Abstract
Understanding how stored information emerges is a main question in the neurobiology of memory that is now increasingly gaining attention. However, molecular events underlying this memory stage, including involvement of protein synthesis, are not well defined. Mammalian target of rapamycin complex 1 (mTORC1), a central regulator of protein synthesis, has been implicated in synaptic plasticity and is required for memory formation. Using inhibitory avoidance (IA), we evaluated the role of mTORC1 in memory retrieval. Infusion of a selective mTORC1 inhibitor, rapamycin, into the dorsal hippocampus 15 or 40 min but not 3 h before testing at 24 h reversibly disrupted memory expression even in animals that had already expressed IA memory. Emetine, a general protein synthesis inhibitor, provoked a similar impairment. mTORC1 inhibition did not interfere with short-term memory retrieval. When infused before test at 7 or 14 but not at 28 days after training, rapamycin impaired memory expression. mTORC1 blockade in retrosplenial cortex, another structure required for IA memory, also impaired memory retention. In addition, pretest intrahippocampal rapamycin infusion impaired object location memory retrieval. Our results support the idea that ongoing protein synthesis mediated by activation of mTORC1 pathway is necessary for long but not for short term memory.
Highlights
Understanding how stored information emerges is a main question in the neurobiology of memory that is increasingly gaining attention
The drawings were adapted from Paxinos and Watson48. (b) Intrahippocampal rapamycin (Rapa) infusion 15 min before test (TS) session carried out 24 h after training (TR) impairs inhibitory avoidance long term memory (IA-long-term memories (LTM)) retrieval. **p < 0.01, vehicle (Veh) vs. Rapa group and Rapa vs. reTS, one-way ANOVA followed by NewmanKeuls Comparison Test, n = 5-6
Confirming and extending recent findings in auditory fear memory retrieval using intraamygdala infusions of PSIs11, we found that intrahippocampal infusions (Fig. 1a) of two different types of protein synthesis inhibitor (PSI), emetine or rapa, 15 min before an IA TS session performed 24 h post training greatly impaired the expression of IA LTM (Fig. 1b, p < 0.01, rapa compared to vehicle rats, Newman-Keuls Comparison Test after one-way ANOVA, n = 5–6 and Fig. 1c, p < 0.05, eme compared to veh rats, Student’s t Test, n = 7–8)
Summary
Understanding how stored information emerges is a main question in the neurobiology of memory that is increasingly gaining attention. A body of evidence suggest that long-term memories (LTM) rely on functional and structural changes at synapses, as Ramón y Cajal had proposed more than a century ago[1,2,3] Neurons and their synapses that are reactivated when the animals are demanded to retrieve are believed to be those that have been changed through the molecular processes that underlie memory formation[1,4]. Nader and coworkers[11] recently found that pretest intramygdala infusion of anisomycin or rapamycin (rapa), a specific mTORC1 inhibitor, impaired auditory fear memory retrieval These findings suggest that ongoing protein synthesis induced by mTORC1 pathway is required in the amygdala to enable memory retrieval. (b) Intrahippocampal rapamycin (Rapa) infusion 15 min before test (TS) session carried out 24 h after training (TR) impairs inhibitory avoidance long term memory (IA-LTM) retrieval. Data are expressed as mean ± SEM of TR or TS session step-down latency
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