Differential activation of the caudate nucleus in primates performing spatial and nonspatial working memory tasks

Abstract

The caudate nucleus is part of an anatomical network subserving functions associated with the dorsolateral prefrontal cortex (DLPFC). The aim of the present study was to investigate whether the metabolic activity in the striatum reflects specific changes in working memory tasks, which are known to be dependent on the DLPFC, and whether these changes reflect the topographic ordering of prefrontal connections within the striatum. Local cerebral glucose utilization (LCGU) rates were assessed in the striatum by the 14C-2-deoxyglucose method in monkeys that performed a spatial (delayed spatial alternation), a nonspatial (delayed object alternation) visual working memory task, or tasks that did not involve working memory, i.e., a visual pattern discrimination or sensorimotor paradigm. The results show a topographic segregation of activation related to spatial and nonspatial working memory, respectively. The delayed spatial alternation task increases LCGU rates bilaterally by 33-43% in the head of the caudate nucleus, where efferents from the dorsolateral prefrontal cortex project most densely. The delayed object alternation task enhances LCGU rates bilaterally by 32-37% in the body of the caudate nucleus, which is innervated by the temporal cortex. The visual pattern discrimination task similarly activated the body of the caudate, but in a smaller region and only in the right hemisphere. These findings provide the first evidence for metabolic activation of the caudate nuclei in working memory, supporting the role of this nucleus as a node in a neural network mediating DLPFC-dependent working memory processes. The double dissociation of activation observed suggests an anatomical and functional segregation of cortico-striatal circuits subserving spatial and nonspatial cognitive operations.

Fig. 1.

Working memory tasks. In these two tasks, the information guiding a correct response changed from trial to trial, and the monkey was required to update this information (i.e., to maintain an internal representation of the immediately preceding trial). InDelayed Spatial Alternation, after a delay, the monkey had to displace alternately a left or right plaque to retrieve a reward. Rewards were hidden by two identical plaques. In Delayed Object Alternation, the monkey had to alternate its choices between two objects (different in color, shape, and size) from trial to trial to obtain rewards. The same two objects were presented throughout the session and from day to day. To prevent monkeys from adopting a spatial strategy, the objects were positioned according to a pseudo-random order. The + sign indicates that a reward is hidden behind the plaques or objects (reinforced stimulus), whereas the − sign signifies the absence of positive reinforcement;arrows indicate the correct response (except for the first trial, in which either choice is correct).

Fig. 2.

Sensorimotor and associative memory tasks. In theSensory Motor condition, memory was not required either because the reward was in sight at the response phase (Fig. 2) or because all stimuli were baited (data not shown). An intertrial interval separated each trial, and there was no relationship between trials. In the Visual Pattern Discrimination condition, the monkey had to learn an association between a stimulus (the + sign card) and the reward. This association did not vary from trial to trial and from day to day. The + sign indicates that a reward is hidden behind the plaques or objects (reinforced stimulus), whereas the − sign signifies the absence of positive reinforcement;arrows indicate the correct response.

Fig. 3.

Levels selected for the image analyses. Seven levels, from the rostral to the caudal parts of the striatum, were selected for LCGU analysis. This schematic lateral view representation of the striatum in the center of the figure displays the anterior–posterior levels selected in each animal. The dark gray image represents the caudate nucleus, whereas thelight gray area is the putamen. Autoradiograms from one monkey are shown at each of the seven levels. Note that the scale is not applicable from one photograph to another.

Fig. 4.

Example showing the two different methods of image analysis. Panels 1 and 2 are photographs from the same section taken at level 3 in a monkey performing the SMC task to illustrate the two different methods of analysis used in this study. The rationale for these two methods and additional methodological details are presented in Material and Methods.Panel 1 shows the “sample” method of image analysis. In this method, LCGU was measured in square samples centrally located in each of nine subdivisions of the caudate nucleus (as defined in the frame). These measurements were performed on three to six sections at each level for a given monkey. A mean LCGU rate was obtained by pooling equivalent samples from all sections at one level. For instance, left dorsolateral samples (box 1) from all sections at level 3 obtained from one monkey were averaged to obtain a mean LCGU rate corresponding to the left dorsolateral subarea at level 3. Thereafter, averages from the dorsal (boxes 1–3), central (boxes 4–6), and ventral (boxes 7–9) samples were pooled to obtain mean LCGU rates for the dorsal, central, and ventral subregions of the caudate nucleus, respectively. Finally, mean LCGU rates from these three regions were averaged to obtain a mean LCGU rate for the caudate nucleus. This procedure was applied to the left and right caudate nuclei separately. Mean LCGU rates for a given region were averaged across monkeys to obtain a group mean LCGU value for that particular region. In the second method of analysis (“regional” analysis, panel 2), instead of taking box samples, the caudate nucleus was divided into three regions (dorsal, central, and ventral), as shown. Measurements of LCGU rates were performed on the entire surface of the region of interest. Results were averaged for each region and across animals by the same method that was applied in the “sample” analysis. Note the decrease in the intensity of labeling according to a dorso-ventral gradient and the patchy zones of higher intensity in the dorsal regions. The dorso-ventral gradient observed in this figure was confirmed by the LCGU measurements in the CONT group, which showed a 24% difference between the dorsal region of the caudate nucleus (adjusted mean LCGU rates, 56 ± 4.67) and the ventral striatum (adjusted mean LCGU rates, 43.2 ± 3.49). L, Lateral border; M, medial border; D, dorsal border; V, ventral border; P, putamen.

Fig. 5.

Percent increase in mean LCGU rates in the spatial working memory group, as compared with the control group. The percent increase in mean LCGU rates of the spatial working memory group (DSA) is shown at each level, as compared with a control group (CONT = VD + SMC tasks). The results presented in this figure are from the “regional” analysis. Results from the dorsal, central, and ventral regions are shown at levels 1–3. At levels 4 and 5, ranges are shown for the overall increase in the dorsal, central, and ventral regions of the caudate nucleus. At levels 6 and 7, only one mean LCGU rate was obtained, because the caudate nucleus was not segmented into subregions at these levels. When shown, the putamen appears without numbers, because this structure was analyzed only at level 4 (the putamen is not shown at that level). Characters in boldand an asterisk indicate the statistically significant increase in mean LCGU rates (p < 0.05) in the DSA group relative to the CONT group. Note that “left” and “right” sides are flipped, because film autoradiograms are the “mirror” images of the actual sections. Also note that the scale differs from one level to another. NC, Caudate nucleus;P, putamen.

Fig. 6.

Percent increase in mean LCGU rates in the nonspatial working memory group, as compared with the control monkeys. The percent increase in mean LCGU rates of the nonspatial working memory group (DOA) is shown at each level, as compared with a control group (CONT = VD + SMC task). Results from the dorsal, central, and ventral regions are shown at levels 3–5. At levels 1 and 2, ranges are shown for the overall increase in the dorsal, central, and ventral regions of the caudate nucleus. At levels 6 and 7, only one mean LCGU rate was obtained, because the caudate nucleus was not segmented into subregions at these levels. Characters inbold and an asterisk indicate the statistically significant increase in mean LCGU rates (p < 0.05) in the DOA group relative to the CONT group.

Fig. 7.

Gradient of changes throughout the anterior–posterior axis of the caudate nucleus in the spatial and nonspatial working memory groups, as compared with a control group. The results presented are the percent increase in adjusted mean LCGU rates in the spatial and nonspatial working memory conditions, as compared with a control group (VD + SMC tasks) for the left (top) and right (bottom) caudate nuclei. Statistically significant increases in mean LCGU rates (p< 0.05) are shown by the asterisks.