RESUMO
Memories are stored into long-term representations through a process that depends on protein synthesis. However, a consolidated memory is not static and inflexible and can be reactivated under certain circumstances, the retrieval is able to reactivate memories and destabilize them engaging a process of restabilization known as reconsolidation. Although the molecular mechanisms that mediate fear memory reconsolidation are not entirely known, so here we investigated the molecular mechanisms in the hippocampus involved in contextual fear conditioning memory (CFC) reconsolidation in male Wistar rats. We demonstrated that the blockade of Src family kinases (SFKs), GluN2B-containing NMDA receptors and TrkB receptors (TrkBR) in the CA1 region of the hippocampus immediately after the reactivation session impaired contextual fear memory reconsolidation. These impairments were blocked by the neurotrophin BDNF and the NMDAR agonist, D-Serine. Considering that the study of the link between synaptic proteins is crucial for understanding memory processes, targeting the reconsolidation process may provide new ways of disrupting maladaptive memories, such as those seen in post-traumatic stress disorder. Here we provide new insights into the cellular mechanisms involved in contextual fear memory reconsolidation, demonstrating that SFKs, GluN2B-containing NMDAR, and TrkBR are necessary for the reconsolidation process. Our findings suggest a link between BDNF and SFKs and GluN2B-containing NMDAR as well as a link between NMDAR and SFKs and TrkBR in fear memory reconsolidation. These preliminary pharmacological findings provide new evidence of the mechanisms involved in the reconsolidation of fear memory and have the potential to contribute to the development of treatments for psychiatric disorders involving maladaptive memories.
Assuntos
Receptores de N-Metil-D-Aspartato , Quinases da Família src , Animais , Masculino , Ratos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Medo/fisiologia , Hipocampo/metabolismo , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Quinases da Família src/metabolismoRESUMO
Wnt proteins activate different signaling pathways, such as the canonical Wnt/ß-catenin signaling pathway and non-canonical ß-catenin-independent signaling pathway and have been related to several functions in central nervous system, including learning and memory. However, whether these signaling pathways are required in the medial prefrontal cortex (mPFC) for fear memory acquisition, consolidation and retrieval remains unclear. To address this question, we submitted male rats to a contextual fear conditioning (CFC) paradigm, and administered canonical Wnt/ß-catenin and non-canonical Wnt/Ca2+ signaling pathways inhibitors, DKK1 and SFRP1, respectively, into the prelimbic (PrL) subdivision of the mPFC at different moments and evaluated short-term and long-term memory acquisition, consolidation and retrieval. We found that blocking canonical Wnt/ß-catenin and non-canonical Wnt/Ca2+ signaling pathways 15 min before or immediately after CFC training had no effect on STM and LTM of CFC, while their blockade 15 min before the retention test prevented the retrieval of STM and LTM of CFC. These results highlight the importance of the mPFC in fear memory retrieval demonstrating that both canonical Wnt/ß-catenin and non-canonical Wnt/Ca2+ signaling pathways participate in this process. To understand how brain systems act on fear memories could provide a new target for the treatment of fear related disorders such as post-traumatic stress disorder and other anxiety disorders.
Assuntos
Medo , beta Catenina , Animais , Cálcio/metabolismo , Medo/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Memória/fisiologia , Córtex Pré-Frontal/metabolismo , Ratos , Via de Sinalização Wnt , beta Catenina/metabolismoRESUMO
Growing evidence indicates that brain carbonic anhydrases (CAs) are key modulators in cognition, particularly in recognition and aversive memories. Here we described a role for these enzymes also in social recognition memory (SRM), defined as the ability to identify and recognize a conspecific, a process that is of paramount importance in gregarious species, such as rodents and humans. Male adult Wistar rats were submitted to a social discrimination task and, immediately after the sample phase, received bilateral infusions of vehicle, the CAs activator D-phenylalanine (D-Phen, 50 nmols/side), the CAs inhibitor acetazolamide (ACTZ; 10 nmols/side) or the combination of D-Phen and ACTZ directly in the CA1 region of the dorsal hippocampus or in the medial prefrontal cortex (mPFC). Animals were tested 30 min (short-term memory) or 24 h later (long-term memory). We found that inhibition of CAs with infusion of ACTZ either in the CA1 or in the mPFC impaired short-term SRM and that this effect was completely abolished by the combined infusion of D-Phen and ACTZ. We also found that activation of CAs with D-Phen facilitated the consolidation of long-term SRM in the mPFC but not in CA1. Finally, we show that activation of CAs in CA1 and in the mPFC enhances the persistence of SRM for up to 7 days. In both cases, the co-infusion of ACTZ fully prevented D-Phen-induced procognitive effects. These results suggest that CAs are key modulators of SRM and unveil a differential involvement of these enzymes in the mPFC and CA1 on memory consolidation.
Assuntos
Anidrases Carbônicas , Hipocampo , Córtex Pré-Frontal , Reconhecimento Psicológico , Animais , Anidrases Carbônicas/fisiologia , Hipocampo/fisiologia , Masculino , Córtex Pré-Frontal/fisiologia , Ratos , Ratos Wistar , Reconhecimento Psicológico/fisiologiaRESUMO
Antioxidant supplementation and physical exercise have been discussed as strategies to minimize neurodegeneration in Alzheimer's disease (AD). We investigated the neuroprotective effects of strength exercise (StrEx) and green tea (GT) supplementation, combined or not, on memory impairments induced by ß-amyloid characterizing an AD-like condition in rats. Wistar rats were submitted to 8 weeks of StrEx, GT supplementation, or StrEx and GT combined. AD-like condition was induced by injection of Aß (25-35) in the hippocampus. We evaluate object recognition (OR) and social recognition (SR) memory, and removed the rats' hippocampus for biochemical analysis. StrEx improved OR and SR. StrEx combined with GT improved OR and did not improve SR. GT reduced antioxidant capacity and improved acetylcholinesterase activity. Both strength exercise and green tea are neuroprotective against impairments resultant of ß-amyloid, but benefits do not add up when the two interventions are associated.
Assuntos
Doença de Alzheimer , Fármacos Neuroprotetores , Treinamento Resistido , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/metabolismo , Animais , Modelos Animais de Doenças , Hipocampo/metabolismo , Humanos , Transtornos da Memória/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo , Fragmentos de Peptídeos/farmacologia , Ratos , Ratos Wistar , CháRESUMO
BACKGROUND: Intentionality to remember is associated with better performances in episodic memory retrieval. The practice effect has better performance in memory retrieval. However, little is known about the effect of intentionality on memory over days and the influence of age, gender, and level of education on it as well as on practice effect. OBJECTIVES: To verify the effect of intentionality and practice effect on memory performance over days, using an ecological approach. METHODS: One hundred and twenty subjects from 18 to 81 years of age and free of psychiatric and neurological disorders were evaluated. They were randomized into a "testing effect group" and a "intentionality group" and then were asked to read a text on the FIFA World Cup. The "intentionality group" was instructed to pay careful attention to the text because they would answer a questionnaire with 10 factual items from the text after 2 and 7 days. The "testing effect group" had the same procedure at the same time as the first group but were not instructed about the intentionality, and answered the questionnaire immediately after reading the text. RESULTS: Memory performance was better 2 days after the exposure session than 7 days later in the "intentionality group". On the other hand, there was no difference in memory performance from the "testing effect group" 2 and 7 days later. CONCLUSIONS: Intention to recall may enhance memory over a short period of days, while retaining similar amount of information over days to what was acquired immediately after text exposure.
INTRODUÇÃO: A intencionalidade de lembrar associa-se a melhores desempenhos na recuperação da memória episódica. O efeito da prática também apresenta melhores desempenhos na recuperação da memória. Entretanto, pouco se sabe sobre a intencionalidade na memória ao longo dos dias sob influência da idade, sexo e escolaridade, assim como sob efeito da prática. OBJETIVOS: Verificar o efeito da intencionalidade e de testes no desempenho da memória ao longo dos dias, utilizando abordagem ecológica. MÉTODOS: Foram avaliados 120 sujeitos (idade 18-81 anos) e a ausência de distúrbios psiquiátricos e neurológicos. Eles foram randomizados para o "grupo de efeito de testes" ou para o "grupo de intencionalidade" e expostos ao texto da Copa do Mundo de Futebol. O "grupo de intencionalidade" foi instruído a prestar muita atenção ao texto, pois seria aplicado um questionário com 10 itens factuais do texto 2 e 7 dias depois. O "grupo de efeito de testes" realizou o mesmo procedimento no mesmo tempo que o primeiro grupo, mas não foi instruído em relação à intencionalidade e responderam ao questionário imediatamente após a leitura do texto. RESULTADOS: O desempenho da memória foi melhor 2 dias após a exposição do que 7 dias depois no "grupo de intencionalidade". Por outro lado, não houve diferença no desempenho de memória no "grupo de efeito de testes" 2 e 7 dias depois. CONCLUSÕES: A intenção de recordar pode melhorar a memória por um curto período de dias. Enquanto o efeito de teste pode reter ao longo de dias quantidade similar de informação que foi adquirida imediatamente após a exposição do texto.
RESUMO
ABSTRACT Background: Intentionality to remember is associated with better performances in episodic memory retrieval. The practice effect has better performance in memory retrieval. However, little is known about the effect of intentionality on memory over days and the influence of age, gender, and level of education on it as well as on practice effect. Objectives: To verify the effect of intentionality and practice effect on memory performance over days, using an ecological approach. Methods: One hundred and twenty subjects from 18 to 81 years of age and free of psychiatric and neurological disorders were evaluated. They were randomized into a "testing effect group" and a "intentionality group" and then were asked to read a text on the FIFA World Cup. The "intentionality group" was instructed to pay careful attention to the text because they would answer a questionnaire with 10 factual items from the text after 2 and 7 days. The "testing effect group" had the same procedure at the same time as the first group but were not instructed about the intentionality, and answered the questionnaire immediately after reading the text. Results: Memory performance was better 2 days after the exposure session than 7 days later in the "intentionality group". On the other hand, there was no difference in memory performance from the "testing effect group" 2 and 7 days later. Conclusions: Intention to recall may enhance memory over a short period of days, while retaining similar amount of information over days to what was acquired immediately after text exposure.
RESUMO Introdução: A intencionalidade de lembrar associa-se a melhores desempenhos na recuperação da memória episódica. O efeito da prática também apresenta melhores desempenhos na recuperação da memória. Entretanto, pouco se sabe sobre a intencionalidade na memória ao longo dos dias sob influência da idade, sexo e escolaridade, assim como sob efeito da prática. Objetivos: Verificar o efeito da intencionalidade e de testes no desempenho da memória ao longo dos dias, utilizando abordagem ecológica. Métodos: Foram avaliados 120 sujeitos (idade 18-81 anos) e a ausência de distúrbios psiquiátricos e neurológicos. Eles foram randomizados para o "grupo de efeito de testes" ou para o "grupo de intencionalidade" e expostos ao texto da Copa do Mundo de Futebol. O "grupo de intencionalidade" foi instruído a prestar muita atenção ao texto, pois seria aplicado um questionário com 10 itens factuais do texto 2 e 7 dias depois. O "grupo de efeito de testes" realizou o mesmo procedimento no mesmo tempo que o primeiro grupo, mas não foi instruído em relação à intencionalidade e responderam ao questionário imediatamente após a leitura do texto. Resultados: O desempenho da memória foi melhor 2 dias após a exposição do que 7 dias depois no "grupo de intencionalidade". Por outro lado, não houve diferença no desempenho de memória no "grupo de efeito de testes" 2 e 7 dias depois. Conclusões: A intenção de recordar pode melhorar a memória por um curto período de dias. Enquanto o efeito de teste pode reter ao longo de dias quantidade similar de informação que foi adquirida imediatamente após a exposição do texto.
Assuntos
Humanos , Envelhecimento , Cognição , Intenção , Memória Episódica , AprendizagemRESUMO
Carbonic anhydrases (CAs; EC 4.2.1.1) are metalloenzymes present in mammals with 16 isoforms that differ in terms of catalytic activity as well as cellular and tissue distribution. CAs catalyze the conversion of CO2 to bicarbonate and protons and are involved in various physiological processes, including learning and memory. Here we report that the integrity of CA activity in the brain is necessary for the consolidation of fear extinction memory. We found that systemic administration of acetazolamide, a CA inhibitor, immediately after the extinction session dose-dependently impaired the consolidation of fear extinction memory of rats trained in contextual fear conditioning. d-phenylalanine, a CA activator, displayed an opposite action, whereas C18, a membrane-impermeable CA inhibitor that is unable to reach the brain tissue, had no effect. Simultaneous administration of acetazolamide fully prevented the procognitive effects of d-phenylalanine. Whereas d-phenylalanine potentiated extinction, acetazolamide impaired extinction also when infused locally into the ventromedial prefrontal cortex, basolateral amygdala, or hippocampal CA1 region. No effects were observed when acetazolamide or d-phenylalanine was infused locally into the substantia nigra pars compacta. Moreover, systemic administration of acetazolamide immediately after the extinction training session modulated c-Fos expression on a retention test in the ventromedial prefrontal cortex of rats trained in contextual fear conditioning. These findings reveal that the engagement of CAs in some brain regions is essential for providing the brain with the resilience necessary to ensure the consolidation of extinction of emotionally salient events.
Assuntos
Anidrases Carbônicas/metabolismo , Medo/fisiologia , Memória/fisiologia , Animais , Complexo Nuclear Basolateral da Amígdala/fisiologia , Região CA1 Hipocampal/fisiologia , Emoções , Aprendizagem , Masculino , Camundongos , Córtex Pré-Frontal/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos WistarRESUMO
Previously we demonstrated that a single physical exercise session promotes the persistence of object recognition (OR) memory and this effect involves the activation of the noradrenergic system. Here, using adult male Wistar rats (3 months old) we confirm that an aerobic single physical exercise session (30 min of treadmill running at an intensity of 60-70 % of indirect VO2 max.) after OR learning promotes memory persistence. We also demonstrate that this effect involves the dopaminergic system, since it is blocked when a D1-family receptor antagonist (SCH-23390, 1µg/µl) is infused into the hippocampus after the physical exercise session. Additionally, through HPLC experiments we demonstrate that a physical exercise session increases the hippocampal dopamine levels. Taken together, our results demonstrate that acute post-learning physical exercise is able to promote the persistence of OR memory, inducing the release of dopamine in hippocampus, which is necessary for the modulation of memory persistence. This work brings new evidences on the benefit of a single physical exercise session to memory, as well as suggests that catecholaminergic mechanisms are behind this effect.
Assuntos
Comportamento Animal/fisiologia , Antagonistas de Dopamina/farmacologia , Hipocampo/metabolismo , Condicionamento Físico Animal/fisiologia , Receptores de Dopamina D1/antagonistas & inibidores , Reconhecimento Psicológico/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Benzazepinas/farmacologia , Antagonistas de Dopamina/administração & dosagem , Hipocampo/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacosRESUMO
Social recognition memory (SRM) enables the distinction between familiar and strange conspecifics, a fundamental ability for sociable species, such as rodents and humans. There is mounting evidence that the medial prefrontal cortex plays a prominent role both in shaping social behavior and in recognition memory. Glutamate is the major excitatory neurotransmitter in the brain, and activity of its ionotropic receptors is known to mediate both synaptic plasticity and consolidation of various types of memories. However, whether these receptors are required in the medial prefrontal cortex (mPFC) for SRM consolidation remains elusive. To address this issue, we submitted rats to a social discrimination paradigm, administered infusions of NMDA- and AMPA/kainate-receptors antagonists into the prelimbic (PrL) subdivision of the mPFC at different post-encoding time points and evaluated long-term memory retention twenty-four hours later. We found that blocking NMDA receptors immediately after the sample phase, but not 3 h later, impaired SRM consolidation, whereas the blockade of AMPA/kainate receptors immediately and 3 h, but not 6 h after the sample phase, prevented long-term memory consolidation. These results highlight the importance of the mPFC in social cognition and may contribute towards the understanding of the dysfunctional social information processing that underlies multiple neuropsychiatric disorders.
Assuntos
Consolidação da Memória/fisiologia , Córtex Pré-Frontal/fisiologia , Receptores Ionotrópicos de Glutamato/fisiologia , Reconhecimento Psicológico/fisiologia , Percepção Social , Animais , Discriminação Psicológica , Masculino , Ratos Wistar , Receptores de AMPA/fisiologia , Receptores de Ácido Caínico/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologiaRESUMO
Fear memory has an essential role on animal's survival once it induces defensive behavior in response to threats. Among other factors, social support is known to down-regulate the expression of fear conditioned response, representing an important modulator of fear memories. Here we studied the effects of social support during acquisition, retrieval and extinction of contextual fear conditioning (CFC) memory in rats, by exposing the animals to the CFC task either in the absence or in the presence of a conspecific during the training, extinction and/or test sessions. The presence of a conspecific during the training session of CFC resulted in impairment to memory retention as verified in the short- and long-term memory test, suggesting that social support exerts a suppressive effect on the acquisition of CFC. On retrieval, social support decreased the expression of the conditioned fear response - as also seen in the extinction session. Nevertheless, the animals were able to learn the extinction memory as verified in the retention test. Therefore, this study demonstrates the effects of social support at crucial moments in CFC: impairing memory acquisition and favoring its extinction, by reducing the expression of the conditioned fear response with no impairment to the extinction learning.
Assuntos
Extinção Psicológica , Medo/fisiologia , Memória de Longo Prazo/fisiologia , Memória de Curto Prazo/fisiologia , Apoio Social , Animais , Comportamento Animal/fisiologia , Masculino , Ratos , Ratos WistarRESUMO
Extinction is the learned inhibition of retrieval. It is the mainstay of exposure therapy, which is widely used to treat drug addiction, phobias and fear-related pathologies such as post-traumatic stress disorder. The serotonin (5-HT) system is positioned to modulate the extinction circuitry via ascending 5-HT projections that innervate certain brain structures including the hippocampus and the basolateral amygdala (BLA). The most recently described serotoninergic receptors 5-HT5A, 5-HT6, 5-HT7 affect different memory processes and so are putative therapeutic targets for disorders related to cognition; however, their role in the extinction of contextual fear conditioning (CFC) has not been studied yet. Here we investigate the role of these receptors in the CA1 region of the hippocampus and the BLA in the extinction of CFC. For this, male rats were implanted with cannulae in the CA1 or in the BLA region through which they received immediately or 3 h after extinction training of CFC infusions of SB699551 (10 µg/side), 5-HT5A antagonist; WAY-208466 (0.04 µg/side), 5-HT6 agonist; SB-271046A (10 µg/side), 5-HT6 antagonist; AS-19 (5 µg/side), 5-HT7 agonist; SB-269970 (5 µg/side), 5-HT7 antagonist. After 24 h, animals were submitted to a 3 min extinction test. Results show that the infusion immediately after extinction training of 5-HT5A, 5-HT6 and 5-HT7 antagonists, and 3 h after extinction training of 5-HT5A and 5-HT7 antagonists in the BLA region, but not in CA1, facilitates the extinction of CFC memory.
Assuntos
Extinção Psicológica/fisiologia , Medo/fisiologia , Receptores de Serotonina/fisiologia , Tonsila do Cerebelo/fisiologia , Animais , Complexo Nuclear Basolateral da Amígdala/fisiologia , Encéfalo/fisiologia , Condicionamento Clássico/fisiologia , Medo/psicologia , Hipocampo/fisiologia , Masculino , Memória/fisiologia , Ratos , Ratos Wistar , Receptores de Serotonina/metabolismoRESUMO
The generalization of aversive memory can be defined as the phenomenon in which a situation similar to (but distinctive from) a previous aversive event triggers an avoidance response. This phenomenon has been suggested to play a role in several psychological disorders. In this study, we investigate the effects of novelty on the generalization of fear memories, and the involvement of noradrenergic and dopaminergic systems in this process. For this study we used male Wistar rats (3 months old, 300-400â¯g). The participation of each neurotransmitter system was evaluated separately (two set of experiments). In each experimental set, the animals were divided in groups (8 animals each): (i) control, (ii) novelty, and, (iii) antagonistâ¯+â¯novelty group (timolol, a ß-adrenergic antagonist, or SCH23390, a D1/D5 dopaminergic antagonist, in the first and in the second set of experiments, respectively). Additionaly, to investigate whether novelty exposure increases the levels of noradrenaline and/or dopamine in the hippocampus fifteen animals were divided in three groups (5 animals each).: (i) naïve, (ii) control; and, (iii) novelty. To examine aversive memory, and generalization of aversive memory, we trained adult male Wistar rats in an inhibitory avoidance (IA) memory task and after in a modified inhibitory avoidance (MIA). Before the MIA training some of the animals were exposed to environmental novelty (open field). Immediately before this novelty exposure, some animals received intrahippocampal infusion of timolol (ß-adrenergic antagonist), SCH23390 (D1/D5 antagonist) or vehicle to evaluate the involvement of noradrenergic and dopaminergic systems. Finally, to evaluate aversive memory and generalization of aversive memory respectively, half of the animals in each group were tested on IA and half on MIA. We confirmed that the exposure to novelty blocks the generalization of aversive memory, but moreover, demonstrated that this process involves activation of ß-adrenergic and dopaminergic D1/D5 pathways. We additionally observed that exposure to novelty raises hippocampal levels of noradrenaline and dopamine. This suggests that these neurotransmitters not only influence long-term memory (LTM) as such, but also aversive memory generalization.
Assuntos
Aprendizagem da Esquiva/fisiologia , Comportamento Exploratório/fisiologia , Generalização Psicológica/fisiologia , Tonsila do Cerebelo/metabolismo , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Benzazepinas/farmacologia , Encéfalo/metabolismo , Condicionamento Clássico/efeitos dos fármacos , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Medo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Memória/fisiologia , Norepinefrina/metabolismo , Ratos , Ratos Wistar , Receptores de Dopamina D1/metabolismoRESUMO
Aerobic exercise induces neuroprotection, but few studies investigated whether strength training has similar potential. Here we examine whether effects of strength training differ from those of running training concerning cognitive symptomatology, oxidative stress and cholinergic status in a model of AD-like cognitive impairment induced by intrahippocampal infusion of a mix of ß-amyloid peptides (Aß) in rats. Male Wistar rats were submitted to 8â¯weeks of running exercise (RunEx; 40â¯min sessions at 70% of indirect VO2 max, 3 times/week) or strength exercise (StrEx; 3 sessions/week, 12 repetitions in 8 sets, 2 sets with repetitions at 50%, 2 at 75%, 2 at 90% and 2 at 100% of the maximum load), followed by Aß infusion in the dorsal hippocampus. Short-term (STM) and long-term (LTM) object recognition (OR) and social recognition (SR) memories were evaluated. Hippocampal oxidative status was determined by quantification of reactive oxygen species, lipid peroxidation by thiobarbituric acid reactive substance test, total antioxidant capacity by ferric reducing/antioxidant power, and acetylcholinesterase enzyme activity (AChE). Aß infusion impaired STM and LTM and resulted in higher hippocampal oxidative damage and impaired AChE activity. StrEx results in better neuroprotection than RunEx by preventing deficits in OR and SR memories, prevents increases in lipid peroxidation, and decreases in AChE activity. RunEx elicits neuroprotection only for SR memory deficits, prevents increase in ROS and lipid peroxidation, and preserves the total antioxidant capacity. While RunEx effects are related to oxidative status, only StrEx shows potential to also influence the cholinergic system.
Assuntos
Doença de Alzheimer/prevenção & controle , Memória/fisiologia , Neuroproteção/fisiologia , Condicionamento Físico Animal/fisiologia , Treinamento Resistido , Corrida/fisiologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/farmacologia , Animais , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Atividade Motora/fisiologia , Estresse Oxidativo/fisiologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismoRESUMO
Extinction of contextual fear conditioning (CFC) in the presence of a familiar nonfearful conspecific (social support), such as that of others tasks, can occur regardless of whether the original memory is retrieved during the extinction training. Extinction with social support is blocked by the protein synthesis inhibitors anisomycin and rapamycin and by the inhibitor of gene expression 5,6-dichloro-1-ß-d-ribofuranosylbenzimidazole infused immediately after extinction training into the ventromedial prefrontal cortex (vmPFC) but unlike regular CFC extinction not in the CA1 region of the dorsal hippocampus. So social support generates a form of learning that differs from extinction acquired without social support in terms of the brain structures involved. This finding may lead to a better understanding of the brain mechanisms involved in the social support of memories and in therapies for disorders related to dysfunctional fear memories. Thus, here we show that the consolidation of extinction memory with social support relies on vmPFC rather than hippocampus gene expression and ribosomal- and mammalian target of rapamycin-dependent protein synthesis. These results provide additional knowledge about the cellular mechanisms and brain structures involved on the effect of social support in changing behavior and fear extinction memory.
Assuntos
Extinção Psicológica/fisiologia , Hipocampo/fisiologia , Aprendizagem/fisiologia , Córtex Pré-Frontal/fisiologia , Biossíntese de Proteínas/fisiologia , Animais , Anisomicina/farmacologia , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Medo/fisiologia , Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Ratos Wistar , Sirolimo/farmacologia , Apoio SocialRESUMO
Fear generalization is defined as the transferring of fear experienced during a traumatic event to safe conditions resembling or not the traumatic event. It has been related to several psychological disorders. Here we set out to determine whether novelty exposure can be effective to avoid fear generalization. We evaluated the effect of a novelty exposure on fear memory generalization using an aversive memory task, the inhibitory avoidance (IA). Male Wistar rats were trained in IA (day 1) and 24 h after (day 2) they were exposed to a new context similar to the original (modified IA - MIA), with some rats being exposed to a novelty just before the exposure to the MIA, while others were not (controls). On day 3, retention tests for IA and MIA contexts were performed. The control rats generalized the memory, expressing aversive behavioral in both contexts whereas rats exposed to novelty only expressed aversion on IA. Furthermore, both anisomycin, an inhibitor of ribosomal protein synthesis, and rapamycin, an inhibitor of mTOR-mediated protein synthesis, injected in the CA1 region of dorsal hippocampus blocked the novelty effect, promoting memory generalization. We conclude that novelty exposure hinders aversive memory generalization depending on hippocampal protein synthesis.
Assuntos
Aprendizagem da Esquiva/fisiologia , Generalização Psicológica/fisiologia , Hipocampo/metabolismo , Memória/fisiologia , Biossíntese de Proteínas , Animais , Anisomicina/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Generalização Psicológica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Testes Neuropsicológicos , Biossíntese de Proteínas/efeitos dos fármacos , Inibidores da Síntese de Proteínas/farmacologia , Ratos Wistar , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismoRESUMO
Recently, nongenetic animal models to study the onset and development of Alzheimer's disease (AD) have appeared, such as the intrahippocampal infusion of peptides present in Alzheimer amyloid plaques [i.e., amyloid-ß (Aß)]. Nonpharmacological approaches to AD treatment also have been advanced recently, which involve combinations of behavioral interventions whose specific effects are often difficult to determine. Here we isolate the neuroprotective effects of three of these interventions-environmental enrichment (EE), anaerobic physical exercise (AnPE), and social enrichment (SE)-on Aß-induced oxidative stress and on impairments in learning and memory induced by Aß. Wistar rats were submitted to 8 wk of EE, AnPE, or SE, followed by Aß infusion in the dorsal hippocampus. Short-term memory (STM) and long-term memory (LTM) of object recognition (OR) and social recognition (SR) were evaluated. Biochemical assays determined hippocampal oxidative status: reactive oxygen species, lipid peroxidation by thiobarbituric acid reactive substance (TBARS) test, and total antioxidant capacity by ferric reducing/antioxidant power (FRAP), as well as acetylcholinesterase activity. Aß infusion resulted in memory deficits and hippocampal oxidative damage. EE and AnPE prevented all memory deficits (STM and LTM of OR and SR) and lipid peroxidation (i.e., TBARS). SE prevented only the SR memory deficits and the decrease of total antioxidant capacity decrease (i.e., FRAP). Traditionally, findings obtained with EE protocols do not allow discrimination of the roles of the three individual factors involved. Here we demonstrate that EE and physical exercise have better neuroprotective effects than SE in memory deficits related to Aß neurotoxicity in the AD model tested.
Assuntos
Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/toxicidade , Terapia por Exercício , Transtornos da Memória/terapia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Animais , Exercício Físico , Hipocampo/metabolismo , Humanos , Peroxidação de Lipídeos , Masculino , Aprendizagem em Labirinto , Memória , Transtornos da Memória/metabolismo , Transtornos da Memória/psicologia , Estresse Oxidativo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Meio SocialRESUMO
Methylphenidate (MPH) is a widely prescribed drug for the treatment of attention-deficit hyperactivity disorder. Findings in the literature suggest that the effects of MPH on memory may result from increased extracellular levels of norepinephrine (NE) and dopamine (DA). Here, we report that the systemic administration of MPH before the acquisition phase in a social discrimination task impaired the retrieval of the social recognition memory (SRM), but made it state-dependent: another administration of MPH before the retention test recovered the SRM. We observed that the induction of state dependency by MPH relies on the ventromedial prefrontal cortex (vmPFC), but not on the CA1 region of the hippocampus (CA1). Also, the inhibitors of NE and DA, nisoxetine and GBR12909, respectively, restored the SRM when infused into the vmPFC. Only the GBR12909 was able to restore the SRM in the CA1, whereas nisoxetine could not restore and even caused an impairment on memory retrieval when infused alone before the retention test. The data suggest that the state-dependence of SRM induced by MPH depends on an influence of both catecholamines on the vmPFC, while NE inhibits the retrieval of SRM on the hippocampus.
Assuntos
Comportamento Animal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Hipocampo/efeitos dos fármacos , Metilfenidato/farmacologia , Reconhecimento Psicológico/efeitos dos fármacos , Comportamento Social , Animais , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
The insular cortex (IC) receives projections from prefrontal, entorhinal and cingulate cortex, olfactory bulb and basal nuclei and has reciprocal connections with the amygdala and entorhinal cortex. These connections suggest a possible involvement in memory processes; this has been borne out by data on several behaviors. Social recognition memory (SRM) is essential to form social groups and to establish hierarchies and social and affective ties. Despite its importance, knowledge about the brain structures and the neurotransmitter mechanisms involved in its processing is still scarce. Here we study the participation of NMDA-glutamatergic, D1/D5-dopaminergic, H2-histaminergic, ß-adrenergic and 5-HT1A-serotoninergic receptors of the IC in the consolidation of SRM. Male Wistar rats received intra-IC infusions of substances acting on these receptors immediately after the sample phase of a social discrimination task and 24h later were exposed to a 5-min retention test. The intra-IC infusion of antagonists of D1/D5, ß-adrenergic or 5-HT1A receptors immediately after the sample phase impaired the consolidation of SRM. These effects were blocked by the concomitant intra-IC infusion of agonists of these receptors. Antagonists and agonists of NMDA and H2 receptors had no effect on SRM. The results suggest that the dopaminergic D1/D5, ß-adrenergic and serotonergic 5-HT1A receptors in the IC, but not glutamatergic NMDA and the histaminergic H2 receptors, participate in the consolidation of SRM in the IC.
Assuntos
Córtex Cerebral/metabolismo , Consolidação da Memória/fisiologia , Receptores de Neurotransmissores/metabolismo , Reconhecimento Psicológico/fisiologia , Percepção Social , Animais , Cateteres de Demora , Córtex Cerebral/efeitos dos fármacos , Discriminação Psicológica/efeitos dos fármacos , Discriminação Psicológica/fisiologia , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Masculino , Consolidação da Memória/efeitos dos fármacos , Neurotransmissores/farmacologia , Testes Psicológicos , Ratos Wistar , Receptores de Neurotransmissores/agonistas , Receptores de Neurotransmissores/antagonistas & inibidores , Reconhecimento Psicológico/efeitos dos fármacosRESUMO
It is well recognized that stress or glucocorticoids hormones treatment can modulate memory performance in both directions, either impairing or enhancing it. Despite the high number of studies aiming at explaining the effects of glucocorticoids on memory, this has not yet been completely elucidated. Here, we demonstrate that a low daily dose of methylprednisolone (MP, 5mg/kg, i.p.) administered for 10-days favors aversive memory persistence in adult rats, without any effect on the exploring behavior, locomotor activity, anxiety levels and pain perception. Enhanced performance on the inhibitory avoidance task was correlated with long-term potentiation (LTP), a phenomenon that was strengthen in hippocampal slices of rats injected with MP (5mg/kg) during 10days. Additionally, in vitro incubation with MP (30-300µM) concentration-dependently increased intracellular [Ca2+]i in cultured hippocampal neurons depolarized by KCl (35mM). In conclusion, a low daily dose of MP for 10days may promote aversive memory persistence in rats.
Assuntos
Potenciação de Longa Duração/efeitos dos fármacos , Memória/efeitos dos fármacos , Metilprednisolona/farmacologia , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Cálcio/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Memória/classificação , Memória/fisiologia , Metilprednisolona/metabolismo , Ratos , Ratos Wistar , Sinapses/fisiologiaRESUMO
Previously we showed the involvement of the hippocampal noradrenergic system in the consolidation and persistence of object recognition (OR) memory. Here we show that one-single physical exercise session performed immediately after learning promotes OR memory persistence and increases norepinephrine levels in the hippocampus. Additionally, effects of exercise on memory are avoided by an intra-hippocampal beta-adrenergic antagonist infusion. Taken together, these results suggest that exercise effects on memory can be related to noradrenergic mechanisms and acute physical exercise can be a non-pharmacological intervention to assist memory consolidation and persistence, with few or no side effects.