Novelty processing can transform short-term into long-term memory. We propose that this memory-reinforcing effect of novelty could be explained by mechanisms outlined in the "synaptic tagging hypothesis." Initial short-term memory is sustained by a transient plasticity change at activated synapses and sets synaptic tags. These tags are later able to capture and process the plasticity-related proteins (PRPs), which are required to transform a short-term synaptic change into a long-term one. Novelty is involved in inducing the synthesis of PRPs [Moncada D, et al. (2011) Proc Natl Acad Sci USA 108:12937-12936], which are then captured by the tagged synapses, consolidating memory. In contrast to novelty, stress can impair learning, memory, and synaptic plasticity. Here, we address questions as to whether noveltyinduced PRPs are able to prevent the loss of memory caused by stress and if the latter would not interact with the tag-setting process. We used water-maze (WM) training as a spatial learning paradigm to test our hypothesis. Stress was induced by a strong foot shock (FS; 5 × 1 mA, 2 s) applied 5 min after WM training. Our data show that FS reduced long-term but not short-term memory in the WM paradigm. This negative effect on memory consolidation was time-and trainingdependent. Interestingly, novelty exposure prevented the stress-induced memory loss of the spatial task and increased BDNF and Arc expression. This rescuing effect was blocked by anisomycin, suggesting that WM-tagged synapses were not reset by FS and were thus able to capture the novelty-induced PRPs, re-establishing FS-impaired long-term memory. memory rescue | memory reinforcement | novelty exploration L earning and memory are important to survive in a changing environment and use a limited, predetermined neural subset to integrate various stimuli. Memory formation includes widespread brain regions and consists of sequential and parallel events that define memory phases (1-4). Underlying mechanisms are based on the activation of preexisting proteins during an early, labile phase (short-term memory, STM) and the synthesis of new proteins for a late, stable phase (long-term memory, LTM) (1, 5). These cellular processes can be activated by a single experience or by two independent, temporally coupled events. Similar mechanisms seem to be involved in long-term potentiation (LTP), a model of synaptic plasticity and cellular memory. Thus, motivation and emotion can reinforce a normally transient, early LTP (E-LTP) into a prolonged, late-LTP (L-LTP), a phenomenon known as behavioral LTP-reinforcement (3). Novelty exploration in an open field (OF) can also effectively reinforce LTP (6). Behavioral LTP-reinforcement is protein synthesis-dependent (7) and basolateral amygdala-stimulation mimics the reinforcing effects of distinct behavioral stimuli (8, 9). LTP reinforcement by behavioral stimuli has been explained by the synaptic-tagging hypothesis (STH) (3). According to this theory, LTP-induction results not only in transient modifications of synaptic e...