed before pressing the previously correct lever. After mastery of the two-link chain, the response chain length was once again increased, and so on until a response chain consisting of six links was completed or until the task timed out. Older children and children with higher IQs mastered longer response chain lengths and were more accurate in performance of this learning task than younger children. In addition, older children and children with higher IQs had higher effective response rates and lower ineffective response rates. No significant effects of the sex of the participant were demonstrated for any of the variables on this task, except overall response rate. The results indicate that this test is sensitive to developmental variables in children, with the degree of sensitivity of certain dependent variables being age-dependent. Characterization of performance of this task by humans facilitates comparisons with animal models employing the same task, thus enhancing its translational utility.

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^☆: This article has been reviewed by the Health Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use.

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ArticleRepeated acquisition of response sequences: The analysis of behavior in transition☆

Abstract

Neurosci. Biobehav. Rev.

Jpn. J. Pharmacol.

Pharmacol. Biochem. Behav.

Neurotoxicol. Teratol.

Pharmacol. Biochem. Behav.

Neurosci. Biobehav. Rev.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Euro. J. Pharmacol.

Repeated acquisition of new behavioral chains

Am. Psychol.

Stimulus fading variables affecting the maximum chain length a monkey can acquire

The repeated acquisition of behavioral chains

J. Exp. Anal. Behav.

Repeated sequence acquisition in the radial arm maze

Soc. Neurosci. Abstr.

The effects of lead exposure on learning in a multiple repeated acquisition and performance schedule

Neurotoxicology

Differential effects of MK-801, scopolamine, and NMDA on a four-member repeated acquisition paradigm

Behav. Pharmacol.

Comparison of error patterns produced by scopolamine and MK-801 on repeated acquisition and transition baselines

Psychopharmacology

The neurotoxicology of cognition: Attention, learning, and memory

Schedules of reinforcement

Repeated acquisition of response sequences by pigeons under chained and tandem schedules with reset and nonreset contingencies

Psych. Rec.

Effects of pentobarbital and d-amphetamine on the repeated acquisition of response sequences by pigeons

Psychopharmacology

Effects of d-amphetamine, org 2766, scopolamine, and physostigmine on repeated acquisition of four-response chains in the rat

Dr. Dev. Res.

Article
Repeated acquisition of response sequences: The analysis of behavior in transition☆