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Physical exercise is known to have beneficial effects on general health and wellbeing in humans and it is also related to neuronal plasticity, increasing neurogenesis and consequently leading to improvements in processes such as learning and memory. In this sense, wheel running performance in mice appears as an extensively used behavioral approach for neurobiological studies. Here, we explored the running patterns in CF1 male and female mice allowing voluntary wheel running for 20 min along three consecutive days. We analyzed differences in the accumulated distance traveled, instant velocity, and latency to run and breaks taken in both males and females, comparing performance between days. Results revealed that after a first experience with the wheel, animals that had learnt how to run on day 1 quickly look forward to stepping into the wheel in subsequent training days, reflected by a significant increase in daily running distance and velocity. Further, no differences were found in the running performance between males and females. In summary, in a first experience with the wheel, animals get familiarized with the wheel and grow accustomed to it.
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Back in 1968, Misanin and his group posited that reactivation of consolidated memories could support changes in that trace, similar to what might happen during the consolidation process. Not until 2000, when Nader et al. (2000) studied the behavioral effect of a protein synthesis inhibitor on retrieved memories, could this previous statement be taken under consideration once again; suggesting that consolidated memories can become labile after reactivation. The process of strengthening after memory labilization was named memory reconsolidation. In recent years, many studies pointed towards a critical participation of the extracellular signal-regulated kinase (ERK)/mitogen activated protein kinases (MAPKs) pathway in different memory processes (e.g., consolidation, extinction, reconsolidation, among others). In this review article, we will focus on how this system might be modulating the processes triggered after retrieval of well-consolidated memories in mice.
RESUMEN
Deposition of amyloid-ß (Aß), the proteolytic product of the amyloid precursor protein (APP), might cause neurodegeneration and cognitive decline in Alzheimer's disease (AD). However, the direct involvement of APP in the mechanism of Aß-induced degeneration in AD remains on debate. Here, we analyzed the interaction of APP with heterotrimeric Go protein in primary hippocampal cultures and found that Aß deposition dramatically enhanced APP-Go protein interaction in dystrophic neurites. APP overexpression rendered neurons vulnerable to Aß toxicity by a mechanism that required Go-Gßγ complex signaling and p38-mitogen-activated protein kinase activation. Gallein, a selective pharmacological inhibitor of Gßγ complex, inhibited Aß-induced dendritic and axonal dystrophy, abnormal tau phosphorylation, synaptic loss, and neuronal cell death in hippocampal neurons expressing endogenous protein levels. In the 3xTg-AD mice, intrahippocampal application of gallein reversed memory impairment associated with early Aß pathology. Our data provide further evidence for the involvement of APP/Go protein in Aß-induced degeneration and reveal that Gßγ complex is a signaling target potentially relevant for developing therapies for halting Aß degeneration in AD.
Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/fisiología , Encéfalo/metabolismo , Disfunción Cognitiva/genética , Disfunción Cognitiva/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/fisiología , Transducción de Señal/genética , Transducción de Señal/fisiología , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/terapia , Animales , Células Cultivadas , Disfunción Cognitiva/patología , Disfunción Cognitiva/terapia , Modelos Animales de Enfermedad , Hipocampo , Ratones Transgénicos , Terapia Molecular Dirigida , Complejos Multiproteicos , RatasRESUMEN
Alzheimer's disease (AD) can be considered as a disease of memory in its initial clinical stages. Amyloid-ß (Aß) peptide accumulation is central to the disease initiation leading later to intracellular neurofibrillary tangles (NFTs) of cytoskeletal tau protein formation. It is under discussion whether different Aß levels of aggregation, concentration, brain area, and/or time of exposure might be critical to the disease progression, as well as which intracellular pathways it activates. The aim of the present work was to study memory-related early molecular and behavioral alterations in a mouse model of AD, in which a subtle deregulation of the physiologic function of Aß can be inferred. For this purpose we used triple-transgenic (3xTg) mice, which develop Aß and tau pathology resembling the disease progression in humans. Memory impairment in novel object recognition task was evident by 5 months of age in 3xTg mice. Hippocampus and prefrontal cortex extra-nuclear protein extracts developed differential patterns of Aß aggregation. ERK1/MAPK showed higher levels of cytosolic activity at 3 months and higher levels of nuclear activity at 6 months in the prefrontal cortex. No significant differences were found in JNK and NF-κB activity and in calcineurin protein levels. Finally, intra-PFC administration of a MEK inhibitor in 6-month-old 3xTg mice was able to reverse memory impairment, suggesting that ERK pathway alterations might at least partially explain memory deficits observed in this model, likely as a consequence of memory trace disruption.
Asunto(s)
Enfermedad de Alzheimer/complicaciones , Inhibidores Enzimáticos/uso terapéutico , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Trastornos de la Memoria/etiología , Trastornos de la Memoria/terapia , Corteza Prefrontal/metabolismo , Factores de Edad , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Animales , Modelos Animales de Enfermedad , Ensayo de Cambio de Movilidad Electroforética , Inhibidores Enzimáticos/farmacología , Flavonoides/uso terapéutico , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/genética , Humanos , Trastornos de la Memoria/enzimología , Ratones , Ratones Transgénicos , Reconocimiento en Psicología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Proteínas tau/metabolismoRESUMEN
We previously reported that administration of a single dose of gabapentin (GBP) immediately after training improves memory of mice in an inhibitory avoidance task (IA), whereas GBP administered repeatedly for 7 days impairs memory. This is in accordance with the observation that long-term clinical treatment with GBP may be associated with adverse cognitive side effects. In the present work we used a GBP-loaded poly(epsilon-caprolactone) implant, allowing controlled release of the drug and maintenance of constant plasma levels over 1 week. When GBP-loaded implants were inserted subcutaneously into mice, immediately after training in the IA task, memory consolidation was enhanced. Moreover, GBP released from implants had an anticonvulsant action against pentylenetetrazole-induced seizures. These results suggest that maintenance of stable GBP plasma levels could protect against seizures without causing memory impairment. Hence, the adverse cognitive effects might be avoided by stabilizing plasma levels of the drug.