James D. Rowan

Differential impairments of rat serial pattern learning and retention induced by MK-801, an NMDA receptor antagonist

Three experiments investigated the role of NMDA receptor dependent systems in sequential learning and memory. Rats tracked serial patterns after systemic administration of MK-801, an NMDA receptor antagonist that blocks plasticity in the hippocampus and other structures. Experiments 1 and 2 sought to describe the effects of MK-801 on acquisition and retention of serial patterns. Patterns were 24 elements long and highly organized, with some groups receiving a “violation” element that did not fit the organization of the rest of the pattern. Experiment 3 evaluated MK-801’s effects on the integration of new information that was either consistent or inconsistent with a previously learned pattern structure. The results of these experiments indicated that MK-801 interfered with serial pattern learning and, to a lesser degree, retention. Learning about structure was relatively spared, whereas learning about interruptions or violations of pattern structure was impaired. The latter differential effects are consistent with the contention in earlier literature that serial pattern learning is subserved by at least two learning/memory systems.

Rule learning in rats: serial tracking in interleaved patterns

Abstract Humans have the ability to chunk together information from nonadjacent serial positions in sequential patterns. For example, human subjects can extrapolate the pattern, A-M-B-N-C-O-D-P-E-..., to find the missing element, Q, by sorting pattern elements into two component interleaved subpatterns: A-B-C-D-E and M-N-O-P-... Two experiments investigated the ability of rats to reorganize pattern elements from nonadjacent serial positions into chunks not presented by the experimenter. Rats learned either a structured or unstructured sequence interleaved with elements of a repeating sequence (experiment 1) or an alternation sequence (experiment 2). In both experiments, rats learned the interleaved subpatterns at different rates. Acquisition rate was correlated with the structural properties of component subpatterns and the nature of the rules required to describe the interleaved subpatterns. The results indicate that rats are sensitive to the organization of nonadjacent elements in serial patterns and that they can detect and sort structural relationships in interleaved patterns.

SERIAL-PATTERN LEARNING IN MICE: PATTERN STRUCTURE AND PHRASING

In two experiments, mice learned 24-element serial patterns. In Experiment 1, patterns either were perfectly structured or had a single violation element and were either phrased by temporal pauses or unphrased. In Experiment 2, the same violation pattern of Experiment 1 was phrased by temporal cues, visual cues, or a combination of the two. For mice, as for rats and humans in earlier studies, pattern structure predicted pattern learning difficulty and also the nature and relative frequency of errors. Mice, like rats and humans, also found a violation element especially difficult to learn and at that point in the pattern made errors consistent with the structure of the remainder of the pattern. However, in both experiments, phrasing interfered with responding correctly on the element after the phrasing cue. In a third experiment, mice were able to use temporal intervals and, to a lesser degree, visual stimuli as discriminative cues to control spatial responses in the same apparatus used in earlier studies. The results support the view that mice are sensitive to pattern organization but may have difficulty using phrasing cues in the context of serial patterns.

Determinants of phrasing effects in rat serial pattern learning.

Two experiments investigated how brief pauses introduced into serial patterns as phrasing cues would affect pattern learning in rats. In Experiment 1, a 24-element pattern consisted of eight 3-element chunks, whereas a 20-element pattern consisted of four 5-element chunks. In both patterns, 3.0-s temporal pauses placed at chunk boundaries (synchronous phrasing cues) facilitated learning compared to no phrasing. Cues “out of sync” with pattern structure (asynchronous phrasing cues) facilitated learning for the 24-element pattern and retarded learning for the 20-element pattern. Evidence suggested that in the latter case, 3.0-s pauses served as “blank” trials that induced rats to “skip” to the next serial position in sequence. In Experiment 2, shorter 0.5-s pauses served as phrasing cues in the 20-element pattern of Experiment 1. Synchronous short cues facilitated learning, whereas asynchronous phrasing cues had no effect. Furthermore, removal of synchronous cues produced deficits in performance on formerly cued trials, whereas removal of asynchronous cues had no effect. The results of Experiment 2 support the notion that in both experiments phrasing cues served as discriminative cues and indirectly suggest that rats are concurrently sensitive to pattern element cues, extra-sequence cues (such as phrasing cues), and to the relative timing of sequential events.

The Organization of Sequential Behavior

For decades, beginning with Lashley’s (1951) celebrated paper or even earlier with the work of Ebbinghaus and others (Hunter, 1920; Skinner, 1934), sequential learning has repeatedly aroused debate over the fundamental nature of learning, memory, and representation in humans and animals. In recent years, debate has centered on whether nonhuman animals can use nonassociative symbolic processes such as rule-induction to learn about the structure of patterned sequences (“serial patterns”) of events. The work by Hulse and colleagues on rats’ serial-pattern learning (SPL) of food reward magnitude in runways, in particular, supported a Rule-Learning (RL) theory (e.g., Hulse & Campbell, 1975; Hulse & Dorsky, 1977; Hulse, 1978; Hulse & Dorsky, 1979; Fountain & Hulse, 1981; Fountain, Evensen, & Hulse, 1983). The RL theory proposed that rats learned some representation of the abstract rules that described organized sequences (Fountain, 1986; Roitblat, Pologe, & Scopatz, 1983; Wathen & Roberts, 1994). The implication was that rats did not have to rely on chaining or remote associations alone to master sequences. Later work in our laboratory involved a somewhat different SPL paradigm employing patterns of stimuli drawn from another stimulus dimension (viz., a spatial dimension rather than food reward magnitude). This work also supported the RL view of serial-pattern learning in both rats and mice (e.g., Fountain, 1990; Fountain & Rowan, 1995b; Fountain & Rowan, 1995a).

Adolescent exposure to methylphenidate impairs serial pattern learning in the serial multiple choice (SMC) task in adult rats

The long-term effects of adolescent exposure to methylphenidate (MPD) on adult cognitive capacity are largely unknown. We utilized a serial multiple choice (SMC) task, which is a sequential learning paradigm for studying complex learning, to observe the effects of methylphenidate exposure during adolescence on later serial pattern acquisition during adulthood. Following 20.0mg/kg/day MPD or saline exposure for 5 days/week for 5 weeks during adolescence, male rats were trained to produce a highly structured serial response pattern in an octagonal operant chamber for water reinforcement as adults. During a transfer phase, a violation to the previously-learned pattern structure was introduced as the last element of the sequential pattern. Results indicated that while rats in both groups were able to learn the training and transfer patterns, adolescent exposure to MPD impaired learning for some aspects of pattern learning in the training phase which are learned using discrimination learning or serial position learning. In contrast adolescent exposure to MPD had no effect on other aspects of pattern learning which have been shown to tap into rule learning mechanisms. Additionally, adolescent MPD exposure impaired learning for the violation element in the transfer phase. This indicates a deficit in multi-item learning previously shown to be responsible for violation element learning. Thus, these results clearly show that adolescent MPD produced multiple cognitive impairments in male rats that persisted into adulthood long after MPD exposure ended.

A multiple species approach to sequential learning: Are you a man or a mouse?

We have developed a method for studying list learning in animals and humans, and we use variants of the task to examine list learning in rats, mice, and humans. This method holds several advantages over other methods. It has been found to be easily learned without lengthy pretraining. The data gathered with this procedure provide a measure of correct response rates, of incorrect responses and the locations of these responses, and of response latency on a trial-by-trialbasis. We have examined mouse, rat, and human list acquisition of patterns ranging from 12 to 48 items in length. This procedure has also been used to examine many aspects of list learning, such as the effects of the placement of phrasing cues that are either consistent or inconsistent with the structure of the list in rats and mice, the effects of phrasing cues of differing modalities in mice, the sensitivity of subjects to violations of list structure in rats, subjects’ abilities to “chunk” from nonadjacent serial positions in structured lists in rats, and subjects’ sensitivity to serial patterns with multiple levels of hierarchical organization. The procedure has also been used to examine the effects of drugs on sequential learning.

Carbon monoxide exposure reduces the rewarding quality of brain-stimulation reward in rats☆

The effect of carbon monoxide (CO) exposure on hypothalamic brain-stimulation reward (BSR) was examined. Rats were trained in a procedure that daily determined their stimulus duration threshold (SDT), that is, the shortest electrical stimulus to the posterior lateral hypothalamus that would support discrete-trial leverpress responding for BSR. After a stable SDT baseline was established using a single response lever, rats were exposed to 0, 5, 10, 20, and 40 ml/kg pure CO by IP injection. The SDT was significantly elevated by the 40 ml/kg exposure (corresponding to approximately 65% carboxyhemoglobin in the blood) compared to control exposures of an equal volume. No change was observed in response rate at any dose in this 1-lever task. No tolerance was observed when 40 ml/kg CO exposure was repeated on alternating days for 14 exposures, but a small reduction in response rate was observed in this procedure. When rats of a second group were required to alternate responses on two levers some distance apart, SDT was elevated by the highest exposure (40 ml/kg) as before. Additionally, response rate was also significantly suppressed by the highest exposure in this 2-lever task. The results support the view that CO has a direct effect on brain reward systems assessed by the SDT task. Response rate changes due to CO exposure may be due to both direct effects on brain reward systems and other effects such as hypoxia-induced fatigue.