RESUMO
Fear conditioning is encoded by strengthening synaptic connections between the neurons activated by a conditioned stimulus (CS) and those activated by an unconditioned stimulus (US), forming a memory engram, which is reactivated during memory retrieval. In temporal associations, activity within the prelimbic cortex (PL) plays a role in sustaining a short-term, transient memory of the CS, which is associated with the US after a temporal gap. However, it is unknown whether the PL has only a temporary role, transiently representing the CS, or is part of the neuronal ensembles that support the retrieval, i.e., whether PL neurons support both transient, short-term memories and stable, long-term memories. We investigated neuronal ensembles underlying temporal associations using fear conditioning with a 5-s interval between the CS and US (CFC-5s). Controls were trained in contextual fear conditioning (CFC), in which the CS-US overlaps. We used Robust Activity Marking (RAM) to selectively manipulate PL neurons activated by CFC-5s learning and Targeted Recombination in Active Populations (TRAP2) mice to label neurons activated by CFC-5s learning and reactivated by memory retrieval in the amygdala, medial prefrontal cortex, hippocampus, perirhinal cortices (PER) and subiculum. We also computed their co-reactivation to generate correlation-based networks. The optogenetic reactivation or silencing of PL encoding ensembles either promoted or impaired the retrieval of CFC-5s but not CFC. CFC-5s retrieval reactivated encoding ensembles in the PL, PER, and basolateral amygdala. The engram network of CFC-5s had higher amygdala and PER centralities and interconnectivity. The same PL neurons support learning and stable associative memories.
Assuntos
Condicionamento Clássico , Medo , Camundongos Endogâmicos C57BL , Neurônios , Córtex Pré-Frontal , Animais , Medo/fisiologia , Camundongos , Condicionamento Clássico/fisiologia , Masculino , Córtex Pré-Frontal/fisiologia , Neurônios/fisiologia , Rememoração Mental/fisiologia , Aprendizagem por Associação/fisiologia , Camundongos Transgênicos , Memória de Curto Prazo/fisiologiaRESUMO
This scoping review aimed to systematically identify and summarize data related to subiculum involvement in learning and memory behavioral tasks in rats and mice. Following a systematic strategy based on PICO and PRISMA guidelines, we searched five indexed databases (PubMed, Web of Science, EMBASE, Scopus, and PsycInfo) using a standardized search strategy to identify peer-reviewed articles published in English (pre-registration: osf.io/hm5ea). We identified 31 articles investigating the role of the subiculum in spatial, working, and recognition memories (n = 11), memories related to addiction models (n = 9), aversive memories (n = 7), and memories related to appetitive learning (n = 5). We highlight a dissociation in the dorsoventral axis of the subiculum with many studies exploring the ventral subiculum (n = 21) but only a few exploring the dorsal one (n = 10). We also observe the necessity of more data including mice, female animals, genetic tools, and better statistical approaches for replication purposes and research refinement. These findings provide a broad framework of the subiculum involvement in learning and memory, showing essential questions that can be explored by further studies.
Assuntos
Hipocampo , Aprendizagem , Ratos , Camundongos , Feminino , AnimaisRESUMO
In fear conditioning with time intervals between the conditioned (CS) and unconditioned (US) stimuli, a neural representation of the CS must be maintained over time to be associated with the later US. Usually, temporal associations are studied by investigating individual brain regions. It remains unknown, however, the effect of the interval at the network level, uncovering functional connections cooperating for the CS transient memory and its fear association. We investigated the functional network supporting temporal associations using a task in which a 5-s interval separates the contextual CS from the US (CFC-5s). We quantified c-Fos expression in forty-nine brain regions of male rats following the CFC-5s training, used c-Fos correlations to generate functional networks, and analyzed them by graph theory. Control groups were trained in contextual fear conditioning, in which CS and US overlap. The CFC-5s training additionally activated subdivisions of the basolateral, lateral, and medial amygdala; prelimbic, infralimbic, perirhinal, postrhinal, and intermediate entorhinal cortices; ventral CA1 and subiculum. The CFC-5s network had increased amygdala centrality and higher amygdala internal and external connectivity with the retrosplenial cortex, thalamus, and hippocampus. Amygdala and thalamic nuclei were network hubs. Functional connectivity among these brain regions could support CS transient memories and their association.
Assuntos
Condicionamento Clássico , Giro do Cíngulo , Ratos , Masculino , Animais , Tonsila do Cerebelo/metabolismo , Hipocampo/metabolismo , TálamoRESUMO
In temporal associations, a conditioned stimulus (CS) is separated by a time interval from the unconditioned stimulus (US), which activates the prelimbic cortex (PL) to maintain a CS representation over time. However, it is unknown whether the PL participates, besides the encoding, in the memory consolidation, and thus directly, with activity-dependent changes or indirectly, by modulation of activity-dependent changes in other brain regions. We investigated brain regions supporting the consolidation of associations with intervals and the influence of PL activity in this consolidation process. For this, we observed in Wistar rats the effect of pre-training PL inactivation by muscimol in CREB (cAMP response element-binding protein) phosphorylation, which is essential for memory consolidation, in subdivisions of the medial prefrontal cortex (mPFC), hippocampus, and amygdala 3 h after the training in the contextual fear conditioning (CFC) or CFC with 5-s interval (CFC-5s), fear associations without or with an interval between the CS and US, respectively. Both the CFC-5s and CFC training increased phosphorylation of CREB in the PL and infralimbic cortex (IL); lateral (LA) and basolateral (BLA) amygdala; dorsal CA1 (dCA1); dorsal (dDG), and ventral dentate gyrus, and the CFC-5s training in the central amygdala (CEA). PL activity was necessary for the CREB phosphorylation in the PL, BLA, CEA, dCA1, and dDG only in animals trained in the CFC-5s. The cingulate cortex, ventral CA1, and ventral subiculum did not have learning-induced phosphorylation of CREB. These results suggest that the mPFC, hippocampus, and amygdala support the consolidation of associations with or without intervals and that PL activity influences consolidation in the dorsal hippocampus and amygdala in temporal associations. Thereby, the PL contributes directly and indirectly by modulation to memory consolidation. The time interval engaged the PL early in recent memory consolidation. Results expanded PL's role beyond the time interval and remote memory consolidation.
Assuntos
Tonsila do Cerebelo , Córtex Pré-Frontal , Ratos , Animais , Córtex Pré-Frontal/fisiologia , Fosforilação , Ratos Wistar , Tonsila do Cerebelo/fisiologia , Hipocampo/fisiologia , Medo/fisiologiaRESUMO
Sleep medications, especially benzodiazepines, are known to cause motor and cognitive impairments as side-effects from their use. However, an evaluation of the effects of sleep medications in general on prospective and retrospective memory remains to be seen. Thus, the effects of the different types of sleep medicines were assessed using the total score and the 8 subscales of the Prospective and Retrospective Memory Questionnaire (PRMQ) in a representative sample from the Municipality of São Paulo. The effects of each type of medication on these same parameters were evaluated afterwards. Each analysis was performed controlling for different covariates to observe their degree of interference on the observed results. Impairment due to use of sleep aid medication was observed in 6 of the 8 subscales, as well in the overall score of the PRMQ when compared to non-users. Prospective subscales were particularly affected, even when controlling for highly interfering covariates such as depression and anxiety, and objective sleep variables related to sleep architecture and wakefulness in the night. Few effects were detected between the various types of medication even when controlling for covariates, suggesting that a sample with higher power is necessary to conduct a more detailed analysis. Using pharmacological aids to improve sleep may impair prospective and (to some extent) retrospective memory. Therefore, the relationship between sleep impairment, memory deficits and medication use must be considered by physicians.
Assuntos
Hipnóticos e Sedativos/administração & dosagem , Transtornos da Memória/induzido quimicamente , Memória Episódica , Memória/efeitos dos fármacos , Transtornos do Sono-Vigília/tratamento farmacológico , Adulto , Brasil , Feminino , Humanos , Hipnóticos e Sedativos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estudos RetrospectivosRESUMO
Although stimuli that are associated often overlap in time, previous events can also predict the occurrence of a later aversive stimulus and be associated with it to better guide future behavior. Associations of stimuli separated in time have been studied using discrete stimulus as the conditioned stimulus (CS) in trace conditioning or, more recently in our lab, using the context as the CS in contextual fear conditioning with temporal discontinuity (CFC-5s), a task that simultaneously includes the processing of time and space components. It is thought that fear memories are encoded by the strengthening of synaptic connections in a distributed neural network. However, it is unclear how this temporal factor, which may differentially require the maintenance of the stimulus over time, affects the interactivity between brain regions to form the association. Because the prelimbic cortex (PL) and the hippocampus have been individually engaged in trace conditioning, they may functionally interact to encode associations separated in time. This is anatomically supported by direct ipsilateral projections from the ventral hippocampal CA1 region (vCA1) to PL. The aim of the present study was to investigate the effect of the functional disconnection of vCA1 and PL on CFC-5s using pre-training asymmetric reversible inactivation with muscimol. For comparison, we also observed its effect on contextual fear conditioning (CFC). Results showed that the functional disconnection impaired the encoding of the CFC-5s, an association of stimuli separated in time, while did not affect the CFC, an association of stimuli overlapped in time. In addition, the preserved connection in one hemisphere was sufficient to support the encoding of CFC-5s. The time interval by itself did not increase freezing responses and both CFC and CFC tasks had similar generalization and higher freezing responses than unconditioned groups. These findings suggest that the time factor alters the requirement of the interactivity of the brain regions underlying fear conditioning and extend the relevance of hippocampal-prefrontal interactions in memory.
Assuntos
Aprendizagem por Associação/fisiologia , Região CA1 Hipocampal/fisiologia , Córtex Cerebral/fisiologia , Condicionamento Clássico/fisiologia , Medo/fisiologia , Animais , Aprendizagem por Associação/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Agonistas de Receptores de GABA-A/farmacologia , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Muscimol/farmacologia , Ratos , Ratos WistarRESUMO
Exposure to stress may contribute to enhanced vulnerability to drug use disorders, by altering sensitivity to drug-related reward and psychomotor effects. This study aimed to characterize the psychomotor effects of nicotine administration and then investigate the consequences of two types of repeated social defeat stress (episodic and continuous) on nicotine-induced psychomotor effects in mice. Adult male Swiss mice were treated for 13 days with daily injections of nicotine (0.1, 0.4, or 1.0 mg/kg, s.c.) and received saline and nicotine challenges (0, 0.1 and 0.4 mg/kg) after a withdrawal period. Dose-dependent effects were observed in locomotor response to nicotine, with trends for locomotor stimulation after intermittent (but not acute) administration of 0.1 mg/kg. Higher nicotine doses caused acute locomotor suppression (0.4 and 1.0 mg/kg) and tolerance after intermittent administration (0.4 mg/kg dose). In separate cohorts, experimental mice were daily defeated by aggressive mice, using the resident-intruder model, for 10 days. After brief confrontations, intruders returned to their home cage (episodic stress) or were continuously exposed to the aggressive resident for 24 h (continuous stress), until the following defeat. After the 10-day stress protocol, mice received saline and nicotine challenges (0 and 0.1 mg/kg, s.c.) in locomotor tests. Mice were also tested for methamphetamine-induced locomotor response (1.0 mg/kg, i.p.). Both defeat protocols induced short-term locomotor suppression (24h after stress), which was further suppressed by nicotine only in mice exposed to continuous defeat stress. Ten days after stress, locomotor behavior was no longer suppressed in defeated mice of either stress protocol. Mice exposed to continuous defeat stress showed a reduced stimulant response to methamphetamine, 12 days after termination of stress. Our findings indicate that exposure to continuous defeat stress facilitates nicotine-induced locomotor suppression shortly after stress and reduces methamphetamine-induced stimulation in the long term.
Assuntos
Atividade Motora/efeitos dos fármacos , Nicotina/administração & dosagem , Comportamento Social , Estresse Psicológico , Agressão , Animais , Comportamento Animal , Estimulantes do Sistema Nervoso Central , Masculino , Metanfetamina/administração & dosagem , CamundongosRESUMO
Several studies have investigated the transition of consolidation of recent memory to remote memory in aversively motivated tasks, such as contextual fear conditioning (CFC) and inhibitory avoidance (IA). However, the mechanisms that serve the retrieval of remote memories, has not yet been fully understood. Some evidences suggest that the central cholinergic system appears be involved in the modulation of these processes. Therefore, the present study aimed to investigate the effects of a pre-test administration of dicyclomine, a high-affinity M1 muscarinic receptor antagonist, on the retrieval of remote memories in fear conditioning and IA tasks. Male Wistar rats were trained, and after 1 or 28days, the rats received dicyclomine (16 or 32mg/kg, intraperitoneally, i.p.) and were tested in CFC, tone fear conditioning (TFC) and IA tasks. At both time intervals, 32mg/kg dicyclomine induced impairment of CFC. In TFC task only the performance of the rats 28days after training was impaired. The IA task was not affected in any of the studied intervals. These findings suggest a differential contribution of muscarinic receptors on recent and remote memories retrieval revealing a more generalized role in remote memory.
Assuntos
Aprendizagem da Esquiva/fisiologia , Condicionamento Clássico/fisiologia , Medo/fisiologia , Rememoração Mental/fisiologia , Receptor Muscarínico M1/metabolismo , Estimulação Acústica/efeitos adversos , Análise de Variância , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Diciclomina/farmacologia , Relação Dose-Resposta a Droga , Medo/efeitos dos fármacos , Masculino , Rememoração Mental/efeitos dos fármacos , Antagonistas Muscarínicos/farmacologia , Ratos , Ratos Wistar , Fatores de TempoRESUMO
Ayahuasca is a hallucinogenic beverage that combines the action of the 5-HT2A/2C agonist N,N-dimethyltryptamine (DMT) from Psychotria viridis with the monoamine oxidase inhibitors (MAOIs) induced by beta-carbonyls from Banisteriopsis caapi. Previous investigations have highlighted the involvement of ayahuasca with the activation of brain regions known to be involved with episodic memory, contextual associations and emotional processing after ayahuasca ingestion. Moreover long term users show better performance in neuropsychological tests when tested in off-drug condition. This study evaluated the effects of long-term administration of ayahuasca on Morris water maze (MWM), fear conditioning and elevated plus maze (EPM) performance in rats. Behavior tests started 48h after the end of treatment. Freeze-dried ayahuasca doses of 120, 240 and 480 mg/kg were used, with water as the control. Long-term administration consisted of a daily oral dose for 30 days by gavage. The behavioral data indicated that long-term ayahuasca administration did not affect the performance of animals in MWM and EPM tasks. However the dose of 120 mg/kg increased the contextual conditioned fear response for both background and foreground fear conditioning. The tone conditioned response was not affected after long-term administration. In addition, the increase in the contextual fear response was maintained during the repeated sessions several weeks after training. Taken together, these data showed that long-term ayahuasca administration in rats can interfere with the contextual association of emotional events, which is in agreement with the fact that the beverage activates brain areas related to these processes.
Assuntos
Ansiedade/induzido quimicamente , Banisteriopsis , Alucinógenos/administração & dosagem , Memória/efeitos dos fármacos , Plantas Medicinais , Animais , Bebidas , Condicionamento Psicológico/efeitos dos fármacos , Medo/efeitos dos fármacos , Alucinógenos/química , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Prematurely-born infants are exposed to multiple invasive procedures while in the intensive care unit. Newborn rats and humans have similar behavioral responses to noxious stimulation. Previous studies have shown that early noxious stimuli may alter dentate gyrus neurogenesis and the behavioral repertoire of adult rats. We evaluated the late effects of noxious stimulation administered during different phases of development on two spatial memory tests; object recognition (OR) and Morris water maze (WM) tests. Noxious stimulation was induced by an intra-plantar injection of complete Freund's adjuvant (CFA) on postnatal (P) day 1 (group P1) or 8 (P8). Control animals were not stimulated. Behavioral tests were conducted on P60 in both male and female animals. In the WM, three domains were evaluated: acquisition, probe trial performance and reversal re-acquisition. The number of Nissl stained cells in the dentate granule cell layer was assessed by stereological counting. The OR test revealed that P1 male rats had poor long-term memory compared to the control and P8 groups. In the WM, no short- or long-term memory differences were detected between early postnatal-stimulated male and female rats and their respective controls. However, the ability to find the hidden platform in a new position was reduced in P1 male rats. The number of dentate granule cells in P8 males was higher than in all other groups. This study demonstrates that noxious stimulation on P1 results in spatial learning deficits in male animals, but does not disrupt the development of the hippocampus-dependent strategies of learning and memory.
Assuntos
Hipocampo/citologia , Neurônios/citologia , Nociceptividade/fisiologia , Reconhecimento Psicológico/fisiologia , Memória Espacial/fisiologia , Animais , Animais Recém-Nascidos , Contagem de Células , Feminino , Masculino , Neurogênese/fisiologia , Ratos , Ratos Wistar , Fatores SexuaisRESUMO
OBJECTIVE: Obstructive sleep apnea syndrome is mainly characterized by intermittent hypoxia (IH) during sleep, being associated with several complications. Exposure to IH is the most widely used animal model of sleep apnea, short-term IH exposure resulting in cognitive and neuronal impairment. Pigment epithelium-derived factor (PEDF) is a hypoxia-sensitive factor acting as a neurotrophic, neuroprotective, and antiangiogenic agent. Our study analyzed performance on learning and cognitive tasks, as well as PEDF gene expression and PEDF protein expression in specific brain structures, in rats exposed to long-term IH. METHODS: Male Wistar rats were exposed to IH (oxygen concentrations of 21-5%) for 6 weeks-the chronic IH (CIH) group-or normoxia for 6 weeks-the control group. After CIH exposure, a group of rats were allowed to recover under normoxic conditions for 2 weeks (the CIH+N group). All rats underwent the Morris water maze test for learning and memory, PEDF gene expression and PEDF protein expression in the hippocampus, frontal cortex, and temporal cortex being subsequently assessed. RESULTS: The CIH and CIH+N groups showed increased PEDF gene expression in the temporal cortex, PEDF protein expression remaining unaltered. PEDF gene expression and PEDF protein expression remained unaltered in the frontal cortex and hippocampus. Long-term exposure to IH did not affect cognitive function. CONCLUSIONS: Long-term exposure to IH selectively increases PEDF gene expression at the transcriptional level, although only in the temporal cortex. This increase is probably a protective mechanism against IH-induced injury.
OBJETIVO: A síndrome da apneia obstrutiva do sono caracteriza-se principalmente por episódios de hipóxia intermitente (HI) durante o sono e associa-se a diversas complicações. A exposição à HI é o mais usado modelo animal de apneia do sono, e protocolos de curta duração causam diversos prejuízos cognitivos e neuronais. Pigment epithelium-derived factor (PEDF, fator derivado do epitélio pigmentado) é um fator neurotrófico, neuroprotetor e antiangiogênico sensível à hipóxia celular. Nosso estudo analisou o desempenho em tarefas cognitivas e de aprendizagem, bem como a expressão do gene PEDF e da proteína PEDF em estruturas cerebrais específicas em ratos expostos a HI de longa duração. MÉTODOS: Ratos Wistar foram expostos a HI (21-5% de oxigênio) durante 6 semanas - o grupo HI crônica (HIC) - ou a normóxia durante 6 semanas - o grupo controle. Após a exposição à HIC, um grupo de ratos foi exposto a normóxia durante 2 semanas (o grupo HIC+N). Todos os animais foram submetidos ao labirinto aquático de Morris para avaliação de memória e aprendizado; avaliou-se também a expressão do gene PEDF e da proteína PEDF no hipocampo e nos córtices frontal e temporal. RESULTADOS: Os grupos HIC e HIC+N apresentaram um aumento de expressão do gene PEDF no córtex temporal, porém sem aumento dos níveis proteicos. A expressão do gene PEDF e da proteína PEDF manteve-se inalterada nas demais estruturas. A exposição de longa duração à HI não afetou a função cognitiva. CONCLUSÕES: A exposição de longa duração à HI aumenta seletivamente a expressão do gene PEDF ao nível transcricional, embora apenas no córtex temporal. Esse aumento é provavelmente um mecanismo de proteção contra a HI.
Assuntos
Proteínas do Olho/genética , Expressão Gênica , Hipóxia/genética , Fatores de Crescimento Neural/genética , Serpinas/genética , Apneia Obstrutiva do Sono/genética , Animais , Transtornos Cognitivos/etiologia , Modelos Animais de Doenças , Hipocampo/patologia , Hipóxia/fisiopatologia , Masculino , Memória , Transtornos da Memória/etiologia , Ratos , Ratos Wistar , Apneia Obstrutiva do Sono/fisiopatologiaRESUMO
Objective: Obstructive sleep apnea syndrome is mainly characterized by intermittent hypoxia (IH) during sleep, being associated with several complications. Exposure to IH is the most widely used animal model of sleep apnea, short-term IH exposure resulting in cognitive and neuronal impairment. Pigment epithelium-derived factor (PEDF) is a hypoxia-sensitive factor acting as a neurotrophic, neuroprotective, and antiangiogenic agent. Our study analyzed performance on learning and cognitive tasks, as well as PEDF gene expression and PEDF protein expression in specific brain structures, in rats exposed to long-term IH. Methods: Male Wistar rats were exposed to IH (oxygen concentrations of 21-5%) for 6 weeks-the chronic IH (CIH) group-or normoxia for 6 weeks-the control group. After CIH exposure, a group of rats were allowed to recover under normoxic conditions for 2 weeks (the CIH+N group). All rats underwent the Morris water maze test for learning and memory, PEDF gene expression and PEDF protein expression in the hippocampus, frontal cortex, and temporal cortex being subsequently assessed. Results: The CIH and CIH+N groups showed increased PEDF gene expression in the temporal cortex, PEDF protein expression remaining unaltered. PEDF gene expression and PEDF protein expression remained unaltered in the frontal cortex and hippocampus. Long-term exposure to IH did not affect cognitive function. Conclusions: Long-term exposure to IH selectively increases PEDF gene expression at the transcriptional level, although only in the temporal cortex. This increase is probably a protective mechanism against IH-induced injury. .
Objetivo: A síndrome da apneia obstrutiva do sono caracteriza-se principalmente por episódios de hipóxia intermitente (HI) durante o sono e associa-se a diversas complicações. A exposição à HI é o mais usado modelo animal de apneia do sono, e protocolos de curta duração causam diversos prejuízos cognitivos e neuronais. Pigment epithelium-derived factor (PEDF, fator derivado do epitélio pigmentado) é um fator neurotrófico, neuroprotetor e antiangiogênico sensível à hipóxia celular. Nosso estudo analisou o desempenho em tarefas cognitivas e de aprendizagem, bem como a expressão do gene PEDF e da proteína PEDF em estruturas cerebrais específicas em ratos expostos a HI de longa duração. Métodos: Ratos Wistar foram expostos a HI (21-5% de oxigênio) durante 6 semanas - o grupo HI crônica (HIC) - ou a normóxia durante 6 semanas - o grupo controle. Após a exposição à HIC, um grupo de ratos foi exposto a normóxia durante 2 semanas (o grupo HIC+N). Todos os animais foram submetidos ao labirinto aquático de Morris para avaliação de memória e aprendizado; avaliou-se também a expressão do gene PEDF e da proteína PEDF no hipocampo e nos córtices frontal e temporal. Resultados: Os grupos HIC e HIC+N apresentaram um aumento de expressão do gene PEDF no córtex temporal, porém sem aumento dos níveis proteicos. A expressão do gene PEDF e da proteína PEDF manteve-se inalterada nas demais estruturas. A exposição de longa duração à HI não afetou a função cognitiva. Conclusões: A exposição de longa duração à HI aumenta seletivamente a expressão do gene PEDF ao nível transcricional, embora apenas no córtex temporal. Esse aumento é provavelmente um mecanismo de proteção contra a HI. .
Assuntos
Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Glicemia/metabolismo , Doenças Cardiovasculares/prevenção & controle , Dieta com Restrição de Carboidratos , Dieta com Restrição de Gorduras , /prevenção & controle , Programas de Redução de Peso , Redução de Peso/fisiologia , Peso Corporal , Estudos de Casos e Controles , Ensaio Clínico , Seguimentos , Hemoglobinas Glicadas/análise , Obesidade/dietoterapia , Obesidade/metabolismo , Obesidade/fisiopatologia , Sobrepeso/dietoterapia , Sobrepeso/metabolismo , Sobrepeso/fisiopatologia , Fatores de RiscoRESUMO
Numerous studies show that sleep deprivation (SD) impacts negatively on cognitive processes, including learning and memory. Memory formation encompasses distinct phases of which acquisition, consolidation and retrieval are better known. Previous studies with pre-training SD induced by the platform method have shown impairment in fear conditioning tasks. Nonetheless, pre-training manipulations do not allow the distinction between effects on acquisition and/or consolidation, interfering, ultimately, on recall of/performance in the task. In the present study, animals were first trained in contextual and tone fear conditioning (TFC) tasks and then submitted to SD with the purpose to evaluate the effect of this manipulation on different stages of the learning process, e.g., in the uptake of (new) information during learning, its encoding and stabilization, and the recall of stored memories. Besides, we also investigated the effect of SD in the extinction of fear memory and a possible state-dependent learning induced by this manipulation. For each task (contextual or TFC), animals were trained and then distributed into control, not sleep-deprived (CTL) and SD groups, the latter being submitted to the modified multiple platform paradigm for 96 h. Subsets of eight rats in each group/experiment were submitted to the test of the tasks, either immediately or at different time intervals after SD. The results indicated that (a) pre- but not post-training SD impaired recall in the contextual and TFC; (b) this impairment was not state-dependent; and (c) in the contextual fear conditioning (CFC), pre-test SD prevented extinction of the learned task. Overall, these results suggest that SD interferes with acquisition, recall and extinction, but not necessarily with consolidation of emotional memory.
RESUMO
Extensive research has shown that the hippocampus and striatum have dissociable roles in memory and are necessary for place and response learning, respectively. Additional evidence indicates that muscarinic cholinergic receptors in the hippocampus and striatum exert an important role in the modulation of these memory systems. In our experiments, we assessed whether intact hippocampal and striatal muscarinic cholinergic transmission may be essential and/or necessary for place and response learning. We addressed these questions using administration of the muscarinic receptor antagonist, scopolamine, on both place and response learning in a food-rewarded T-maze task. The administration of scopolamine (15 µg or 30 µg) directly into the dorsal hippocampus impaired the performance of rats subjected to both place and cue-rich response version of the task, but did not affect the response version, when the task was performed under cue-poor conditions. However, the administration of scopolamine in the dorsolateral striatum impaired the cue-poor response version of the T-maze task without interfering with the place version or cue-rich response version. Taken together, these results indicate that activation of muscarinic cholinergic receptors in the hippocampus and striatum facilitate the use of different strategies of learning, thus strengthening the hypothesis of multiple memory systems. Additionally, these results emphasize the importance of the environmental conditions under which tasks are performed.
Assuntos
Corpo Estriado/fisiologia , Memória/efeitos dos fármacos , Memória/fisiologia , Antagonistas Muscarínicos/farmacologia , Receptores Muscarínicos/fisiologia , Animais , Corpo Estriado/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Microinjeções , Antagonistas Muscarínicos/administração & dosagem , Ratos , Escopolamina/administração & dosagem , Escopolamina/farmacologiaRESUMO
We investigated the relationship between deficits in fear memory induced by sleep deprivation and pCREB expression in the basal and central nuclei of the amygdala. Sleep deprivation reduced pCREB expression in the central nucleus compared to control or sleep recovered groups, and in the basal nucleus only compared to sleep recovered group. Moreover, 24h of sleep recovery prior to training prevented changes in both pCREB expression and performance.
Assuntos
Tonsila do Cerebelo/metabolismo , Condicionamento Psicológico/fisiologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Medo/fisiologia , Privação do Sono , Animais , Imuno-Histoquímica , Masculino , Memória/fisiologia , Fosforilação , Desempenho Psicomotor/fisiologia , Ratos , Ratos WistarRESUMO
Modafinil is a non-amphetaminic psychostimulant used therapeutically for sleep and psychiatric disorders. However, some studies indicate that modafinil can have addictive properties. The present study examined whether modafinil can produce behavioral sensitization in mice, an experience and drug-dependent behavioral adaptation, and if individual differences play a role in this process. We further tested context-related factors and cross-sensitization between modafinil and methamphetamine. Important individual differences in the behavioral sensitization of Swiss Albino mice were observed after repeated administration of 50 mg/kg modafinil (Experiment 1), or 1 mg/kg methamphetamine (Experiment 2). Only mice classified as sensitized subgroup developed clear behavioral sensitization to the drugs. After a withdrawal period, mice received challenges of modafinil (Experiment 1), or methamphetamine (Experiment 2) and locomotor activity was evaluated in the activity cages (previous context) and in the open field arena (new context) in order to evaluate the context dependency of behavioral sensitization. The expression of sensitization to modafinil, but not to methamphetamine, was affected by contextual testing conditions, since modafinil-sensitized mice only expressed sensitization in the activity cage, but not in the open field. Subsequently, locomotor cross-sensitization between methamphetamine and modafinil was assessed by challenging modafinil-pretreated mice with 1mg/kg methamphetamine (Experiment 1), and methamphetamine-pretreated mice with 50mg/kg modafinil (Experiment 2). We observed a symmetrical cross-sensitization between the drugs only in those mice that were classified as sensitized subgroup. Our findings indicate that repeated exposure to modafinil induces behavioral sensitization only in some animals by similar neurobiological, but not contextual, mechanisms to those of methamphetamine.
Assuntos
Comportamento Animal/efeitos dos fármacos , Compostos Benzidrílicos/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Individualidade , Metanfetamina/farmacologia , Análise de Variância , Animais , Aprendizagem por Associação/efeitos dos fármacos , Aprendizagem da Esquiva/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Medo/efeitos dos fármacos , Masculino , Camundongos , Modafinila , Atividade Motora/efeitos dos fármacos , Fatores de TempoRESUMO
Few data exists about the pharmacological properties of Heteropterys aphrodisiaca O. Mach. (Malpighiaceae), which is native to the scrubland regions of Brazil. The present study investigated the effects of oral treatment with H. aphrodisiaca extract (BST0298) on the learning and memory of young (3-6 months) and aged (21-23 months) rats, and compared the in vitro antioxidant activity of three lots collected in different years. An improvement in the number of sessions to learn the task was observed in the left/right discrimination test in aged rats treated for 45 days with 25 mg/kg (7.0 ± 0.5; p=0.005) or 50 mg/kg (7.6 ± 0.6; p=0.012) compared with control old rats (11.0 ± 1.6). On the other hand, pre-treatment did not improve the performance of scopolamine-treated mice in the passive avoidance test. The in vitro malondialdehyde test showed that all three different extracts presented similar antioxidant activity. The flavonoids astilbin, isoastilbin and neoastilbin were isolated from the extract and may contribute to the biological activity. These results suggest that repeated treatment with H. aphrodisiaca improves learning and memory, probably by a non-muscarinic mechanism.
Existem poucos dados disponíveis sobre as propriedades farmacológicas da Heteropterys aphrodisiaca O. Mach. (Malpighiaceae), nativa da região do pantanal brasileiro. O presente estudo investigou o efeito do tratamento oral com um extrato de H. aphrodisiaca (BST0298) sobre a memória e aprendizagem de ratos jovens (3-6 meses) e idosos (21-23 meses) e comparou a atividade antioxidante in vitro de três lotes, coletados em diferentes anos. Melhora quanto ao número de sessões necessárias para aprender a tarefa foi observada no teste de discriminação direita/esquerda em ratos idosos tratados por 45 dias com doses de 25 mg/kg (7,0 ± 0,5; p=0,005) e 50 mg/kg (7,6 ± 0,6; p=0,012) comparados com ratos idosos controle (11,0 ± 1,6). Por outro lado, o pré-tratamento com o extrato não melhorou o desempenho de camundongos tratados com escopolamina no teste da esquiva passiva. Em relação à avaliação da atividade antioxidante in vitro pelo teste do malonodialdeído, os três lotes analisados apresentaram atividade antioxidante semelhante. Os flavonóides astilbina, isoastilbina e neoastilbina foram isolados do extrato e podem contribuir para a atividade biológica. Estes resultados sugerem que a administração repetida de H. aphrodisiaca melhora a memória e aprendizagem provavelmente por um mecanismo não muscarínico.
Assuntos
Ratos , Ratos/classificação , Malpighiaceae , Memória/classificação , Flavonoides/farmacologia , Extratos Vegetais/farmacologia , Antioxidantes/análiseRESUMO
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
Increasing evidence indicates that sleep deprivation (SD) alters responses to pharmacological agents by affecting specific transmitter systems. The present work addressed deficits in passive avoidance (PA) performance that are seen after SD, and investigated whether treatment with the inverse benzodiazepine agonist beta-CCM could prevent such deficits. Male Wistar rats were deprived of sleep for 96 h using the platform method (SD group), or were sleep deprived and then allowed to recover sleep for 24h (SR group). Animals were treated with saline or 0.5mg/kg beta-CCM before PA training, and were tested 30 min or 24h later. A separate set of animals was sacrificed for [(3)H]Ro 15-4513 binding analysis. beta-CCM increased PA performance in control animals in both short and long term retention tests, whereas SD and SR animals were unaffected by the drug treatment. Interestingly, [(3)H]Ro 15-4513 binding was reduced in the entorhinal cortex in both SD and SR groups. These findings suggest that the lack of promnesic effects of beta-CCM after SD and SR may be associated with benzodiazepine receptor downregulation in specific brain regions related to memory formation.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Carbolinas/farmacologia , Antagonistas de Receptores de GABA-A , Privação do Sono , Animais , Autorradiografia , Azidas/farmacologia , Benzodiazepinas/farmacologia , Agonismo Inverso de Drogas , Masculino , Ensaio Radioligante , RatosRESUMO
NMDA receptor antagonist D-AP5 was injected into the dorsal hippocampus of Wistar rats before or immediately after the training session in fear conditioning. Training was conducted both with signaled (background context) or unsignaled (foreground context) footshocks. Contextual fear conditioning was assessed 24 h later and tone fear conditioning 48 h after training (only in the signaled footshock condition). Pretraining injections impaired conditioned fear to contextual features, both in background and foreground configurations, whereas tone fear conditioning was left intact. Posttraining injections were ineffective in all cases. We conclude that dorsal hippocampal NMDA receptors are required for contextual fear acquisition independently of context saliency and that they are not required to early consolidation processes.