RESUMO
Memory storage is a temporally graded process involving different phases and different structures in the mammalian brain. Cortical plasticity is essential to store stable memories, but little is known regarding its involvement in memory processing. Here we show that fear memory consolidation requires early post-training macromolecular synthesis in the anterior part of the retrosplenial cortex (aRSC), and that reversible pharmacological inactivation of this cortical region impairs recall of recent as well as of remote memories. These results challenge the generally accepted idea that neocortical areas are slow encoding systems that participate in the retrieval of remote memories only.
Assuntos
Córtex Cerebral/fisiologia , Medo/psicologia , Hipocampo/fisiologia , Substâncias Macromoleculares/metabolismo , Memória de Curto Prazo/fisiologia , Rememoração Mental/fisiologia , Animais , Anisomicina/farmacologia , Córtex Cerebral/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Inibidores da Síntese de Proteínas/farmacologia , RatosRESUMO
The retrosplenial cortex (RSC) is involved in a range of cognitive functions. However, its precise involvement in memory processing is unknown. Pharmacological and behavioral experiments demonstrate that protein synthesis and c-Fos expression in the anterior part of RSC (aRSC) are necessary late after training to maintain for many days a fear-motivated memory. Long-lasting memory storage is regulated by D1/D5 dopamine receptors in aRSC and depends on the functional interplay between dorsal hippocampus and aRSC. These results suggest that the RSC recapitulates some of the molecular events that occur in the hippocampus to maintain memory trace over time.
Assuntos
Córtex Cerebral/fisiologia , Memória de Longo Prazo/fisiologia , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Análise de Variância , Animais , Anisomicina/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Benzazepinas/farmacologia , Córtex Cerebral/efeitos dos fármacos , Dopaminérgicos/farmacologia , Eletrochoque/efeitos adversos , Emetina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Memória de Longo Prazo/efeitos dos fármacos , Oligonucleotídeos Antissenso/farmacologia , Inibidores da Síntese de Proteínas/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Fatores de TempoRESUMO
Although much is known about long-term memory (LTM) consolidation, what puts the "long" in LTM is the exclusive feature of persisting over time. However, until recently the molecular mechanisms underneath memory persistence had never been properly studied. In rats, the protein translation inhibitor anisomycin impaired memory persistence when injected into the dorsal hippocampus 12 h after inhibitory avoidance (IA) training without affecting memory formation. Here, we also show learning-induced changes in hippocampal c-Fos, Homer 1a, Akt, CamKIIα, and ERK2 levels around 18-24 h after IA training. Thus, memory persistence is associated with a late phase of plasticity-related protein synthesis in the hippocampus.
Assuntos
Química Encefálica/fisiologia , Hipocampo/fisiologia , Memória de Longo Prazo/fisiologia , Biossíntese de Proteínas/fisiologia , Animais , Aprendizagem da Esquiva/fisiologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/química , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/fisiologia , Hipocampo/química , Humanos , Proteína Quinase 1 Ativada por Mitógeno/química , Proteína Quinase 1 Ativada por Mitógeno/fisiologia , Plasticidade Neuronal/fisiologia , Fatores de TempoRESUMO
Memory formation is a temporally graded process during which transcription and translation steps are required in the first hours after acquisition. Although persistence is a key characteristic of memory storage, its mechanisms are scarcely characterized. Here, we show that long-lasting but not short-lived inhibitory avoidance long-term memory is associated with a delayed expression of c-Fos in the hippocampus. Importantly, this late wave of c-Fos is necessary for maintenance of inhibitory avoidance long-term storage. Moreover, inhibition of transcription in the dorsal hippocampus 24 h after training hinders persistence but not formation of long-term storage. These findings indicate that a delayed phase of transcription is essential for maintenance of a hippocampus-dependent memory trace. Our results support the hypothesis that recurrent rounds of consolidation-like events take place late after learning in the dorsal hippocampus to maintain memories.
Assuntos
Hipocampo , Memória/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Animais , Aprendizagem da Esquiva/fisiologia , Condicionamento Clássico , Hipocampo/anatomia & histologia , Hipocampo/metabolismo , Hipocampo/fisiologia , Masculino , Biossíntese de Proteínas , Proteínas Proto-Oncogênicas c-fos/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Transcrição GênicaRESUMO
BACKGROUND: The mammalian target of Rapamycin (mTOR) kinase plays a key role in translational control of a subset of mRNAs through regulation of its initiation step. In neurons, mTOR is present at the synaptic region, where it modulates the activity-dependent expression of locally-translated proteins independently of mRNA synthesis. Indeed, mTOR is necessary for different forms of synaptic plasticity and long-term memory (LTM) formation. However, little is known about the time course of mTOR activation and the extracellular signals governing this process or the identity of the proteins whose translation is regulated by this kinase, during mnemonic processing. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that consolidation of inhibitory avoidance (IA) LTM entails mTOR activation in the dorsal hippocampus at the moment of and 3 h after training and is associated with a rapid and rapamycin-sensitive increase in AMPA receptor GluR1 subunit expression, which was also blocked by intra-hippocampal delivery of GluR1 antisense oligonucleotides (ASO). In addition, we found that pre- or post-training administration of function-blocking anti-BDNF antibodies into dorsal CA1 hampered IA LTM retention, abolished the learning-induced biphasic activation of mTOR and its readout, p70S6K and blocked GluR1 expression, indicating that BDNF is an upstream factor controlling mTOR signaling during fear-memory consolidation. Interestingly, BDNF ASO hindered LTM retention only when given into dorsal CA1 1 h after but not 2 h before training, suggesting that BDNF controls the biphasic requirement of mTOR during LTM consolidation through different mechanisms: an early one involving BDNF already available at the moment of training, and a late one, happening around 3 h post-training that needs de novo synthesis of this neurotrophin. CONCLUSIONS/SIGNIFICANCE: IN CONCLUSION, OUR FINDINGS DEMONSTRATE THAT: 1) mTOR-mediated mRNA translation is required for memory consolidation during at least two restricted time windows; 2) this kinase acts downstream BDNF in the hippocampus and; 3) it controls the increase of synaptic GluR1 necessary for memory consolidation.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Memória , Proteínas Quinases/metabolismo , Receptores de AMPA/metabolismo , Animais , Hipocampo/metabolismo , Masculino , Modelos Biológicos , Plasticidade Neuronal , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Sinapses/patologia , Serina-Treonina Quinases TOR , Fatores de TempoRESUMO
Persistence is a characteristic attribute of long-term memories (LTMs). However, little is known about the molecular mechanisms that mediate this process. We recently showed that persistence of LTM requires a late protein synthesis- and BDNF-dependent phase in the hippocampus. Here, we show that intrahippocampal delivery of BDNF reverses the deficit in memory persistence caused by inhibition of hippocampal protein synthesis. Importantly, we demonstrate that BDNF induces memory persistence by itself, transforming a nonlasting LTM trace into a persistent one in an ERK-dependent manner. Thus, BDNF is not only necessary, but sufficient to induce a late postacquisition phase in the hippocampus essential for persistence of LTM storage.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/farmacologia , Memória/efeitos dos fármacos , Animais , Ativação Enzimática/efeitos dos fármacos , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Ratos , Ratos Wistar , Fatores de TempoRESUMO
It is widely accepted that the formation of long-term memory (LTM) requires mRNA translation, but little is known about the cellular mechanisms in the brain that regulate this process. Mammalian target of rapamycin (mTOR) is a key regulator of translational efficacy and capacity. Here, we show that LTM formation of one-trial inhibitory avoidance (IA) in rats, a hippocampus-dependent fear-motivated learning task, requires mTOR activation. IA training is specifically associated with a rapid increase in the phosphorylation state of mTOR and its substrate ribosomal S6 kinase (p70S6K). Bilateral intra-CA1 infusion of rapamycin, a selective mTOR inhibitor, 15 min before, but not immediately after training completely hinders IA LTM without affecting short-term memory (STM) retention. Therefore, our findings indicate that the regulation of hippocampal mRNA translation is a major control step in memory consolidation.