Chronic stress modulates the use of spatial and stimulus-response learning strategies in mice and man
Introduction
Memory consists of multiple systems which differ regarding the processed kind of information, the performed operations and the underlying neural structure (Gabrieli, 1998, Squire, 2004). “Cognitive” memory supports the acquisition of flexible, consciously accessible knowledge, such as the memory of your last birthday party, and is based on the medial temporal lobe, in particular the hippocampus (Eichenbaum, 2004, Scoville and Milner, 1957). “Habit” memory, on the other hand, processes simple stimulus-response (S-R) associations, such as “stop your car when the traffic lights are red”. It is not necessarily accessible and relies on the caudate nucleus (Jog et al., 1999, Knowlton et al., 1996).
Hippocampus- and caudate-based systems work in parallel and process information simultaneously (Mizumori, Yeshenko, Gill, & Davis, 2004). The nature of interactions between these systems has been described as cooperative by some authors (Voermans et al., 2004) and competitive by others (Poldrack & Packard, 2003) raising the question which factors coordinate their use. Recent findings suggested that stress plays a critical role in the modulation of multiple memory systems. Acute stress prior to training in a task that could be acquired by a hippocampus-based spatial and a caudate-based S-R strategy favored caudate-based learning both in rodents and humans (Kim et al., 2001, Packard and Wingard, 2004, Schwabe et al., 2007). This stress-induced modulation of hippocampus-dependent and caudate-dependent systems is assumed to be mediated by the amygdala (Packard & Wingard, 2004). Effects of prolonged or repeated periods of stress on the modulation of caudate-dependent and hippocampus-dependent learning have not been studied yet. This, however, would be particularly valuable since chronic stress has been related to psychiatric disorders such as depression (for a review: Willner, 1997).
Chronic stress impairs hippocampus-dependent learning and memory (Bodnoff et al., 1995, Conrad, 2006). Non-hippocampal memory systems respond differently. Working memory was not affected after repeated restraint stress (Kleen, Sitomer, Killeen, & Conrad, 2006), but fear memory was even strengthened following a prolonged stress period (Conrad, Magarinos, LeDoux, & McEwen, 1999). Interestingly, Wright and Conrad (2005) demonstrated in chronically stressed rats that salient intramaze cues prevented impaired performance in a spatial Y-maze task. We suggest that the introduction of intramaze cues allowed for S-R learning and thus, compensated for impairment of spatial functions. Consequently, we hypothesize that chronic stress modulates multiple memory systems in favor of caudate-based and at the expense of hippocampus-based learning.
To test this hypothesis, we used experimental designs that provide a single proximal and multiple distal cues for learning the task, i.e., allowing stimulus-response learning and spatial learning. Changing the position of the proximal cue in the last trial of the learning session revealed the used strategy in mice and humans. First, we examined in mice the effect of chronic stress (i.e., by repeatedly exposing the mouse to a rat, but separated by a partition) on the use of spatial and S-R learning strategies during the acquisition of a circular hole board task, followed by a retention test 24 h later. Second, we examined in humans the influence of self reported chronic stress as assessed by the Trier Inventory of Chronic Stress on the learning strategy used in a 2D spatial task in which the position of a win-field could be acquired by spatial and S-R strategies.
Section snippets
Animals
Male C57BL6/j mice (12 weeks old; purchased from Charles River, The Netherlands) were single-housed in a temperature- (21 ± 1 °C) and humidity-controlled room on a 12 h light/dark cycle (lights on at 07:00) with ad libitum access to food and water. Behavioral experiments were performed in the same room. Three times during the week before training started, mice were “pretrained” to climb through an S-shaped tube into their home cage after weighing. Experiments were approved by the Local Committee for
Learning strategy
Mice were repeatedly exposed to a rat over a period of 2 weeks, a procedure with long-lasting and profound effects on the stress responsive system and behavior of mice (Grootendorst et al., 2001a, Grootendorst et al., 2001b). One week after the last contact with a rat, mice were trained in six trials on a circular hole board (CHB) to find an open hole providing access to the home cage. This hole was marked by a cue (a bottle) and could thus be located by caudate-dependent S-R and
Discussion
Our results showed that the experience of prolonged or repeated stress in mice and humans affects the learning strategy (S-R or spatial) used to acquire a task. (1) Repeated exposure to rats increased the use of an S-R strategy in mice. (2) Experiencing relatively high levels of stress within the three months prior to testing was associated with a significant change in the used learning strategy (derived from test trial performance and confirmed by subjects’ verbal reports) towards more S-R
Acknowledgments
This work was part of the Trier-Leiden IRTG program, supported by Grants DFG GRK 1389/1, NWO DN 95-420 and KNAW Dr. J.L. Dobberke Stichting 8848. We gratefully acknowledge the assistance of Maaike van der Mark in the animal study.
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