RESUMO
The ability to retrieve contextual fear memories depends on the coordinated activation of a brain-wide circuitry. Transition from recent to remote memories seems to involve the reorganization of this circuitry, a process called systems consolidation that has been associated with time-dependent fear generalization. However, it is unknown whether emotional memories acquired under different stress levels can undergo different systems consolidation processes. Here, we explored the activation pattern and functional connectivity of key brain regions associated with contextual fear conditioning (CFC) retrieval after recent (2 days) or remote (28 days) memory tests performed in rats submitted to strong (1.0 mA footshock) or mild (0.3 mA footshock) training. We used brain tissue from Wistar rats from a previous study, where we observed that increasing training intensity promotes fear memory generalization over time, possibly due to an increase in corticosterone (CORT) levels during memory consolidation. Analysis of Fos expression across 8 regions of interest (ROIs) allowed us to identify coactivation between them at both timepoints following memory recall. Our results showed that strong CFC elicits higher Fos activation in the anterior insular and prelimbic cortices during remote retrieval, which was positively correlated with freezing along with the basolateral amygdala. Rats trained either with mild or strong CFC showed broad functional connectivity at the recent timepoint whereas only animals submitted to the strong CFC showed a widespread loss of coactivation during remote retrieval. Post-training plasma CORT levels are positively correlated with FOS expression during recent retrieval in strong CFC, but negatively correlated with FOS expression during remote retrieval in mild CFC. Our findings suggest that increasing training intensity results in differential processes of systems consolidation, possibly associated with increased post-training CORT release, and that strong CFC engages activity from the aIC, BLA and PrL - areas associated with the Salience Network in rats - during remote retrieval.
RESUMO
Overgeneralized fear has long been implicated in generalized anxiety and post-traumatic stress disorder, however, time-dependent mechanisms underlying memory retrieval are still not completely understood. Previous studies have revealed that stronger fear conditioning training protocols are associated with both increased post-training corticosterone (CORT) levels and fear responses at later retrieval tests. Here we used contextual fear conditioning (CFC) to investigate the relationship between post-training CORT levels and memory specificity in different retrieval timepoints. Wistar rats were exposed to CFC training with increasing footshock intensities (0.3, 0.6 or 1.0mA) and had their blood collected 30 min afterwards to measure post-training plasma CORT. After 2, 14 or 28 days, rats were tested for memory specificity either in the training or in the novel context. Regression analysis was used to verify linear and non-linear interactions between CORT levels and freezing. Higher footshock intensities increased post-training CORT levels and freezing times during tests in all timepoints. Moreover, stronger trainings elicited faster memory generalization, which was associated with higher CORT levels during memory consolidation. The 0.3mA training maintained memory specificity up to 28 days. Additionally, linear regressions suggest that the shift from specific to generalized memories is underway at 14 days after training. These results are consistent with the hypotheses that stronger training protocols elicit a faster generalization rate, and that this process is associated with increased post-training CORT release.
Assuntos
Condicionamento Psicológico/fisiologia , Corticosterona/metabolismo , Eletrochoque/psicologia , Medo/psicologia , Memória/fisiologia , Animais , Condicionamento Clássico/fisiologia , Corticosterona/sangue , Eletrochoque/efeitos adversos , Pé , Masculino , Consolidação da Memória/fisiologia , Ratos , Ratos Wistar , Fatores de TempoRESUMO
It is well established that corticosterone (CORT) enhances memory consolidation of emotionally arousing experiences. Despite emotional memories being usually referred to as well remembered for long periods, there are no studies that have investigated the effects of CORT in modulating the duration and specificity of memory. In the present study, we trained Wistar rats in a single-trial contextual fear conditioning protocol and injected CORT (0.3, 1.0 or 3.0mg/kg), immediately after training, to investigate its effects on memory consolidation. Rats were tested 2 and 29days after the training session or only 29days after training to assess recent or remote memory. Our results show that animals tested for recent memory discriminated the training context from a novel one, while those tested only for remote memory generalized the fear response to both contexts. Animals tested for remote memory after being tested for recent memory were able to discriminate both contexts. These results support the literature regarding memory specificity and duration. However, CORT treatment, even at the dose of 1.0mg/kg that effectively enhanced the plasmatic hormone levels, did not affect the strength or the specificity of memory in either recent or remote memory tests. We hypothesize that the lack of effect of CORT treatment could be due to the low arousing training experience of the single-trial protocol which, despite being sufficient to induce significant recent and remote memory consolidation, may not be sufficient to allow the memory-enhancing effect of CORT.
Assuntos
Anti-Inflamatórios/administração & dosagem , Condicionamento Clássico/efeitos dos fármacos , Corticosterona/administração & dosagem , Medo/efeitos dos fármacos , Memória de Longo Prazo/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Análise de Variância , Animais , Anti-Inflamatórios/sangue , Corticosterona/sangue , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Wistar , Fatores de TempoRESUMO
STUDY OBJECTIVES: Evaluation of modafinil effects on the inhibitory avoidance task (IA). DESIGN: Rats were trained on a multiple trial IA task after receiving modafinil or vehicle injections. In experiment 1 they were trained with a weak protocol under baseline condition and in experiment 2, with a stronger protocol under sleep-deprivation condition. RESULTS: In experiment 1 modafinil improved rats' acquisition whereas the retention test remained unaffected. In Experiment 2 modafinil did not interfere with training performance, but the lower dose prevented the retention impairment in sleep-deprived animals. CONCLUSIONS: Modafinil is able to improve acquisition in normal rats and reverse the long-term memory impairment induced by sleep-deprivation.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Compostos Benzidrílicos/farmacologia , Transtornos da Memória/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Privação do Sono/complicações , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Transtornos da Memória/etiologia , Modafinila , Ratos , Ratos WistarRESUMO
A number of studies have suggested that the glutamatergic and cholinergic systems are both involved in learning and memory processes and that they interact in order to facilitate these processes. However, the role of M1-muscarinic receptors in mediating this interaction has not been elucidated. The aim of this study was to determine whether the concomitant administration of MK-801 (non-competitive NMDA antagonist) and dicyclomine (M1-muscarinic antagonist--DIC) in sub-effective doses impairs contextual fear conditioning (hippocampal-dependent task) and tone fear conditioning tasks (hippocampal-independent task). The results showed that concomitant pre-training administration of DIC (8.0 mg/kg) and MK-801 (0.07 mg/kg)--two sub-effectives doses for the contextual fear conditioning task--does impair the performance of animals on this task (as measured by freezing behavior time). Tone fear conditioning tasks were not affected by the drugs either administered separately or concurrently. The pre-training administration of sub-effective doses of MK-801 and DIC in combination impairs performance on contextual fear conditioning task (hippocampal-dependent), but not on tone fear conditioning task (hippocampal-independent). These data support the hypothesis that the interaction between glutamatergic and cholinergic systems in hippocampus-dependent learning and memory processes probably occurs through M1 receptor.
Assuntos
Condicionamento Clássico , Diciclomina/farmacologia , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Medo , Antagonistas Muscarínicos/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Diciclomina/metabolismo , Maleato de Dizocilpina/metabolismo , Antagonistas de Aminoácidos Excitatórios/metabolismo , Medo/efeitos dos fármacos , Medo/fisiologia , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Masculino , Antagonistas Muscarínicos/metabolismo , N-Metilaspartato/metabolismo , Ratos , Ratos Wistar , Receptor Muscarínico M1/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
The objective of the present study was to observe the effects of pre-training or post-training administration of dicyclomine, a M1 muscarinic antagonist, on inhibitory avoidance (IA) and contextual fear conditioning (CFC) and to investigate if the effects observed with the pre-training administration of dicyclomine are state-dependent. For each behavioral procedure (IA and CFC) groups of Wistar male rats were treated with saline or dicyclomine either 30 min before training (pre-training), immediately after training or 30 min before training/30 min before test (pre-training/pre-test). The animals were tested 24 h after training. The acquisition of IA and CFC was impaired by pre-training administration of dicyclomine. The consolidation of both tasks was not affected by dicyclomine given immediately after training. Pre-training/pre-test administration of dicyclomine impaired both tasks, an effect similar to that observed in the group which only received pre-training administration. Pre-test treatment induced dissociation between both tasks, impairing CFC retrieval, without interfering with the animals avoidance response. These results show that the dicyclomine did not affect IA and CFC consolidation, suggesting specific involvement of M1 muscarinic receptor only in acquisition these tasks, and these effects was not state-dependent. However, it is possible that the retrieval of these tasks may be mediated, at least in part, by different neurochemical mechanisms and may be dissociated by dicyclomine.