RESUMO
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 novelty-induced 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 training-dependent. 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.
Assuntos
Eletrochoque , Comportamento Exploratório , Pé/patologia , Transtornos da Memória/fisiopatologia , Memória/fisiologia , Sinapses/metabolismo , Animais , Regulação da Expressão Gênica , Masculino , Aprendizagem em Labirinto , Biossíntese de Proteínas , Ratos , Ratos Wistar , Fatores de TempoRESUMO
Long-term memory (LTM) consolidation requires the synthesis of plasticity-related proteins (PRPs). In addition, we have shown recently that LTM formation also requires the setting of a "learning tag" able to capture those PRPs. Weak training, which results only in short-term memory, can set a tag to use PRPs derived from a temporal-spatial closely related event to promote LTM formation. Here, we studied the involvement of glutamatergic, dopaminergic, and noradrenergic inputs on the setting of an inhibitory avoidance (IA) learning tag and the synthesis of PRPs. Rats explored an open field (PRP donor) followed by weak (tag inducer) or strong (tag inducer plus PRP donor) IA training. Throughout pharmacological interventions around open-field and/or IA sessions, we found that hippocampal dopamine D1/D5- and ß-adrenergic receptors are specifically required to induce PRP synthesis. Moreover, activation of the glutamatergic NMDA receptors is required for setting the learning tags, and this machinery further required α-Ca(2+)/calmodulin-dependent protein kinase II and PKA but not ERK1/2 activity. Together, the present findings emphasize an essential role of the induction of PRPs and learning tags for LTM formation. The existence of only the PRP or the tag was insufficient for stabilization of the mnemonic trace.
Assuntos
Aprendizagem da Esquiva/fisiologia , Memória de Longo Prazo/fisiologia , Memória de Curto Prazo/fisiologia , Plasticidade Neuronal/fisiologia , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Benzazepinas/farmacologia , Região CA1 Hipocampal/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Dobutamina/farmacologia , Inibidores Enzimáticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Comportamento Exploratório/fisiologia , Masculino , Memória de Longo Prazo/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Propranolol/farmacologia , Ratos , Ratos Wistar , Receptores Adrenérgicos beta/metabolismo , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D5/antagonistas & inibidores , Receptores de Dopamina D5/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Affective factors importantly interact with behavior and memory. Physiological mechanisms that underlie such interactions are objects of intensive studies. This involves the direct investigation of its relevance to understand learning and memory formation as well as the search for possibilities to treat memory disorders. The prolonged maintenance of long-term potentiation (LTP) - a cellular model for memory formation - is characterized by neuromodulatory, associative requirements. During the last years, we have delineated a neural system that may be responsible for affective-cognitive interactions at the cellular level. The stimulation of the basolateral amygdala (BLA), within an effective, associative time window, reinforces a normally transient, protein synthesis-independent early-LTP (less than 4-6h) into a long-lasting, protein synthesis-dependent late-LTP in the dentate gyrus (DG) in freely moving rats (Frey et al., 2001 [12]). LTP reinforcement by stimulation of the BLA was mediated by cholinergic projection of the medial septum to the DG, and the noradrenergic projection from the locus coeruleus (Bergado et al., 2007 [2]). We were now interested to investigate a possible interaction of the nucleus raphe medialis (NRM) with DG-LTP. Although, NRM stimulation resulted in a depressing effect on basal synaptic transmission, we did not observe any interactions with early-LTP or with the BLA-DG LTP-reinforcement system.
Assuntos
Tonsila do Cerebelo/fisiologia , Giro Denteado/fisiologia , Potenciação de Longa Duração , Núcleos da Rafe/fisiologia , Reforço Psicológico , Transmissão Sináptica , Animais , Estimulação Elétrica , Masculino , Ratos , Ratos WistarRESUMO
Transient long-term potentiation (E-LTP) can be transformed into a long-lasting LTP (L-LTP) in the dentate gyrus (DG) by behavioral stimuli with high motivational content. Previous research from our group has identified several brain structures, such as the basolateral amygdala (BLA), the locus coeruleus (LC), the medial septum (MS) and transmitters as noradrenaline (NA) and acetylcholine (ACh) that are involved in these processes. Here we have investigated the functional interplay among brain structures and systems which result in the conversion of a E-LTP into a L-LTP (reinforcement) by stimulation of the BLA (BLA-R). We used topical application of specific drugs into DG, and other targets, while following the time course of LTP induced by stimulation of the perforant pathway (PP) to study their specific contribution to BLA-R. One injection cannula, a recording electrode in the DG and stimulating electrodes in the PP and the BLA were stereotactically implanted one week before electrophysiological experiments. Topical application of atropine or propranolol into the DG blocked BLA-R in both cases, but the effect of propranolol occurred earlier, suggesting a role of NA within the DG during an intermediate stage of LTP maintenance. The injection of lidocaine into the LC abolished BLA-R indicating that the LC is part of the functional neural reinforcing system. The effect on the LC is mediated by cholinergic afferents because application of atropine into the LC produced the same effect. Injection of lidocaine inactivating the MS also abolished BLA-R. This effect was mediated by noradrenergic afferents (probably from the LC) because the application of propranolol into the MS prevented BLA-R. These findings suggest a functional loop for BLA-R involving cholinergic afferents to the LC, a noradrenergic projection from the LC to the DG and the MS, and finally, the cholinergic projection from the MS to the DG.
Assuntos
Acetilcolina/metabolismo , Tonsila do Cerebelo/fisiologia , Potenciação de Longa Duração/fisiologia , Vias Neurais/fisiologia , Neurônios Aferentes/metabolismo , Norepinefrina/metabolismo , Análise de Variância , Animais , Fibras Colinérgicas/metabolismo , Giro Denteado/fisiologia , Locus Cerúleo/fisiologia , Masculino , Memória/fisiologia , Plasticidade Neuronal/fisiologia , Ratos , Ratos Wistar , Reforço Psicológico , Septo do Cérebro/fisiologia , Fatores de TempoRESUMO
Growing evidence suggests that processes of synaptic plasticity, such as long-term potentiation (LTP) occurring in one synaptic population, can be modulated by consolidating afferents from other brain structures. We have previously shown that an early-LTP lasting less than 4 h (E-LTP) in the dentate gyrus can be prolonged by stimulating the basolateral amygdala, the septum or the locus coeruleus within a specific time window. Pharmacological experiments have suggested that noradregeneric (NE) and/or cholinergic systems might be involved in these effects. We have therefore investigated whether the direct intraventricular application of agonists for NE- or muscarinic receptors is able to modulate synaptic plasticity. E-LTP was induced at the dentate gyrus of freely moving rats using a mild tetanization protocol that induces only an E-LTP. NE or oxotremorine (OXO) were applied icv 10 min after the tetanus. Results show that low doses of NE (1.5 and 5 nM) effectively prolong LTP. A higher dose (50 nM) was not effective. None of the OXO doses employed (5, 25, and 50 nM) showed similar effects. These results stress the importance of transmitter-specific modulatory influences on the time course of synaptic plasticity, in particular NE whose application mimics the reinforcing effect of directly stimulating limbic structures on LTP.
Assuntos
Giro Denteado/fisiologia , Potenciação de Longa Duração/fisiologia , Norepinefrina/administração & dosagem , Oxotremorina/administração & dosagem , Reforço Psicológico , Análise de Variância , Animais , Giro Denteado/efeitos dos fármacos , Relação Dose-Resposta a Droga , Estimulação Elétrica , Injeções Intraventriculares , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Agonistas Muscarínicos/administração & dosagem , Norepinefrina/fisiologia , Ratos , Ratos Sprague-Dawley , Estatísticas não ParamétricasRESUMO
A transient, protein synthesis-independent long-term potentiation (early-LTP, <4 h) can be reinforced into a maintained protein synthesis-dependent late-LTP (>4 h) by specific electrical stimulation of limbic structures (J. Neurosci. 21 (2001) 3697). Similarly, LTP-modulation can be obtained by behavioral stimuli with strong motivational content. However, the requirement of protein synthesis during behavioral reinforcement has not been shown so far. Thus, we have studied here this specific question using a behavioral reinforcement protocol, i.e. allowing water-deprived animals to drink 15 min after induction of early-LTP. This procedure transformed early-LTP into late-LTP. Anisomycin, a reversible protein synthesis inhibitor, abolished behavioral LTP-reinforcement. These results demonstrate that behavioral reinforcement depends on protein synthesis.