Role of Aging and Hippocampus in Time-Place Learning: Link to Episodic-Like Memory?

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.

Automated dissection of permanent effects of hippocampal or prefrontal lesions on performance at spatial, working memory and circadian timing tasks of C57BL/6 mice in IntelliCage

“…Interestingly, the peculiar local de-synchronization during Drink adaptation (see above) might indicate that circadian triggering is overridden by some more short-term rhythmicity memory hampered by hippocampal lesions. Whether this could be in line with an eliminated intrahippocampal clock sense as postulated by Mulder et al [41] remains open at present. From a practical point of view, one may note that IntelliCages can be easily programmed to monitor conditioning schemes for analyzing episodic-like memory.…”

“…Another clear deficit in HIPP mice was found during place as well as reversal learning trials when mice faced the task to obtain water reward only at two given 1 h time periods during conditioning. The task is a circadian-based time-place learning [41] and fits the scheme of episodic-like memory that includes the triple knowledge of what, where and when, which is disturbed in hippocampal lesioned mice [36] . Since the hallmark of (bilateral) destruction of the hippocampus in humans is the loss of episodic memory, there is a wide interest in finding animal models of episodic memory.…”

Whole Body Vibration Improves Attention and Motor Performance in Mice Depending on the Duration of the Whole-Body Vibration Session

“…Nevertheless, vibrated CD1 mice showed a tendency to improve, which did not reach significant levels. CD1 mice are believed to have a relatively poor functioning hippocampus (Mulder et al, 2016). CD1 mice have a preference for a striatal-driven over a hippocampal-driven strategy to solve spatial tasks; this preference is most likely due to a poor functioning of the hippocampus.…”

Translational Difficulties in Querying Rats on “Orientation”

“…Another possibility may be that LE rats were 18 months old at the beginning of the 2-platform + board experiment thus might be constrained to mentally less demanding learning strategies. Mulder et al showed that 17-month-old mice-in contrast to 4-month-old counterparts-were unable to learn de novo a time-place discrimination task [15]. However, as 20-month-old LEJ2 rats did show a win-stay strategy in a very similar two choice assay, a more probable explanation may be that the initial strategy of Long-Evans rats in a choice paradigm may be the win-stay one, but in case of its ineffectiveness they change to a simpler one, namely random choice.…”

“…TPL can be considered as a particular case of episodic-like memory in which the "what" component is preset for the animal (finding food or an escape route) and this fixed event (episode) should be connected to a particular place-time ("where"-"when") pairing. Interestingly, studies on time-place learning, which have come from comparative behavioral research with an evolutionary approach only recently reached an intersection with the studies on episodic-like memory primarily with a translational approach [14,15]. e current study is part of a bigger project, namely to establish a complex rodent cognitive test battery of high translational value [16].…”