Time-Place Learning and Memory Persist in Mice Lacking FunctionalPer1andPer2Clock Genes

Abstract

With time-place learning, animals link a stimulus with the location and the time of day. This ability may optimize resource localization and predator avoidance in daily changing environments. Time-place learning is a suitable task to study the interaction of the circadian system and memory. Previously, we showed that time-place learning in mice depends on the circadian system and Cry1 and/or Cry2 clock genes. We questioned whether time-place learning is Cry specific or also depends on other core molecular clock genes. Here, we show that Per1/Per2 double mutant mice, despite their arrhythmic phenotype, acquire time-place learning similar to wild-type mice. As well as an established role in circadian rhythms, Per genes have also been implicated in the formation and storage of memory. We found no deficiencies in short-term spatial working memory in Per mutant mice compared to wild-type mice. Moreover, both Per mutant and wild-type mice showed similar long-term memory for contextual features of a paradigm (a mild foot shock), measured in trained mice after a 2-month nontesting interval. In contrast, time-place associations were lost in both wild-type and mutant mice after these 2 months, suggesting a lack of maintained long-term memory storage for this type of information. Taken together, Cry-dependent time-place learning does not require Per genes, and Per mutant mice showed no PER-specific short-term or long-term memory deficiencies. These results limit the functional role of Per clock genes in the circadian regulation of time-place learning and memory.

Time–place learning over a lifetime: absence of memory loss in trained old mice

“…The used TPL test apparatus and testing procedures were described before ( Van der Zee et al 2008;Mulder et al 2013aMulder et al ,b, 2014. Briefly, the TPL test apparatus consisted of a round middle chamber (diameter 12.5 cm; height 7 cm) made of gray PVC and a transparent Plexiglas lid with ventilation holes.…”

“…Daily performance was calculated for each animal as the percentage of correct sessions (e.g., 0%, 33%, 67%, or 100%) and these performances were averaged over all mice, forming a learning curve over multiple testing days. Before mice were tested for the first time, testing was preceded by 10 d of habituation steps as described previously (Van der Zee et al 2008;Mulder et al 2013aMulder et al ,b, 2014. In short, during the first 4 d all locations were baited and safe to explore freely (no footshock delivery).…”

“…This paradigm emulates the natural situation in which hungry animals seek food while different feeding locations can be predictably safe or unsafe to visit depending on the TOD. We have shown repeatedly that young wild-type mice readily acquire this paradigm and will structurally use a circadian strategy (Van der Zee et al 2008;Mulder et al 2013aMulder et al , 2014.…”

Synchrony and desynchrony in circadian clocks: impacts on learning and memory

“…In time place learning, the incorporation of temporal information may also occur through extra-SCN or noncanonical oscillatory mechanisms as rats with lesioned SCNs continue to show time-of-day discrimination in a two-lever T-maze test (Mistlberger et al 1996). When food comprises the reward component in time place learning, the food-entrainable oscillator may be responsible for conveyance of temporal information (Aragona et al 2002;Mulder et al 2013). However, the mechanism through which temporal information in time place learning remains unknown as animals with mutations in two of the circadian period genes (Per12/2;Per22/2) show no difference in time place learning when compared with wild-type mice (Mulder et al 2013).…”

“…When food comprises the reward component in time place learning, the food-entrainable oscillator may be responsible for conveyance of temporal information (Aragona et al 2002;Mulder et al 2013). However, the mechanism through which temporal information in time place learning remains unknown as animals with mutations in two of the circadian period genes (Per12/2;Per22/2) show no difference in time place learning when compared with wild-type mice (Mulder et al 2013). Reception and transmission of temporal information to the unknown oscillator still appears to require Cryptochrome (CRY), a light sensitive clock molecule and core component of the mammalian circadian clock, as CRY double knockout mice (Cry1 2/2 ;Cry2 2/2 ) are unable to acquire time place learning (Van der ).…”