Abstract
Introduction: With time-place learning (TPL), animals link an event with the spatial location and the time of day (TOD). The what–where–when TPL components make the task putatively episodic-like in nature. Animals use an internal sense of time to master TPL, which is circadian system based. Finding indications for a role of the hippocampus and (early) aging-sensitivity in TPL would strengthen the episodic-like memory nature of the paradigm.Methods: Previously, we used C57Bl/6 mice for our TPL research. Here, we used CD1 mice which are less hippocampal-driven and age faster compared to C57Bl/6 mice. To demonstrate the low degree of hippocampal-driven performance in CD1 mice, a cross maze was used. The spontaneous alternation test was used to score spatial working memory in CD1 mice at four different age categories (young (3–6 months), middle-aged (7–11 months), aged (12–18 months) and old (>19 months). TPL performance of middle-aged and aged CD1 mice was tested in a setup with either two or three time points per day (2-arm or 3-arm TPL task). Immunostainings were applied on brains of young and middle-aged C57Bl/6 mice that had successfully mastered the 3-arm TPL task.Results: In contrast to C57Bl/6 mice, middle-aged and aged CD1 mice were less hippocampus-driven and failed to master the 3-arm TPL task. They could, however, master the 2-arm TPL task primarily via an ordinal (non-circadian) timing system. c-Fos, CRY2, vasopressin (AVP), and phosphorylated cAMP response element-binding protein (pCREB) were investigated. We found no differences at the level of the suprachiasmatic nucleus (SCN; circadian master clock), whereas CRY2 expression was increased in the hippocampal dentate gyrus (DG). The most pronounced difference between TPL trained and control mice was found in c-Fos expression in the paraventricular thalamic nucleus, a circadian system relay station.Conclusions: These results further indicate a key role of CRY proteins in TPL and confirm the limited role of the SCN in TPL. Based on the poor TPL performance of CD1 mice, the results suggest age-sensitivity and hippocampal involvement in TPL. We suspect that TPL reflects an episodic-like memory task, but due to its functional nature, also entail the translation of experienced episodes into semantic rules acquired by training.
Highlights
With time-place learning (TPL), animals link an event with the spatial location and the time of day (TOD)
We studied CD1 mice in the TPL paradigm and showed that the CD1 mouse, which is relatively poor in hippocampal functioning and ages relatively fast, cannot master the 3-arm TPL task
They can master the 2-arm TPL task, but middle-aged and notably aged CD1 mice use an ordinal strategy. This strategy most likely depends on the striatum instead of a circadian strategy by which they use their circadian system as a timing device
Summary
With time-place learning (TPL), animals link an event with the spatial location and the time of day (TOD). Results: In contrast to C57Bl/6 mice, middle-aged and aged CD1 mice were less hippocampus-driven and failed to master the 3-arm TPL task. They could, master the 2-arm TPL task primarily via an ordinal (non-circadian) timing system. The paradigm emulates the natural situation in which hungry animals seek food while different feeding locations (arms of the maze) can be predictably safe or unsafe to visit in a TODdependent manner (Van der Zee et al, 2008). Investigating TPL can help to gain better understanding of the foraging dynamics in prey or predators Besides this ecological relevance, TPL is interesting in the field of Neuroscience. CTPL must be primarily driven by non-SCN oscillators such as hippocampal cell assemblies, the SCN may still play a modulatory role
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