Research reportImpairment of object recognition memory by rapamycin inhibition of mTOR in the amygdala or hippocampus around the time of learning or reactivation
Highlights
► Rapamycin impaired recognition memory when infused into the amygdala or hippocampus. ► Memory was also impaired by rapamycin given around the time of reactivation. ► mTOR in the amygdala and hippocampus regulates formation and stabilization of recognition memory.
Introduction
It is now well established that the basolateral complex of the amygdala (BLA) plays a crucial role in enhancing the formation of memories for emotionally arousing events (for a review, see [1]). Novel object recognition (NOR), a memory task based on the natural preference towards novel objects displayed by rodents, involves no explicit rewarding or aversive stimuli [2]. However, recent evidence indicates that formation of memory for NOR training under specific experimental conditions is modulated by stress hormones and noradrenergic activation of the BLA [3], [4], [5], [6]. The involvement of molecular processes including protein synthesis and intracellular signaling pathways within the BLA in NOR memory remains poorly understood.
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates cell growth and cell cycle progression by integrating signals from growth factors to influence the activity of downstream targets. mTOR is selectively inhibited by rapamycin (sirolimus), a naturally occurring macrolide derived from the soil bacterium Streptomyces hygroscopius mTOR (for reviews, see [7], [8], [9]). In the central nervous system, mTOR signaling, which acts as a central regulator of mRNA translation and protein synthesis, has been increasingly implicated in synaptic plasticity and memory formation [9]. Rapamycin injected systemically, or microinfused into selective brain areas including the BLA and the dorsal hippocampus (DH), has been shown to impair memory for fear conditioning when given around the time of acquisition (thus affecting memory formation) or reactivation (interfering with memory reconsolidation or long-term stabilization) [10], [11], [12], [13], [14], [15], [16]. We have recently shown that intra-BLA or intra-DH infusions of rapamycin inhibit formation and reconsolidation of long-term memory for inhibitory avoidance, a type of fear-motivated conditioning [14]. A previous study examining the role of mTOR in NOR memory found that rapamycin impaired retention when given into the DH within a limited time window after training, and could either impair reconsolidation or have no effect when given after reactivation, depending on specific training conditions [17]. However, previous studies have not verified whether mTOR in the BLA is involved in NOR memory. In the present study, we examined the effects of mTOR inhibition by rapamycin in the BLA before or after training or reactivation, on memory for NOR, and compared the effects of intra-BLA rapamycin with those obtained with intra-DH infusions.
Section snippets
Animals
Adult male Wistar rats (340–430 g at time of surgery) were obtained from the institutional breeding facility (CREAL, ICBS, UFRGS). Animals were housed five per cage in plastic cages with sawdust bedding, and maintained on a 12 h light/dark cycle at a room temperature of 22 ± 1 °C. The rats were allowed ad libitum access to standardized pellet food and water. All experiments took place between 9 AM and 6 PM. All experimental procedures were performed in accordance with the National Institutes of Health
Pre- or posttraining intra-BLA infusion of rapamycin impairs NOR memory retention
We first examined the effects of intra-BLA infusions of rapamycin on NOR memory. In the first experiment, rats were given NOR training and tested for retention 3 and 24 h later. Fifteen minutes before (pretraining infusions) training, vehicle or rapamycin was infused into the BLA. Rapamycin significantly impaired retention tested at 24 h (p < 0.05), but not at 3 h after training, compared to vehicle-injected controls (Fig. 1A). In the second experiment, rapamycin was infused immediately after
Discussion
Previous studies have indicated that NOR, generally considered a memory task that does not involve explicit emotional arousal, is regulated by stress hormones and BLA activation, particularly under conditions in which rats are not extensively habituated to the context before training. For example, consolidation of long-term memory for NOR is enhanced by systemic administration of adrenaline or glucocorticoids, as well as by intra-BLA infusion of noradrenaline after training, whereas
Conclusions
In conclusion, the present findings provide evidence that mTOR signaling in both the BLA and DH is required for consolidation of NOR memory. In addition, mTOR may play a role in reconsolidation-like processes or long-term stabilization of recognition memory. The findings support the view that signaling mechanisms involved in regulating protein synthesis, synaptic plasticity, and cell metabolism in the BLA modulate memory for low-arousing tasks.
Acknowledgments
This research was supported by the National Council for Scientific and Technological Development (CNPq) grant 303703/2009-1 to R.R.), National Institute for Translational Medicine (INCT-TM), Coordination for the Improvement of Higher Education Personnel (CAPES), HCPA institutional research fund (FIPE/HCPA), and the South American Office for Anticancer Drug Development.
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