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RATIONALE: The accumulation of beta-amyloid peptide (Aß) in the forebrain leads to cognitive dysfunction and neurodegeneration in Alzheimer's disease. Studies have shown that individuals with a consistently cognitively active lifestyle are less vulnerable to Aß toxicity. Recent research has demonstrated that intrahippocampal Aß can impact catecholaminergic release and spatial memory. Interestingly, exposure to novelty stimuli has been found to stimulate the release of catecholamines in the hippocampus. However, it remains uncertain whether repeated enhancing catecholamine activity can effectively alleviate cognitive impairment in individuals with Alzheimer's disease. OBJECTIVES: Our primary aim was to investigate whether repeated exposure to novelty could enable cognitive resilience against Aß. This protection could be achieved by modulating catecholaminergic activity within the hippocampus. METHODS: To investigate this hypothesis, we subjected mice to three different conditions-standard housing (SH), repeated novelty (Nov), or daily social interaction (Soc) for one month. We then infused saline solution (SS) or Aß (Aß1-42) oligomers intrahippocampally and measured spatial memory retrieval in a Morris Water Maze (MWM). Stereological analysis and extracellular baseline dopamine levels using in vivo microdialysis were assessed in independent groups of mice. RESULTS: The mice that received Aß1-42 intrahippocampal infusions and remained in SH or Soc conditions showed impaired spatial memory retrieval. In contrast, animals subjected to the Nov protocol demonstrated remarkable resilience, showing strong spatial memory expression even after Aß1-42 intrahippocampal infusion. The stereological analysis indicated that the Aß1-42 infusion reduced the tyrosine hydroxylase axonal length in SH or Soc mice compared to the Nov group. Accordingly, the hippocampal extracellular dopamine levels increased significantly in the Nov groups. CONCLUSIONS: These compelling results demonstrate the potential for repeated novelty exposure to strengthen the dopaminergic system and mitigate the toxic effects of Aß1-42. They also highlight new and promising therapeutic avenues for treating and preventing AD, especially in its early stages.
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Resveratrol (3,5,4'-trihydroxy-trans-stilbene), a phenol commonly found in grapes and wine, has been associated as protective in experimental models involving alterations in different neurotransmitter systems. However, studies are reporting that resveratrol could have adverse effects. This study evaluated if the association of a low dose of ketamine and resveratrol could induce behavioral manifestations associated with biochemical alterations. Moreover, the effects of treatment with resveratrol and/or ketamine on monoamine oxidase (MAO) activity, oxidative stress markers, and IL-6 levels in the brain were also investigated. Male Swiss mice received a low dose of ketamine (20 mg/kg) for 14 consecutive days, and resveratrol (10, 30, or 100 mg/kg) from day 8 up to day 14 of the experimental period, intraperitoneally. Locomotor, stereotyped behavior, Y-maze, novel recognition object test (NORT), and social interaction were quantified as well as ex vivo analysis of MAO activity, IL-6 levels, and oxidative stress markers (TBARS and total thiol levels) in brain tissues. Ketamine per se reduced the number of bouts of stereotyped behavior on day 8 of the experimental period. Resveratrol per se reduced the locomotor and exploratory activity in the open field, the time of exploration of new objects in the NORT, MAO-A activity in the striatum and increased the IL-6 levels in the cortex. These effects were attenuated when the mice were co-treated with ketamine and resveratrol. There was a decrease in MAO-A activity in the cortex of mice treated with ketamine + resveratrol 100 mg/kg. No significant alterations were found in oxidative stress markers. Resveratrol does not appear to cause summative effects with ketamine on behavioral alterations. However, the effect of resveratrol per se, mainly on locomotor and exploratory activity, should be better investigated.
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Ketamina , Monoaminoxidase , Estresse Oxidativo , Resveratrol , Animais , Resveratrol/farmacologia , Resveratrol/administração & dosagem , Ketamina/farmacologia , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Monoaminoxidase/metabolismo , Monoaminoxidase/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Comportamento Exploratório/efeitos dos fármacos , Interleucina-6/metabolismo , Comportamento Estereotipado/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Interação Social/efeitos dos fármacos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Atividade Motora/efeitos dos fármacosRESUMO
The cognitive effects of nicotine are linked to persistent modifications in extended neural systems that regulate cognitive and emotional processes, and these changes occur during development. Additionally, acute stress has modulatory effects on cognition that involve broad neural systems and can be influenced by prior environmental challenges. The effects of nicotine and stress may be interconnected, leading to modifications in a network of shared brain substrates. Here, we explored the interaction between nicotine and stress by evaluating the effects of acute stress exposure in spatial memory retrieval for animals pretreated with nicotine during adolescence or adulthood. Adolescent (35 days old) and adult (70 days old) male Wistar rats were treated for 21 days with one daily subcutaneous injection of nicotine 0.14 mg/ml (free base). 30 days after the last injection, rats were trained in the Barnes maze and tested 24 h later, half the rats were tested under regular conditions, and half of them were exposed to 1 h of restraining stress before the retrieval test, and brain samples were collected and c-Fos immunopositive cells were stained. Prolonged nicotine withdrawal or acute stress improved spatial memory retrieval. Acute stress in nicotine pretreated adults impaired spatial memory retrieval. Nicotine exposure during early adulthood resulted in long-lasting brain adaptations that amplified emotional responses to acute stress after prolonged drug withdrawal.
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Nicotina , Síndrome de Abstinência a Substâncias , Ratos , Masculino , Animais , Nicotina/farmacologia , Memória Espacial , Ratos Wistar , Encéfalo/metabolismo , Síndrome de Abstinência a Substâncias/metabolismoRESUMO
Introduction: Neuronal Ca2+ signals generated through the activation of Ca2+-induced Ca2+ release in response to activity-generated Ca2+ influx play a significant role in hippocampal synaptic plasticity, spatial learning, and memory. We and others have previously reported that diverse stimulation protocols, or different memory-inducing procedures, enhance the expression of endoplasmic reticulum-resident Ca2+ release channels in rat primary hippocampal neuronal cells or hippocampal tissue. Methods and Results: Here, we report that induction of long-term potentiation (LTP) by Theta burst stimulation protocols of the CA3-CA1 hippocampal synapse increased the mRNA and protein levels of type-2 Ryanodine Receptor (RyR2) Ca2+ release channels in rat hippocampal slices. Suppression of RyR channel activity (1 h preincubation with 20 µM ryanodine) abolished both LTP induction and the enhanced expression of these channels; it also promoted an increase in the surface expression of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits GluR1 and GluR2 and caused a moderate but significant reduction of dendritic spine density. In addition, training rats in the Morris water maze induced memory consolidation, which lasted for several days after the end of the training period, accompanied by an increase in the mRNA levels and the protein content of the RyR2 channel isoform. Discussion: We confirm in this work that LTP induction by TBS protocols requires functional RyR channels. We propose that the increments in the protein content of RyR2 Ca2+ release channels, induced by LTP or spatial memory training, play a significant role in hippocampal synaptic plasticity and spatial memory consolidation.
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Introduction: Skilled walking is influenced by memory, stress, and anxiety. While this is evident in cases of neurological disorders, memory, and anxiety traits may predict skilled walking performance even in normal functioning. Here, we address whether spatial memory and anxiety-like behavior can predict skilled walking performance in mice. Methods: A cohort of 60 adult mice underwent a behavioral assessment including general exploration (open field), anxiety-like behavior (elevated plus maze), working and spatial memory (Y-maze and Barnes maze), and skilled walking performance (ladder walking test). Three groups were established based on their skilled walking performance: superior (SP, percentiles ≥75), regular (RP, percentiles 74-26), and inferior (IP, percentiles ≤25) performers. Results: Animals from the SP and IP groups spent more time in the elevated plus maze closed arms compared to the RP group. With every second spent in the elevated plus maze closed arms, the probability of the animal exhibiting extreme percentiles in the ladder walking test increased by 1.4%. Moreover, animals that spent 219 s (73% of the total time of the test) or more in those arms were 4.67 times more likely to exhibit either higher or lower percentiles of skilled walking performance. Discussion: We discuss and conclude anxiety traits may influence skilled walking performance in facility-reared mice.
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Introducción. El estrés agudo altera la memoria y aprendizaje espacial y la expresión de la interleuquina 6 (IL-6), mientras que el estímulo masticatorio evitaría dichos efectos. Objetivo. Determinar el efecto del estímulo masticatorio y el estrés agudo sobre la expresión de interleuquina 6, la memoria y el aprendizaje espacial en ratones. Métodos. Experimento con 70 ratones albinos machos de 2 meses de edad de la cepa Balb/c que fueron distribuidos aleatoriamente en grupo A1: estrés agudo 1 hora; grupo A2: estrés agudo 1 hora + estímulo masticatorio 1 hora; grupo B1: estrés agudo 2 horas; grupo B2: estrés agudo 2 horas + estímulo masticatorio 2 horas; grupo C1: estrés agudo 3 horas; grupo C2: estrés agudo 3 horas + estímulo masticatorio 3 horas; y grupo D: sin intervención. Durante 3 días, se evaluó la memoria y el aprendizaje espacial en el laberinto acuático de Morris. La IL-6 fue determinada mediante ELISA. Resultados. La IL-6 fue mayor en el grupo B2 vs los demás grupos (p < 0,001). Además, en el primer día de evaluación, la adquisición de memoria y aprendizaje espacial fue menor en el grupo A1 vs A2 (p = 0,042). Conclusión. Solo en el primer día de evaluación encontramos que el estímulo masticatorio previno la disminución de la adquisición de memoria y aprendizaje espacial en ratones sometidos a estrés agudo de baja intensidad. Los resultados en general no fueron concluyentes sobre el efecto del estímulo masticatorio. Además, la IL-6 fue mayor en el estrés + el estímulo masticatorio (grupo B2) sobre el resto.
Introduction. Acute stress alters memory and spatial learning and the expression of interleukin 6, the chewing stimulus would prevent these effects. Objective. To determine the effect of chewing stimulation and acute stress on the expression of interleukin 6 and memory and spatial learning in mice. Methods. Experiment where 70 male albino mice of the Balb/c of age 2 month were randomly distributed into: Group A1: acute stress 1 hour; Group A2: acute stress 1 hour + chewing stimulus 1 hour; Group B1: acute stress 2 hours; Group B2: acute stress 2 hours + chewing stimulus 2 hours; Group C1: acute stress 3 hours; C2: acute stress 3 hours + chewing stimulus 3 hours; Group D: without intervention. For 3 days, spatial memory and learning were tested in the Morris water maze. Interleukin 6 (IL-6) was analyzed by ELISA test. Results. IL-6 was higher in the B2 group vs the other groups (p<0.0001). In addition, on the first day of evaluation, the acquisition of spatial memory and spatial was lower in the A1 vs. A2 group (p=0.042). Conclusión. Only on the first day of evaluation, we found that the masticatory stimulus prevented the decrease in memory acquisition and spatial learning in mice subjected to low-intensity acute stress. The results were generally inconclusive on the effect of masticatory stimulation. In addition, IL-6 was higher in the stress + masticatory stimulus (group B2) over the rest.
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Introduction: Alzheimer's disease (AD) is the leading cause of dementia worldwide, but its pathophysiological phenomena are not fully elucidated. Many neurophysiological markers have been suggested to identify early cognitive impairments of AD. However, the diagnosis of this disease remains a challenge for specialists. In the present cross-sectional study, our objective was to evaluate the manifestations and mechanisms underlying visual-spatial deficits at the early stages of AD. Methods: We combined behavioral, electroencephalography (EEG), and eye movement recordings during the performance of a spatial navigation task (a virtual version of the Morris Water Maze adapted to humans). Participants (69-88 years old) with amnesic mild cognitive impairment-Clinical Dementia Rating scale (aMCI-CDR 0.5) were selected as probable early AD (eAD) by a neurologist specialized in dementia. All patients included in this study were evaluated at the CDR 0.5 stage but progressed to probable AD during clinical follow-up. An equal number of matching healthy controls (HCs) were evaluated while performing the navigation task. Data were collected at the Department of Neurology of the Clinical Hospital of the Universidad de Chile and the Department of Neuroscience of the Faculty of Universidad de Chile. Results: Participants with aMCI preceding AD (eAD) showed impaired spatial learning and their visual exploration differed from the control group. eAD group did not clearly prefer regions of interest that could guide solving the task, while controls did. The eAD group showed decreased visual occipital evoked potentials associated with eye fixations, recorded at occipital electrodes. They also showed an alteration of the spatial spread of activity to parietal and frontal regions at the end of the task. The control group presented marked occipital activity in the beta band (15-20 Hz) at early visual processing time. The eAD group showed a reduction in beta band functional connectivity in the prefrontal cortices reflecting poor planning of navigation strategies. Discussion: We found that EEG signals combined with visual-spatial navigation analysis, yielded early and specific features that may underlie the basis for understanding the loss of functional connectivity in AD. Still, our results are clinically promising for early diagnosis required to improve quality of life and decrease healthcare costs.
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Vitamin D3 deficiency is associated with an increased risk of dementia. An association between vitamin D3 deficiency and subjective cognitive complaints in geriatric patients has been previously reported. This study aimed to evaluate the effects of two doses of vitamin D3 on spatial memory (using the Radial Maze) and cytokine levels [tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and interleukin-10 (IL-10)] on 2-, 6-, 13-, 22-, and 31-month-old male Wistar rats. Animals were supplemented with vitamin D3 at doses of 42 IU/kg and 420 IU/kg for 21 days. A radial maze test was performed to evaluate spatial memory. After the behavioral test, the frontal cortex and hippocampus were dissected for enzyme immunoassay analyses to measure the cytokine levels (TNFα, IL-1ß, IL-6, and IL-10). Our results showed that vitamin D3 supplementation reversed spatial memory impairment at the supplemented doses (42 and 420 IU/kg) in 6-, 13-, and 22-month-old animals and at a dose of 420 IU/kg in 31-month-old animals. The lower dose (42 IU/kg) regulates both pro- and anti-inflammatory cytokines mainly in the frontal cortex. Our results suggest that vitamin D3 has a modulatory action on pro- and anti-inflammatory cytokines, since older animals showed increased cytokine levels compared to 2-month-old animals, and that vitamin D3 may exert an immunomodulatory effect on aging.
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Colecalciferol , Deficiência de Vitamina D , Ratos , Masculino , Animais , Colecalciferol/farmacologia , Colecalciferol/uso terapêutico , Citocinas , Interleucina-10 , Ratos Wistar , Interleucina-6 , Memória Espacial , Fator de Necrose Tumoral alfa , Anti-InflamatóriosRESUMO
Methylphenidate is a stimulant used to treat attention deficit and hyperactivity disorder (ADHD). In the last decade, illicit use of methylphenidate has increased among healthy young adults, who consume the drug under the assumption that it will improve cognitive performance. However, the studies that aimed to assess the methylphenidate effects on memory are not consistent. Here, we tested whether the effect of methylphenidate on a spatial memory task can be explained as a motivational and/or a reward effect. We tested the effects of acute and chronic i.p. administration of 0.3, 1 or 3 mg/kg of methylphenidate on motivation, learning and memory by using the 8-arm radial maze task. Adult male Wistar rats learned that 3 of the 8 arms of the maze were consistently baited with 1, 3, or 6 sucrose pellets, and the number of entries and reentries into reinforced and non-reinforced arms of the maze were scored. Neither acute nor chronic (20 days) methylphenidate treatment affected the number of entries in the non-baited arms. However, chronic, but not acute, 1-3 mg/kg methylphenidate increased the number of reentries in the higher reward arms, which suggests a motivational/rewarding effect rather than a working memory deficit. In agreement with this hypothesis, the methylphenidate treatment also decreased the approach latency to the higher reward arms, increased the approach latency to the low reward arm, and increased the time spent in the high, but not low, reward arm. These findings suggest that methylphenidate may act more as a motivational enhancer rather than a cognitive enhancer in healthy people.
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Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central , Metilfenidato , Animais , Ratos , Masculino , Metilfenidato/farmacologia , Metilfenidato/uso terapêutico , Motivação , Ratos Wistar , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Recompensa , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológicoRESUMO
ABSTRACT. The working memory (WM) training in older adults can benefit their cognition. However, there is a dearth of literature reviews on the subject. Objective: This study aimed to investigate and evaluate the effects of WM training on the cognition of healthy older adults, in individual and group interventions reported in the literature. Methods: This is a systematic review involving a qualitative analysis of publications on the SciELO, LILACS, and MEDLINE databases carried out between March and June 2021. Results: A total of 47 studies were identified and analyzed, comprising 40 in older adults only and 7 comparing older and younger adults, investigating individual or group WM training or other types of intervention focused on WM effects. Conclusions: Both individual and group intervention contributed to the maintenance and/or improvement of cognition in older adults exploiting brain plasticity to promote mental health and prevent cognitive problems that can negatively impact quality of life of this group.
RESUMO. O treino da memória operacional (WM) com idosos pode gerar benefícios em sua cognição. Entretanto, há escassez de revisões da literatura sobre o tema. Objetivo: Investigar e avaliar, na literatura, os efeitos do treino da WM na cognição de idosos saudáveis, em intervenções individuais e grupais. Métodos: Estudo de revisão sistemática realizado entre março e junho de 2021, utilizando-se as bases Scientific Electronic Library Online (SciELO), Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS) e Medical Literature Analysis and Retrieval System Online (MEDLINE). Resultados: Foram identificados e analisados 47 estudos, 40 apenas com idosos, e sete comparativos entre idosos e adultos mais jovens, que realizaram treino individual ou em grupo com foco nos efeitos na WM. Conclusões: Os trabalhos analisados mostraram que ambos os tipos de intervenções podem contribuir para a manutenção e/ou melhoria da cognição de pessoas idosas, aproveitando sua plasticidade cerebral e, portanto, para a promoção de sua saúde mental e para a prevenção de problemas cognitivos que podem interferir em sua qualidade de vida.