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Relevance of Synaptic Tagging and Capture to the Persistence of Long-Term Potentiation and Everyday Spatial Memory

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Relevance of Synaptic Tagging and Capture to the Persistence of Long-Term Potentiation and Everyday Spatial Memory Relevance of synaptic tagging and capture to the persistence of long-term potentiation and everyday spatial memory Szu-Han Wang, Roger L. Redondo, and Richard G. M. Morris1 Centre for Cognitive and Neural Systems, Neuroscience, University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom Edited* by Richard D. Palmiter, University of Washington, Seattle, WA, and approved September 21, 2010 (received for review June 22, 2010) Memory for inconsequential events fades, unless these happen generally forgotten each day. This is a closer analogy to everyday before or after other novel or surprising events. However, our memory in humans than many current behavioral tasks studied in understanding of the neurobiological mechanisms of novelty- animals, and is likely subserved by temporary engrams mediated by enhanced memory persistence is mainly restricted to aversive or distributed associative potentiation in the hippocampus. fear-associated memories. We now outline an “everyday appetitive” Interestingly, unrelated novelty or surprise may stabilize the behavioral model to examine whether and how unrelated novelty persistence of memories, even for inconsequential events that facilitates the persistence of spatial memory coupled to parallel elec- are normally forgotten. An example of this is the curious halo of “fl ” trophysiological studies of the persistence of long-term potentiation incidental memories surrounding ashbulb memories (10, 11), (LTP). Across successive days, rats were given one trial per day to find such as what happened to us on the occasion of momentous food in different places and later had to recall that day’s location. events such as the terrorist attacks in 2001 in the 9/11 tragedy. It This task is both hippocampus and NMDA receptor dependent. has recently been reported that memory for inhibitory avoidance First, encoding with low reward induced place memory that decayed by rats can also persist longer if exploration in a novel environ- ment occurs around the time of learning (12). Similar findings over 24 h; in parallel, weak tetanization of CA1 synapses in brain have been shown for contextual fear conditioning, spatial object slices induced early-LTP fading to baseline. Second, novelty explora- recognition and taste memory (13, 14). tion scheduled 30 min after this weak encoding resulted in persistent To further explore the relevance of STC, we conducted parallel NEUROSCIENCE place memory; similarly, strong tetanization—analogous to novelty — behavioral and physiological studies. We occasionally scheduled both induced late-LTP and rescued early- into late-LTP on an inde- brief unrelated novelty exploration to evaluate its impact on pendent but convergent pathway. Third, hippocampal dopamine memory of individual subjects across successive conditions. Nov- D1/D5 receptor blockade or protein synthesis inhibition within 15 elty exploration is known increase the firing of VTA dopamine min of exploration prevented persistent place memory and blocked neurons (15), hippocampal dopamine release (16) and the tran- late-LTP. Fourth, symmetrically, when spatial memory was encoded scription of a number of activity-related genes (17) and so, like using strong reward, this memory persisted for 24 h unless encoding strong tetanization, may induce the PRPs that the STC hypothesis occurred under hippocampal D1/D5 receptor blockade. Novelty ex- asserts as critical for memory persistence. The continuity of ex- ploration before this encoding rescued the drug-induced memory perience, memory and then forgetting through the day is similar to impairment. Parallel effects were observed in LTP. These findings what happens with activity-dependent synaptic plasticity in vivo can be explained by the synaptic tagging and capture hypothesis. that is presumably triggered frequently (18) and for which protein synthesis-independent and protein synthesis-dependent mecha- hippocampus | flashbulb memory | synaptic plasticity | dopamine | protein nisms are variously engaged (19). This commonality is the basis of synthesis our conducting parallel studies. Results eurobiological theories of long-term memory (LTM) assert Nthat strong events are remembered better than weak because The rats were trained in an event arena to dig for food pellets that they alone trigger “consolidation.” However, the memory of ap- they carried back to the start boxes to eat (Fig. S1). The regular parently unimportant things is an intriguing challenge to these daily training consisted of a memory encoding trial and a later re- accounts—particularly when these occur in association with sur- trieval choice trial. In encoding, the start box door opened allowing prising or emotionally significant events. The synaptic tagging and entry into the arena containing a single sandwell (with one or three capture (STC) hypothesis of protein synthesis-dependent long- food pellets) at a changing place each day. This trial constituted an term potentiation (1, 2) may offer an explanation of this associative opportunity to incidentally encode where food was available on – process, based on the idea that the neural mechanisms of initial that day. In retrieval, 30 40 min after encoding, the same sandwell long-term potentiation (LTP) expression (potentiation and tag- again contained food (three pellets), but there were now four other ging) can be dissociated from those regulating the availability of nonrewarded sandwells available (exacting controls for olfactory plasticity-related proteins (PRPs) that stabilize synaptic change. cues are given in SI Materials and Methods). The animal could use Thus, weakly induced LTP that is normally transient is sustained one-trial place memory from the earlier encoding trial to retrieve fi because PRPs associated with strong LTP on a separate pathway ef ciently. The main study began once the animals were routinely are captured by the synaptic tags set on the weakly tetanized making one error or fewer per retrieval trial. There followed “ ” pathway. As synaptic plasticity may be one component of the neural a series of separate conditions conducted over 6 months con- mechanisms of information storage (3–6), the persistence of memory should parallel the persistence of synaptic potentiation (7). An important characteristic of ‘everyday memory’ is that we Author contributions: S.-H.W., R.L.R., and R.G.M.M. designed research; S.-H.W. and R.L.R. retain incidental information within LTM for only a short period, performed research; S.-H.W. and R.L.R. contributed new reagents/analytic tools; S.-H.W., rarely creating an enduring memory (e.g., where we parked our car R.L.R., and R.G.M.M. analyzed data; and S.-H.W., R.L.R., and R.G.M.M. wrote the paper. when out shopping). To model this kind of episodic-like memory, The authors declare no conflict of interest. we have developed an analogous one-trial spatial memory task in *This Direct Submission article had a prearranged editor. an ‘event arena’ that depends on synaptic transmission and plas- 1To whom correspondence should be addressed. E-mail: [email protected]. ticity in the dorsal hippocampus (8, 9). The protocol continues This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. everyday for months, with a new spatial memory encoded and 1073/pnas.1008638107/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1008638107 PNAS Early Edition | 1of6 Downloaded by guest on October 1, 2021 sisting of analogous electrophysiological and behavioral compo- Condition 2: Novelty-Enhanced Persistence of Weak Memory. We nents. Performance stability is shown in Fig. S2. then investigated whether unexpected novelty exploration would affect the persistence of memory. In the parallel electrophysiology Condition 1: Decay of Early-LTP (E-LTP) and Weak Memory. Electro- study, we weakly tetanized one pathway (S1) and, 30 min later, physiological studies of synaptic tagging and capture (STC) were applied strong tetanization (“novelty”) to a separate pathway, S2 conducted in hippocampal brain slices using the methods of (Fig. 2 A and B). This is theoretically appropriate as behavioral Redondo et al. (20). We first examined the induction of LTP by novelty and strong tetanization both up-regulate immediate early weak tetanization in brain slices (Fig. 1 A and B). This caused LTP genes, necessary for PRP synthesis/availability; we return to on an input pathway to CA1 at 30 min posttetanus that declined to a justification of this in the discussion. Strong tetanization not only baseline over 10 h with statistically significant decay over this period. led to 10-h LTP in S2, i.e., late-LTP (L-LTP), but also rescued the The analogous “event arena” study evaluated retention, at 30 transient decay of E-LTP on S1, converting it to nondecaying L- min or 24 h, of one-trial place memory rewarded by one food LTP. This replicates a key phenomenon of STC (21). pellet only at encoding (weak encoding). We used a memory In the behavioral experiments, the same animals used in probe test in which five nonrewarded sandwells were presented condition 1 (above) were given a weak encoding trial followed by for 60 s with time spent digging at each sandwell recorded. The a probe test 24 h later, with or without (in counterbalanced or- order of the 30-min and the 24-h encoding-probe test pairs was der) the opportunity for 5-min novelty exploration in a box counterbalanced, interleaved by 1 regular training day. This in- placed within the arena 30 min after encoding (Fig. S1C and Fig. terleaved training, used throughout the study, was essential to 2C). Without exploration, there was the usual indifferent place sustain digging at the sandwells across days, as probe tests con- memory, whereas with exploration, memory was persistent (Fig. fi stituted extinction trials. There was good memory at 30 min but 2 D and E). Taken together, these ndings show that strong not at 24 h, with significant decay between 30 min and 24 h (Fig. tetanization/novelty can enhance the persistence of LTP/memory 1D). Of note is the directly analogous “pattern” of the electro- for an unrelated pathway/experience.
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