Behavioral tagging is a general mechanism of long-term memory formation

Abstract

In daily life, memories are intertwined events. Little is known about the mechanisms involved in their interactions. Using two hippocampus-dependent (spatial object recognition and contextual fear conditioning) and one hippocampus-independent (conditioned taste aversion) learning tasks, we show that in rats subjected to weak training protocols that induce solely short term memory (STM), long term memory (LTM) is promoted and formed only if training sessions took place in contingence with a novel, but not familiar, experience occurring during a critical time window around training. This process requires newly synthesized proteins induced by novelty and reveals a general mechanism of LTM formation that begins with the setting of a "learning tag" established by a weak training. These findings represent the first comprehensive set of evidences indicating the existence of a behavioral tagging process that in analogy to the synaptic tagging and capture process, need the creation of a transient, protein synthesis-independent, and input specific tag.

Fig. 1.

Spatial novelty promotes SOR-LTM in a protein synthesis-dependent manner. A–E show the percentage of exploration time as mean ± SEM. (A) Animals explored the arena for 4 min. Independent groups of rats were tested at 30 min (STM, n = 13) or 24 h (LTM, n = 15) after training. ***, P < 0.001 vs. training, Student's t test. (B) Control animals (n = 20) received 4 min SOR training. Animals in the OF group were exposed to a novel OF 240, 120, or 60 min before (n = 15, 17, and 17, respectively) or 0, 15, 60, 120, or 240 min after (n = 15, 20, 15, 18, and 15, respectively) SOR training. In the group + 0′, animals explore the OF immediately after the SOR training. **, P < 0.01 vs. control, Dunnet test after one-way ANOVA. (C) Animals were subjected, or not (Control, n = 20), to a novel (n = 18) or familiar (n = 15) OF 1 h after a 4 min SOR training and LTM was tested 24 h later. **, P < 0.01 vs. Control and Fam test sessions, Newman-Keuls after one-way ANOVA. (D) Animals were subjected, or not (Control, n = 20), to a novel OF 15 min after a 4 min SOR training. Experimental groups received intra-CA1 infusions of vehicle (Nov + Veh, n = 17) or anisomycin (Nov + Ani, n = 15) immediately after OF. **, P < 0.01 vs. all groups in test sessions, Newman-Keuls after one-way ANOVA. (E) Rats were tested 24 h after a weak SOR training in the absence (Control, n = 8) or in the presence of OF 1 h before training. Experimental groups received intra-CA1 infusions of vehicle (Nov + Veh, n = 8) or anisomycin (Nov + Ani, n = 7) 15 min before training. **, P < 0.01 vs. Control test session, Newman-Keuls after one-way ANOVA.

Fig. 2.

Spatial novelty promotes CFC-LTM in a protein synthesis-dependent manner. All data is expressed as mean ± SEM. (A) Animals received a weak training and were tested 15 min (STM, n = 7) or 24 h (LTM, n = 7) after the training session. ***, P < 0.001 vs. all groups, Newman-Keuls after one-way ANOVA (Basal, n = 7). (B) Animals were subjected, or not (Control, n = 13), to a novel (n = 13) or familiar (n = 13) OF 1 h before a weak CFC training. ***, P < 0.001 vs. all groups, Newman-Keuls after one-way ANOVA (Basal, n = 15). (C) Animals were subjected, or not (Control, n = 13), to a novel OF 1 h before a weak CFC training. Experimental groups received intra-CA1 infusions of vehicle (Nov + Veh, n = 11) or anisomycin (Nov + Ani, n = 11) immediately post-OF. ***, P < 0.001 vs. all groups, Newman-Keuls after one-way ANOVA (Basal, n = 11).

Fig. 3.

Novel taste promotes CTA-LTM in a protein synthesis-dependent manner. Saccharin consumption in the test session is expressed as mean percentage ± SEM relative to acquisition session (A) Animals were subjected to a weak CTA training session and memory was tested 30 min (STM, n = 15) or 72 h (LTM, n = 24) after acquisition. ***, P < 0.001 Student's t test. (B) Animals were subjected to a weak CTA training and LTM was tested. Rats in the novel taste groups drank 10 mL of NaCl 0.3% at 60 or 30 min before (n = 10 and 8) or 0, 30, 60, or 150 min after (n = 10, 12, 8, and 18, respectively) saccharin intake. In the group + 0′, animals drank NaCl immediately after the saccharin intake. *, P < 0.05 vs. Control, Dunnet test after one-way ANOVA. (C) Animals were subjected to a weak CTA training and LTM was tested. (Left) Animals drank, or not (Control, n = 13), a novel (n = 9) or familiar (n = 10) NaCl (0.3%) taste 1 h before saccharin intake. *, P < 0.05 vs. all groups, Newman-Keuls after one-way ANOVA. (Right) All groups received intra-insular cortex infusion of vehicle (n = 12) or anisomycin (n = 12) 75 min before saccharin intake. Half of them also drank a novel taste 60 min before drinking the saccharin solution. *, P < 0.05 vs. all groups, Newman-Keuls after one-way ANOVA.

Fig. 4.

Novelty promotes LTM in specific inputs: regional and temporal requirements. (A) Saccharin consumption in the test session is expressed as mean percentage ± SEM relative to acquisition session. (Left) Animals were subjected to a weak CTA training session and exposed to a novel OF 60 min before or 150 min after saccharin intake (n = 8 and 12). Control animals (n = 13) did not explore the arena. P > 0.05, one-way ANOVA. (Right) Animals were subjected to a weak CTA training and drank, or not (Control, n = 13), NaCl (0.3%) (n = 11) or water (H₂O, n = 7) 150 min after saccharin intake. *, P < 0.05 vs. all groups, Newman-Keuls after one-way ANOVA. (B) Rats were deprived of water for 24 h and then habituated to drink water from a graduated tube twice a day for 2 days. The next day animals received a 4 min SOR training 1 h after the consumption of water (H₂O, n = 9), a novel taste (NaCl, n = 8) or the exposure to a novel open field (OF, n = 8). Control rats did not drink water (n = 8). SOR-LTM was tested 24 h after training. Exploration time is expressed as mean ± SEM. ***, P < 0.001 vs. all test sessions, Newman-Keuls after one-way ANOVA. (C) Rats were trained with two consecutive (3-h spaced) weak SOR tasks, using two different pair of identical objects at different position. 24-h later half of the animals were tested for SOR-LTM, changing the position of one object of the pair 1 (Control Pair 1, n = 8) and the rest changing one of the pair 2 (Control Pair 2, n = 7). Exploration time is expressed in percentage of mean ± SEM. P > 0.05, one-way ANOVA. Separate groups were trained as above but 1-h before they were exposed to a novel OF. Again, one group of rats was tested for pair 1 SOR- LTM (OF + Pair 1, n = 7) and the other for pair 2 (OF + Pair 2, n = 7). *, P < 0.05, vs. all groups; Newman-Keuls after one-way ANOVA.