Reiter RJ. The role of neurohormone melatonin as a buffer againstmacromolecular oxidative damage. Neurochem Int ; 27 6 : Melatonin in relation to cellular antioxidativedefense mechanisms.
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Bilateral infusion of SKF 7. In contrast, full retrograde amnesia was obtained when SCH 0. Intrahippocampal infusion of 8Br-cAMP 1. KT 0. Rats submitted to the avoidance task showed learning-specific increases in hippocampal 3 H-SCH binding and in the endogenous levels of cAMP 3 and 6 h after training. Memory is a temporally graded process during which new information becomes consolidated and stored 1 — 3. From mollusks to mammals, memory can be divided into at least two phases: a protein and RNA synthesis-independent phase that lasts minutes to 1—3 h short term memory and a protein and RNA synthesis-dependent component [long term memory LTM ] that lasts several hours to days, weeks, or even longer periods 4 — 7.
Taken together, these findings strongly suggest that cAMP-regulated pathways, via phosphorylation of CREB isoforms, are important for the long term consolidation of memories. This molecular switch depends on the functional ratio of CREB activators to blockers In this context, by using a one trial step-down inhibitory avoidance task in rats, we recently demonstrated that hippocampal cAMP appears to be crucial for consolidating the late phase of an aversive memory In remarkable parallel with memory, long term potentiation LTP , a long lasting activity-dependent mechanism of synaptic plasticity 16 , 17 , has been shown to possess also two components: an early transient phase that lasts less than 2—3 h and is resistant to inhibitors of protein synthesis, and a late, persistent component that requires both transcription and protein synthesis during a critical time window 17 — Postmortem histological controls of the cannula placements 28 — 30 showed that the injection tips were within 1.
Only the behavioral data from animals with the cannula located in the intended sites were used. Once recovered from surgery, animals were trained in a one-trial step down inhibitory avoidance task and tested for retention 24 h later 28 , Rats were placed on a 2.
Their latency to step down, placing their four paws on the grid, was measured. In training sessions, immediately upon stepping down, the rats received a 0. No foot shock was given in test sessions.
Test minus training session step down latencies to a ceiling of s were taken as a measure of retention. At the time of infusion, g cannulae were fitted into the guide cannula. The animals were gently withdrawn from the training apparatus, wrapped in a soft cloth left with their head out, and subjected to the infusion procedure. Handling was kept as gentle as possible to minimize stress. It is to be noted, however, that this was the same for all animals, vehicle or drug-treated.
The time between withdrawal of the animals from the training apparatus and the start of the first infusion was between 20 and 60 s. Infusions were performed immediately 0 h , 3, 6, or 9 h after training. The infusion cannula was connected to a microsyringe by a polyethylene tube. The tip of the infusion cannula protruded 1 mm beyond that of the guide cannulae and was therefore aimed at CA 1 in the dorsal hippocampus. The animals received bilateral 0. For all of the biochemical measurements, nonimplanted male Wistar rats weighing — g were divided into three groups: naive controls, killed immediately after withdrawal from their home cages; shocked animals, placed directly over the electrified grid, given a 2-s, 0.
Animals from the three groups were killed by decapitation at different time intervals after training. The autoradiograms were analyzed using a computerized microdensitometer mcid 4. Statistical analysis was performed using statistical software instat , Graph Pad, San Diego. The hippocampi were rapidly dissected out, placed in buffer sodium acetate 0. The pellet was discarded, and a radioimmunoassay was performed using the ligand I-cAMP 25,—28, cpm and an anti-cAMP antibody Sigma , according to the method of Domino et al.
Then, the tubes were centrifuged at rpm for 15 min, the supernatant was discarded, and the radioactivity in the pellet was counted. The resulting supernatants were collected and counted in liquid scintillator. After centrifugation at 2. Filters were dried and then counted by liquid scintillation. Quantitative densitometric analysis was performed using a computerized microdensitometer mcid 4.
Test session step down latency in the inhibitory avoidance, when either SKF or SCH was infused into the CA 1 region of the dorsal hippocampus, is depicted in Fig. Earlier work has shown that the early phase of memory formation of a one-trial stepdown avoidance task is associated with a learning-specific, time-dependent increase in both 3 H-AMPA binding to AMPA glutamate receptors and 3 H-phorbol dibutyrate binding to membrane-bound PKC in the hippocampus 26 , Effects of bilateral intrahippocampal infusion of 7.
Data are expressed as median interquartile range. Number of animals ranged between 10 and 12 per group. Confirming and extending recent findings from our laboratories 15 , the bilateral intrahippocampal infusion of the membrane-permeable analog of cAMP 8Br-cAMP; 1.
No changes in memory retention scores were observed when 8Br-cAMP was administered immediately or 9 h after training. In addition, we found that rats submitted to the avoidance learning showed a learning-specific, time-dependent increase in the endogenous levels of cAMP in the hippocampus Fig. These results suggest that cAMP signaling pathways in the hippocampus are important for the late, but not the early, posttraining phase of memory consolidation of this task.
Endogenous cAMP levels in the hippocampus of naive, shocked, or trained animals killed at different time intervals after training. To test whether these changes in hippocampal cAMP levels might be related to an increased breakdown of the cyclic nucleotide, we determined the activity of cAMP-dependent phosphodiesterase in hippocampal samples from naive, shocked, or trained rats To explore further the possibility that hippocampal cAMP signaling pathways are involved in the late phase of memory formation, we next examined the effect on inhibitory avoidance memory of forskolin, an activator of adenylyl cyclase, given into the CA 1 region at different time intervals after training Fig.
Forskolin 0. Effects of bilateral intrahippocampal infusion of vehicle or forskolin 0. Data are expressed as in Fig. Number of rats ranged between 9 and 12 per group. The effect of forskolin on memory consolidation was quite similar in both the nature and time course to those observed with SKF Fig. The activation of adenylyl cyclases leads to the dissociation of regulatory and catalytic subunits of PKA.
Only the free catalytic subunit is active. Therefore, to determine more directly the role of hippocampal PKA in memory of an avoidance learning, we next examined the effects of KT, a specific inhibitor of the catalytic subunit of PKA, on memory consolidation. The bilateral infusion of KT 0. No changes in test session latencies were observed when KT was administered 9 h after training.
These results are consistent with the effects of 8BrcAMP and forskolin on the late posttraining phase of memory consolidation. However, PKA activation in the hippocampus also appears to be required for the early phase of memory formation.
Effects of KT on memory of step down inhibitory avoidance learning in rats that received a bilateral infusion of vehicle or KT 0. If activation of hippocampal PKA were involved in memory consolidation, training rats in the avoidance task should probably cause an increase in PKA activity. We therefore carried out biochemical assays to measure directly the activity of PKA in hippocampal preparations from naive, shocked, and trained animals.
Shocked animals had similar values of PKA activity as naive controls. Effect of an inhibitory avoidance learning on hippocampal PKA activity. We have used a specific antibody against the activated, phosphorylated form of CREB 37 to show that acquisition and consolidation of an aversively motivated learning task induced the phosphorylation of CREB in CA 1 hippocampal neurons Fig. This effect appears to be learning-specific because no alteration in P-CREB immunoreactivity was found in shocked animals.
Quantitative densitometric analysis of the immunocytochemistry of P-CREB in CA 1 region of the dorsal hippocampus of naive, shocked, or trained rats. Memories are not acquired directly in their definitive form.
They are labile and can be modified in the period that follows acquisition. This is due to the influence of modulatory systems 1 — 3 , 24 , 25 , 39 , These modulatory systems regulate a process of consolidation, whereby memories are transformed from their initial labile into a later stable state.
Consolidation leads to storage: What becomes consolidated is stored. The hippocampus and related brain areas are mainly involved in the acquisition and consolidation of an inhibitory avoidance learning but apparently do not participate in the long term storage of memory 23 — The role of the hippocampus in the acquisition and consolidation of this task has been confirmed recently using reversible inactivation with tetrodotoxin We have shown that hippocampal ionotropic and metabotropic glutamate receptors 24 , CAMK II 30 , protein kinase C 26 , 28 , and retrograde messengers 25 , 29 are critically involved in the early within 1 h neural events responsible for the acquisition and consolidation of an inhibitory avoidance learning.
This is based on five series of data. Second, the intrahippocampal infusion of 8Br-cAMP provoked enhancement of memory only when given 3 or 6 h posttraining Fig. Fourth, rats submitted to the avoidance learning showed significant increases in hippocampal cAMP levels and PKA activity at the same time window observed in the behavioral experiments Fig. Taken together, these results strongly suggest that cAMP signal transduction pathways in the hippocampus are mainly involved in the late phase of memory consolidation.
Nonassociative learning in Aplysia , odor avoidance learning in Drosophila , and Pavlovian conditioning and spatial learning in mice have provided strong evidence that the activation of the CREB family of transcriptional factors is a necessary step for the establishment of LTM 8 — As a corollary, these data, taken together with those found in the present study, suggest that, even though different forms of learning probably activate different distributed neuronal pathways, the molecular mechanism for the storage of LTM may be conserved.
Both D 1 and D 5 receptors stimulate adenylyl cyclase However, the involvement of other hippocampal modulatory neurotransmission that might contribute to the late phase of memory consolidation cannot be ruled out Earlier work has shown that the dopaminergic system participates in learning and memory.
Using a foot shock-motivated brightness discrimination task in rats, Grekch and Matthies 45 found that the intrahippocampal infusion of the nonspecific dopaminergic agonist apomorphine improves memory, whereas haloperidol, a nonspecific dopamine receptor antagonist, impairs memory consolidation.
Moreover, posttraining i. In accordance, we found that inhibitory avoidance in rats provoked a learning-specific, time-dependent increase in 3 H-SCH binding in the hippocampus. This learning-induced change occurred 3 and 6 h posttraining, the same critical period when SKF and SCH modulate memory consolidation. Consistent with Hebbian models of learning and memory 16 , 17 , 23 and in remarkable parallel with the present findings, cAMP signaling pathways participate in the late phase of LTP in several regions of the hippocampus 18 , Thus, our results may be taken to further endorse the hypothesis that LTP in the hippocampus underlies memory processes 24 , A dopamine-independent, PKA-mediated mechanism may be also required in the immediate early phase of memory formation in the hippocampus.
The amnestic effect of the PKA inhibitor when given 0 h posttraining Fig. These findings are consistent with previous results in Drosophila , showing that cAMP signaling pathways also are important for the acquisition and the early phase of memory processing 14 , In this context, it has been postulated recently that, in the early phase of LTP, the cAMP signaling pathway functions as a gate to modulate the establishment of LTP The early peak of increased P-CREB immunoreactivity coincides with a small but significant increase in PKA activity observed immediately after training.
Esteróides - Anabolizantes no Esporte
2002, Número 1
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