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-trial basis. 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.

Effects of sequential exposure to multiple concentrations of methylmercury in the rat hippocampal slice.

Two experiments explored the effects of sequential exposure to multiple concentrations of methylmercury (MeHg) on rat hippocampal slice synaptic transmission and excitability in area CA1. When hippocampal slices were exposed to 0.1, 1, 10, and 100 microM MeHg chloride in successive 30-min exposures, MeHg produced an increase in excitability over baseline levels throughout the 1 microM exposure and the first 5 min of the 10 microM exposure, followed by profound suppression of excitability at the 100 microM level. When hippocampal slices were exposed to 10, 25, 50, 75, and 100 microM concentrations, MeHg produced an increase in excitability throughout most of the 10 and 25 microM exposures, followed by profound suppression of excitability at the 50 microM level of exposure. In both series of concentrations, MeHg suppressed local inhibitory systems prior to suppressing excitatory systems. In a third experiment, a single exposure of 50 microM MeHg suppressed both presynaptic and postsynaptic responses recorded in stratum radiatum with the same time course, suggesting that the observed suppressive effects of MeHg were not primarily synaptic.

Coding of hierarchical versus linear pattern structure in rats and humans.

In 3 experiments, rats and humans learned serial patterns composed of 24, 30, or 36 items. Patterns had a 2-, 3-, or 4-level hierarchical rule structure. In Experiments 1 and 2, patterns had either perfect hierarchical structure or 2 modified chunks that violated hierarchical structure, thus producing linear structure (i.e., nonhierarchical structure). For both rats and humans, pattern structure predicted pattern learning difficulty and also the nature and relative frequency of errors. Both treated chunks that were inconsistent with hierarchical structure as violation chunks, that is, they made errors that reflected their "tendency to regularize the perception of an irregular pattern" (F. Restle & B. L. Burnside, 1972). The results support the view that rats can abstract and encode a representation of multilevel hierarchical structure in serial patterns in much the same way as humans do in analogous tasks.

Sensitivity to violations of "run" and "trill" structures in rat serial-pattern learning.

Rats learned serial patterns composed of either "run" chunks (e.g., 123 234 ...) or "trill" chunks (e.g., 121 232 ...). For each type of pattern, 1 group of rats encountered an element at the end of the pattern that violated the run or trill structure. In both run and trill patterns, violations were unusually difficult for rats to learn, whereas corresponding elements in "perfect" patterns that did not violate pattern structure were easy. Additionally, rats' errors on violation elements conformed to the structure of the patterns in which they were embedded. Thus, rats were sensitive to the run or trill organization of their patterns and mastered the rules governing the pattern before learning "exceptions to the rule."

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.

Threshold procedures for assessing the impact of agents on brain reward systems.

Chemical effects on the reinforcing quality of electrical stimulation of the rat brain can be assessed using a variety of methods, most commonly by observing changes in response rates maintained under specific schedules of reinforcement. We present results demonstrating the utility of procedures for assessing the minimum amount of electrical stimulation required to support rat leverpress responding, that is, the brain-stimulation reward (BSR) threshold. In these threshold procedures, each leverpress produced by the rat decreases the duration of the electrical stimulus delivered to the posterior lateral hypothalamus until the rat fails to respond. The stimulus duration is then reset to its initial value and the procedure begins again. The last stimulus duration in a series supporting a response is defined as the stimulus duration (SD) threshold, and the mean SD threshold is determined daily. Stable SD thresholds are achieved within 2 weeks, and this measure is sensitive to agent-induced changes in rats' response to BSR. To illustrate the utility of this approach, data are presented showing that rats' BSR thresholds changed significantly following exposure to triethyltin or carbon monoxide. The results support the view that threshold methods can be used to dissociate agent-induced effects on brain reward systems and BSR quality from changes in performance or effects on other behavioral processes.