Nature © Macmillan Publishers Ltd 19988 T he formation of long-term memory takes several hours 1-3 , during which time memories rely on short-term systems 1,2,4,5 . For over 100 years 1 , the main unanswered question of memory research has been whether short-term memory is a necessary step towards long-term memory 4,5 , or whether they are separate processes 1,2 . Here we report four treatments that block shortterm memory while leaving long-term memory intact, showing that these memory systems are separate to some degree.The treatments we used here all alter longterm memory when infused into the CA1 subregion of the hippocampus or the entorhinal cortex of rats that have been trained to perform certain behaviours 6-8 . These treatments were the glutamate AMPA (Ȋ-amino-3hydroxy-5-methyl-4-isoxazole propionic acid) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 0.5 Ȗg), the GABA A (ȍ-aminobutyric acid type A) receptor agonist muscimol (MUS, 0.5Ȗg), the serotonin 1A receptor agonist 8-hydroxy-2-(di-npropylamino) tetralin (DPAT, 2.5 Ȗg) and the serotonin 1A receptor antagonist 1-(2methoxyphenyl)-4-(4-(2-phthalimido)) butylpiperazine (NAN, 2.5 Ȗg).We implanted 30-gauge guides bilaterally 1 mm above the dorsal CA1 region of the hippocampus (A ǁ4.3, L DŽ4.0, V 3.4) or 1 mm above the surface of the entorhinal cortex (A ǁ7.0, L DŽ5.0, V 8.4) of Wistar rats (240-300 g) under deep thionembutal anaesthesia; stereotaxic coordinates are given in millimetres according to ref. 9. After recovery, the rats were placed on a platform that was 25 cm high and 7 cm wide. This platform faced a 43 ǂ25 cm grid of stainless steel bars, spaced 1.0 cm apart and of 0.1 cm in width. The platform was used for inhibitory avoidance training. We measured how quickly the rats stepped down onto the grid with all four paws. Once on the grid, the rats received a scrambled electric shock to their paws of 0.3 mA for 1 second. They immediately received bilateral infusions of 0.5 Ȗl saline, a vehicle (20% dimethylsulphoxide) or a drug. MUS and DPAT were dissolved in saline, and CNQX and NAN were dissolved in the vehicle. Infusion cannulae protruded 1.0 mm beyond the guides. Infusion procedures and verification of cannula placement were performed as described 6-8 .There were two main experiments. In the first, animals were tested twice to see whether they had retained the memory of the electric shock: once at 1.5 hours after training, to measure short-term memory, and once at 24 hours after training, to measure longterm memory (Fig. 1a, b). In the second experiment, we tested the animals 1.5, 3.0 and 4.5 hours after training (Fig. 1c, d). Test sessions for both experiments were as above, except that the foot-shock was omitted (so we were measuring how long it took for rats to step down to the grid, and we used this time as a measurement of their memory of the shock). We stopped measuring the time taken to step down to the grid after 180 seconds 6-8 . This required the use of nonparametric statistics 7,8 .When given into the CA1 subregion of t...

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From mollusks to mammals the activation of cAMP response element-binding protein (CREB) appears to be an important step in the formation of long-term memory (LTM). Here we show that a 5 min exposure to a novel environment (open field) 1 hr after acquisition of a one-trial inhibitory avoidance training hinders both the formation of LTM for the avoidance task and the increase in the phosphorylation state of hippocampal Ser 133 CREB [phosphorylated CREB (pCREB)] associated with the avoidance training. To determine whether this LTM deficit is attributable to the reduced pCREB level, rats were bilaterally cannulated to deliver Sp-adenosine 3', 5'-cyclic monophosphothioate (Sp-cAMPS), an activator of PKA. Infusion of Sp-Adenosine 3',5'-cyclic monophosphothioate Sp-cAMPS to CA1 region increased hippocampal pCREB levels and restored normal LTM of avoidance learning in rats exposed to novelty. Moreover, a 5 min exposure to the open field 10 min before the avoidance training interferes with the amnesic effect of a second 5 min exposure to the open field 1 hr after avoidance training and restores the hippocampal levels of pCREB. In contrast, the avoidance training-associated activation of extracellular signal-regulated kinases (p42 and p44 mitogen-activated protein kinases) in the hippocampus is not altered by novelty. Together, these findings suggest that novelty regulates LTM formation by modulating the phosphorylation state of CREB in the hippocampus.

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