Working memory for temporal order is impaired after selective neonatal hippocampal lesions in adult rhesus macaques

Abstract

A previous study in this laboratory demonstrated, for the first time, that neonatal lesions of the hippocampus impair monitoring working memory, as measured by a self-order task, but spare recency memory, as measured by the session-unique delayed nonmatching task. To substantiate and extend this novel finding, we assessed working memory in these same animals using a serial order memory task. In humans and non-human primates the serial order memory task has been shown to be dependent upon the integrity of the dorsolateral prefrontal cortex. Additionally, the serial order task has the ability to examine the integrity of non-dorsolateral dependent working memory functions, providing specificity to conclusions drawn from this task. Thus, monkeys with neonatal lesions of the hippocampus and sham-operated control subjects were tested on two versions of the serial order memory task (3 and 4 objects). The results of this study demonstrated that neonatal hippocampal lesions did not impair performance on the 3-object version of the task, confirming our previous finding of intact non-dlPFC dependent working memory. In contrast, these same animals showed a significant impairment on the dlPFC dependent phase of the 4-object serial order task. This finding was further confirmed through a series of probe trials. These results, in combination with our earlier finding, suggest that early lesions of the hippocampus may have impacted the function of the dlPFC or its interactions with the hippocampus.

Figure 1

Transverse T1-weighed images through the brain of a normal control monkey (Neo-C-1) on the left and a monkey with a neonatal lesion of the hippocampus (Neo-H-ibo-2) on the right. Comparisons between the two series of images clearly illustrate the 67% reduction in hippocampal volume in case Neo-Hibo-2, estimated from the one year post-surgical scan (see Table 2). Arrows point to increased lateral ventricle due to volume reduction of the hippocampus.

Figure 2

Scores are Mean number of sessions (± SEM) to reach criterion (A) on the three phases (1 vs. 3, 1 vs. 2 and 2 vs 3) of the 3-SOMT and (B) the six phases (1 vs. 4, 1 vs. 3, 1 vs. 2, 2 vs. 4, 3 vs. 4, and 2 vs. 3) of the 4-SOMT for sham-operated controls (white bars) and monkeys with neonatal hippocampal lesions (black bars). * indicates p = 0.004.

Figure 3

(A) Averaged ratio of scores (± SEM) on the 4-SOMT probe trials for sham-operated controls (Group Neo-C, white bars) and monkeys with neonatal hippocampal lesions (Group Neo-Hibo, black bars). Scores are cumulative correct responses on the inner object discrimination (2 vs 3) divided by the number of correct responses on the outer discrimination (1 vs 4) across the three-day probe sessions. A score near one indicates equivalent performance on the two trial types, whereas a score below one indicates poor performance on the inner object discrimination. * indicates p = 0.002. (B) A graph of the correlation between the extent of hippocampal lesion and the ratio score earned on the 4-SOMT probe test (r = 0.820, p = 0.046), however it is clear that this correlation is driven by one individual (Neo-H-3 highlighted with a circle), and this correlation does not remain when this animal is removed from the analysis (r = 0.698, p = 0.199).