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The beneficial effects of increasing histamine levels on memory have acquired special interest due to their applicability to psychiatric conditions that cause memory impairments. In addition, by employing drug repurposing approaches, it was demonstrated that dihydroergotamine (DHE), an FDA drug approved to treat migraines, inhibits Histamine N Methyl Transferase (HNMT), the enzyme responsible for the inactivation of histamine in the brain. For this reason, in the present work, the effect of DHE on histamine levels in the hippocampus and its effects on memory was evaluated, employing the scopolamine-induced amnesia model, the Novel Object Recognition (NOR) paradigm, and the Morris Water Maze (MWM). Furthermore, the role of histamine 1 receptor (H1R) and histamine 2 receptor (H2R) antagonists in the improvement in memory produced by DHE in the scopolamine-induced amnesia model was evaluated. Results showed that the rats that received DHE (10 mg/kg, i.p.) showed increased histamine levels in the hippocampus after 1 h of administration but not after 5 h. In behavioral assays, it was shown that DHE (1 mg/kg, i.p.) administered 20 min before the training reversed the memory impairment produced by the administration of scopolamine (2 mg/kg, i.p.) immediately after the training in the NOR paradigm and MWM. Additionally, the effects in memory produced by DHE were blocked by pre-treatment with pyrilamine (20 mg/kg, i.p.) administered 30 min before the training in the NOR paradigm and MWM. These findings allow us to demonstrate that DHE improves memory in a scopolamine-induced amnesia model through increasing histamine levels at the hippocampus due to its activity as an HNMT inhibitor.
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Dihidroergotamina , Escopolamina , Animales , Ratas , Histamina , Amnesia/inducido químicamente , Amnesia/tratamiento farmacológico , Encéfalo , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Antagonistas de los Receptores H2 de la HistaminaRESUMEN
Corticosterone (CORT) release during learning experiences is associated with strong memories and activity of the glucocorticoid receptor. It has been shown that lesions of the dorsal striatum (DS) of rats trained in the cued version of the Morris water maze impair memory, and that local injection of CORT improves its performance, suggesting that DS activity is involved in procedural memory which may be modulated by CORT. We trained rats in cued Morris water maze and analyzed the effect of CORT synthesis inhibition on performance, CORT levels, expression of plasticity-involved genes, such as the brain derived neurotrophic factor (BDNF), casein kinase 2 (CK2), and the serum/glucocorticoid regulated kinase 1 (SGK1), as well as the presence of phosphorylated nuclear glucocorticoid receptor in serine 232 (pGR-S232) in the DS. The inhibition of CORT synthesis by metyrapone reduced CORT levels in plasma, prevented its increment in DS and impaired the performance of cued water maze. Additionally, there was an increase of CK2 and SGK1 mRNAs expression in trained subjects, which was unrelated to CORT levels. Finally, we did not observe changes in nuclear pGR-S232 in any condition. Our findings agree with evidence demonstrating that decreasing CORT levels hinders acquisition and consolidation of the spatial version of the Morris water maze; these novel findings broaden our knowledge about the involvement of the DS in the mechanisms underlying procedural memory.
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BACKGROUND: The application of automated analyses in neuroscience has become a practical approach. With automation, the algorithms and tools employed perform fast and accurate data analysis. It minimizes the inherent errors of manual analysis performed by a human experimenter. It also reduces the time required to analyze a large amount of data and the need for human and financial resources. METHODS: In this work, we describe a protocol for the automated analysis of the Morris Water Maze (MWM) and the Open Field (OF) test using the OpenCV library in Python. This simple protocol tracks mice navigation with high accuracy. RESULTS: In the MWM, both automated and manual analysis revealed similar results regarding the time the mice stayed in the target quadrant (p = 0.109). In the OF test, both automated and manual analysis revealed similar results regarding the time the mice stayed in the center (p = 0.520) and in the border (p = 0.503) of the field. CONCLUSIONS: The automated analysis protocol has several advantages over manual analysis. It saves time, reduces human errors, can be customized, and provides more consistent information about animal behavior during tests. We conclude that the automated protocol described here is reliable and provides consistent behavioral analysis in mice. This automated protocol could lead to deeper insight into behavioral neuroscience.
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Algoritmos , Programas Informáticos , Humanos , Ratones , Animales , Conducta AnimalRESUMEN
Morris water maze (MWM) test is widely used to evaluate the learning and memory deficits in rodents. Image processing and pattern recognition can be used to analyse videos and recognize automatically the tracking in MWM. There are several commercial and free access software that allows analyzing the behavioral tasks although they also have limitations such as automation, cost, user intervention among other things. The aim of this paper was to develop a new image processing technique to automatically analyse the track of the rat in the MWM, which we called RatsTrack. The MWM test was performed with an animal model for Alzheimer, and the videos were recorded to measure the distance, time, and speed. The segmentation method based on the projection of the video frames was made for pool identification, eliminating the rat, while conserving the shape of the pool. Then, the Hough transformation was used to recognize the position and radius of the pool. Finally, the frame in which the rat is released into the pool was established automatically using mathematical morphology techniques and added as a plugin on free access ImageJ software. The new image processing technique, RatsTrack, successfully detected and located the pool and rat without user intervention, significantly decreasing operational time and providing results for distance, time, speed, and acceleration parameters of the MWM test. Alzheimer's rats compared with the control group presented significant data measured with the RatsTrack. RatsTrack is a plugin of ImageJ software and will be made freely available for public use.
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The prevalence of autism spectrum disorder (ASD), a neurodevelopmental condition that impacts social interaction and sensory processing, is rising. Valproic acid (VPA) exposure during pregnancy causes autistic-like traits in offspring. Olanzapine (OLZ), an atypical antipsychotic, is used to treat ASD. We assessed the impact of OLZ on behavior, neuromorphology, and nitric oxide (NO) levels in the hippocampus using prenatal VPA treatment in rats. It is commonly known that ASD patients exhibit sensory abnormalities. As such, we utilized the tail flick test to validate the ASD model. In the novel object recognition test (NORT), VPA exposure reduces the discrimination index (DI) in the first introduction to the novel object. Moreover, OLZ and vehicle-treated rats perform differently in the second exposition to the DI of the novel object, suggesting that OLZ reverses VPA-induced deficits in recognition memory. The latency to find the hidden platform in the Morris water maze test of memory and learning improves in VPA-exposed rats after OLZ administration, indicating that OLZ improves spatial memory in these rats. Administration of prenatal VPA induces neuronal hypotrophy and reduces spine density in pyramidal neurons of the CA1 region of the hippocampus. Treatment with OLZ corrects the neuromorphological changes brought on by VPA. In the CA1 region of the hippocampus, VPA treatment increases the number of neurons, which normalizes with OLZ treatment. OLZ increases the NO levels in the dorsal hippocampus in control rats. In rats exposed to VPA, the second-generation antipsychotic OLZ reduces memory-related and neuroplastic alterations. The current findings support the use of OLZ in this illness and further validate the use of prenatal VPA as a model of ASD.
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Antipsicóticos , Trastorno del Espectro Autista , Trastorno Autístico , Efectos Tardíos de la Exposición Prenatal , Embarazo , Femenino , Ratas , Masculino , Animales , Humanos , Trastorno Autístico/inducido químicamente , Trastorno Autístico/tratamiento farmacológico , Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Olanzapina/efectos adversos , Trastorno del Espectro Autista/inducido químicamente , Ácido Valproico/farmacología , Ácido Valproico/uso terapéutico , Neuronas , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Modelos Animales de Enfermedad , Efectos Tardíos de la Exposición Prenatal/tratamiento farmacológico , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Conducta Animal , Conducta SocialRESUMEN
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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Here, we investigate the effects of obesity induced by monosodium glutamate (MSG) on cognitive impairment and whether this model induces any alteration in the affinity, density, and subtypes of muscarinic acetylcholine receptors (mAChRs) in rat hippocampus. Healthy rats were used as controls, and MSG-obese rats were selected via the Lee index > 0.300. The effects of MSG-induced obesity on hippocampal spatial learning and memory processes were evaluated by using the working memory versions of the Morris’ water maze task and the evaluation of mAChRs by binding assay and their subtypes by immunoprecipitation assays. [3H]Quinuclidinyl benzilate specific binding analysis showed that the equilibrium dissociation constant (KD) did not differ between control and MSG, indicating that affinity is not affected by obesity induced by MSG. The maximum number of binding sites (Bmax) obtained in MSG subjects was lower than that obtained from control rats, indicating a decrease in the expression of total mAChRs. Immunoprecipitation assays reveal a decrease in the expression of M1 subtype of MSG when compared with control rats (M2 to M5 subtypes did not differ between control and MSG). We also observed that MSG promotes a disruption of the spatial working memory which was accompanied by a decrease in the M1 mAChR subtype in rat hippocampus, thus suggesting deleterious long-term effects besides the obesity. In conclusion, these findings provide new insights into how obesity can influence spatial learning and memory that is hippocampal-dependent. The data suggest that the M1 mAChR subtype protein expression is a potential therapeutic target.
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Abstract Studies have revealed beneficial role of vitamin D3 in neuro-cognitive function. There is also supporting evidence on the involvement of nitric oxide (NO) in the neuro-protective action. However, its over production could contribute to brain disorders. In this study, demyelination was induced by ethidium bromide (EB) injection into the right side of the hippocampus area of male rats. Vitamin D3 was administered to rats for 7 and 28 days prior to behavioral experiments using Morris water maze (MWM). Travelled distance, time spent to reach the platform, and time spent in target zone, were considered for learning and spatial memory evaluation. Nitrite oxide (NO2-) concentration was measured as an indicator for nitric oxide production. The time spent to reach the platform and the travelled distance were decreased significantly by 28 days of vitamin D3 administration (compared to 7 days experiment). Time spent in target quadrant was significantly lowered by administered vitamin on day 28. Therefore, considering a number of studies that have shown the effect of vitamin D3 on cognition, these findings could support their potential effect. Besides, nitric oxide concentration significantly differed in 28 days of vitamin D3 treated group compared with the groups treated with EB or 7 days of vitamin D3.
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Colecalciferol/análisis , Óxido Nítrico/efectos adversos , Encefalopatías/patología , Enfermedades Desmielinizantes/clasificación , Etidio/efectos adversos , Memoria Espacial/clasificación , Prueba del Laberinto Acuático de MorrisRESUMEN
Object recognition (OR) and the Morris water maze (MWM) are classical tasks widely used to assess memory parameters and deficits in rodents. Learning processes in both tasks involve integrity of the hippocampus and associated regions, and prefrontal cortex connections. Here, we highlight the idea that these classical tests can be used to indicate memory deficits caused by models of disease that affect hippocampal function in rats, and identify some practical issues of OR and MWM, based on the literature and our experience. Additionally, we have shown that the performance of both tasks does not alter blood levels of corticosterone, considering exposure to a single task. Hence, taking into consideration the difficulties and care required during task execution, the infrastructure needed and the training of the experimenter, we suggest that OR and its variations offer minimal manageable stressful conditions, representing an effective and practical tool for hippocampal-related memory assessment of rats. Thus, OR may provide similar information to that of the MWM, despite controversy regarding hippocampus participation in OR and given due differences in the types of memory evaluated and researchers' objectives. We recommend the observation of some important precautions and details, also based on the literature and our own experience.
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Disfunción Cognitiva/diagnóstico , Hipocampo/metabolismo , Prueba del Laberinto Acuático de Morris , Reconocimiento en Psicología , Animales , Conducta Animal , Disfunción Cognitiva/metabolismo , Corticosterona/sangre , Hipocampo/lesiones , Masculino , Trastornos de la Memoria/diagnóstico , Ratas , Ratas Wistar , Percepción VisualRESUMEN
ABSTRACT Purpose: To explore the role and mechanisms of octreotide in neurofunctional recovery in the traumatic brain injury (TBI) model. Methods: Rats were subjected to midline incision followed by TBI in the prefrontal cortex region. After 72 hours, the behavioural and neurological deficits tests were performed, which included memory testing on Morris water maze for 5 days. Octreotide (15 and 30 mg/kg i.p.) was administered 30 minutes before subjecting to TBI, and its administration was continued for three days. Results: In TBI-subjected rats, administration of octreotide restored on day 4 escape latency time (ELT) and increased the time spent in the target quadrant (TSTQ) on day 5, suggesting the improvement in learning and memory. It also increased the expression of H2S, Nrf2, and cystathionine-γ-lyase (CSE) in the prefrontal cortex, without any significant effect on cystathionine-β-synthase. Octreotide also decreased the TNF-α levels and neurological severity score. However, co-administration of CSE inhibitor (D,L-propargylglycine) abolished octreotide-mediated neurofunctional recovery, decreased the levels of H2S and Nrf2 and increased the levels of TNF-α. Conclusions: Octreotide improved the neurological functions in TBI-subjected rats, which may be due to up-regulation of H2S biosynthetic enzyme (CSE), levels of H2S and Nrf2 and down-regulation of neuroinflammation.
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Animales , Ratas , Octreótido/farmacología , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Sulfuro de Hidrógeno/metabolismo , Sulfuro de Hidrógeno/farmacología , Factor de Necrosis Tumoral alfa , Factor 2 Relacionado con NF-E2RESUMEN
BACKGROUND: Alzheimer's disease (AD) is a chronic, progressive neurodegenerative disease. Recent studies have reported the close association between cognitive function in AD and purinergic receptors in the central nervous system. In the current study, we investigated the effect of CD73 inhibitor α, ß-methylene ADP (APCP) on cognitive impairment of AD in mice, and to explore the potential underlying mechanisms. RESULTS: We found that acute administration of Aß142 (i.c.v.) resulted in a significant increase in adenosine release by using microdialysis study. Chronic administration of APCP (10, 30 mg/kg) for 20 d obviously mitigated the spatial working memory impairment of Aß142-treated mice in both Morris water maze (MWM) test and Y-maze test. In addition, the extracellular adenosine production in the hippocampus was inhibited by APCP in Aß-treated mice. Further analyses indicated expression of acetyltransferase (ChAT) in hippocampus of mice of was significantly reduced, while acetylcholinesterase (AChE) expression increased, which compared to model group. We observed that APCP did not significantly alter the NLRP3 inflammasome activity in hippocampus, indicating that anti-central inflammation seems not to be involved in APCP effect. CONCLUSIONS: In conclusion, we report for the first time that inhibition of CD73 by APCP was able to protect against memory loss induced by Aß142 in mice, which may be due to the decrease of CD73-driven adenosine production in hippocampus. Enhancement of central cholinergic function of the central nervous system may also be involved in the effects of APCP.
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Animales , Masculino , Ratones , Adenosina Difosfato/análogos & derivados , Enfermedades Neurodegenerativas/prevención & control , Hipocampo , Nucleotidasas/antagonistas & inhibidores , Acetilcolinesterasa , Adenosina Difosfato/administración & dosificación , Enfermedad de Alzheimer/prevención & control , Prueba del Laberinto Acuático de Morris , Ratones Endogámicos C57BLRESUMEN
Spatial learning and memory enables individuals to orientate themselves in an external environment. Synaptic stimulation of dendritic spines on hippocampal place cells underlies adaptive cognitive performance, inducing plastic changes such as spinogenesis, pruning and structural interconversion. Such plastic changes are driven by complex molecular machinery that relies on several actin cytoskeleton-associated proteins (ACAP's), these interacting with actin filaments in the postsynaptic density to guide the conformational changes to spines in accordance with the synaptic information they receive. However, the specific dynamics of the plastic changes in spines driven by ACAP's are poorly understood. Adult rats exhibit efficient allocentric reference memory 30 days after training in a spatial learning paradigm in the Morris water maze. A Golgi study revealed this behavior to be associated with a reduction in both spine density and in mushroom spines, as well as a concomitant increase in thin spines. These changes were accompanied by the overexpression of mRNA encoding ß-actin, Spinophilin and Cortactin, whilst the expression of Profilin, α-actinin, Drebrin, Synaptopodin and Myosin decreased. By contrast, no changes were evident in Cofilin, Gelsolin and Arp2/3 mRNA. From this analysis, it appears that neither spinogenesis nor new mushroom spines are necessary for long-term spatial information retrieval, while thin spines could be potentiated to retrieve pre-learned spatial information. Further studies that focus on the signaling pathways and their related molecules may shed further light on the molecular dynamics of the plastic changes to dendritic spines that underlie cognitive performance, both under normal and pathological conditions.
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Región CA1 Hipocampal/fisiología , Proteínas del Citoesqueleto/fisiología , Espinas Dendríticas/fisiología , Memoria a Largo Plazo/fisiología , Plasticidad Neuronal , Animales , Masculino , Ratas Sprague-Dawley , Aprendizaje Espacial/fisiología , Memoria Espacial/fisiologíaRESUMEN
Resumen Introducción: La masticación es una actividad periférica que influye positivamente sobre el sistema nervioso central (SNC). Sin embargo, a pesar de los diferentes estudios realizados, aún no está claro cómo la masticación afecta a los procesos cognitivos. Debido a ello se buscó determinar el efecto de la masticación sobre la memoria y aprendizaje espacial en ratones adultos y seniles. Materiales: Se empleó un grupo de 16 ratones adultos y de 16 ratones seniles que fueron aleatorizados en 2 subgrupos de 8 ratones cada uno. Un subgrupo se alimentó con dieta granosa convencional para ratón (subgrupo masticación normal), el otro subgrupo se alimentó con dieta en polvo (subgrupo masticación deficiente). Durante 2 meses se sometió a cada subgrupo a su dieta respectiva. Se evaluó en el laberinto acuático de Morris a los ratones adultos a los 7 meses de edad y a los seniles a los 12 meses de edad, mediante la fase de adquisición y de fase de recuperación de memoria y aprendizaje espacial. Resultados: Los ratones adultos, con masticación normal, mostraron mejor adquisición de memoria y aprendizaje espacial con respecto a los ratones con masticación deficiente en el primer día de evaluación (p = 0,035). Al agrupar a los ratones bajo el mismo tipo de masticación se encontró, en los subgrupos bajo masticación normal, una mejor adquisición de memoria y aprendizaje espacial en el subgrupo adulto sobre el subgrupo senil (p < 0,05). Conclusiones: La masticación normal tuvo un efecto positivo sobre la adquisición de información espacial en los ratones adultos.
Introduction: Chewing is a peripheral activity that positively influences the central nervous system (CNS). However, despite the different studies carried out, it is still not clear how chewing affects cognitive processes. Because of this, was trying to find the effect of chewing on memory and spatial learning in adult and senile mice. Methods: A group of 16 adult and senile mice were randomized into 2 subgroups of 8 mice each group. One subgroup was fed with conventional grainy diet for mice (normal chewing subgroup), the other subgroup was fed dietary powder (deficient chewing subgroup). During 2 months each subgroup was submitted to their respective diet. Adult mice at 7 months of age and senile at 12 months of age were evaluated in the Morris' water maze; through of the acquisition phase and the probe test of memory and spatial learning. Results: Adult mice with normal chewing showed better memory acquisition and spatial learning with respect to mice with deficient chewing on the first day of evaluation (p = 0.035). When grouping the mice in the same type of chewing, in the subgroups under normal chewing, a better acquisition of memory and spatial learning was found in the adult subgroup on than in the senile subgroup (p < 0.05). Conclusions: Normal chewing had a positive effect on the acquisition of spatial information in adult mice.
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Animales , Ratones , Sistema Nervioso Central , Cognición , Aprendizaje Espacial , Masticación , MemoriaRESUMEN
The locus coeruleus (LC)-norepinephrine (NE) system modulates a range of salient brain functions, including memory and response to stress. The LC-NE system is regulated by neurochemically diverse inputs, including a range of neuropeptides such as arginine-vasopressin (AVP). Whilst the origins of many of these LC inputs, their synaptic connectivity with LC neurons, and their contribution to LC-mediated brain functions, have been well characterized, this is not the case for the AVP-LC system. Therefore, our aims were to define the types of synapses formed by AVP+ fibers with LC neurons using immunohistochemistry together with confocal and transmission electron microscopy (TEM), the origins of such inputs, using retrograde tracers, and the plasticity of the LC AVP system in response to stress and spatial learning, using the maternal separation (MS) and Morris water maze (MWM) paradigms, respectively, in rat. Confocal microscopy revealed that AVP+ fibers contacting tyrosine hydroxylase (TH)+ LC neurons were also immunopositive for vesicular glutamate transporter 2, a marker of presynaptic glutamatergic axons. TEM confirmed that AVP+ axons formed Gray type I (asymmetric) synapses with TH+ dendrites thus confirming excitatory synaptic connections between these systems. Retrograde tracing revealed that these LC AVP+ fibers originate from hypothalamic vasopressinergic magnocellular neurosecretory neurons (AVPMNNs). MS induced a significant increase in the density of LC AVP+ fibers. Finally, AVPMNN circuit upregulation by water-deprivation improved MWM performance while increased Fos expression was found in LC and efferent regions such as hippocampus and prefrontal cortex, suggesting that AVPMMN projections to LC could integrate homeostatic responses modifying neuroplasticity.
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Objective: To determine whether performance in a virtual spatial navigational task is poorer in persistent postural perceptual dizziness (PPPD) patients than in healthy volunteers and patients suffering other vestibular disorders. Methods: Subjects were asked to perform three virtual Morris water maze spatial navigational tasks: (i) with a visible target, (ii) then with an invisible target and a fixed starting position, and finally (iii) with an invisible target and random initial position. Data were analyzed using the cumulative search error (CSE) index. Results: While all subjects performed equally well with a visible target, the patients with PPPD (n = 19) performed poorer (p < 0.004) in the invisible target/navigationally demanding tasks (CSE median of 8) than did the healthy controls (n = 18; CSE: 3) and vestibular controls (n = 19; CSE: 4). Navigational performance in the most challenging setting allowed us to discriminate PPPD patients from controls with an area under the receiver operating characteristic curve of 0.83 (sensitivity 78.1%; specificity 83.3%). PPPD patients manifested more chaotic and disorganized search strategies, with more dispersion in the navigational pool than those of the non-PPPD groups (standard distance deviation of 0.97 vs. 0.46 in vestibular controls and 0.20 in healthy controls; p < 0.001). Conclusions: While all patients suffering a vestibular disorder had poorer navigational abilities than healthy controls did, patients with PPPD showed the worst performance, to the point that this variable allowed the discrimination of PPPD from non-PPPD patients. This distinct impairment in spatial navigation abilities offers new insights into PPPD pathophysiology and may also represent a new biomarker for diagnosing this entity.
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Unbalanced nutrition during perinatal period causes varying degrees of perturbations in the metabolism and cognitive functions of offspring. The aim of this study was to investigate effects of maternal and postweaning high-fat diet (HFD) exposure on the growth parameters, hippocampal functions and morphology of offspring in a sex-dependent manner. Spraque-Dawley rats were fed either standard (10 % fat) or saturated-fat (65 % fat) diet during their gestation and lactation period. After weaning, pups were sustained in same diet for 6 more weeks. Body mass index (BMI) of pups were monitored weekly, then spontaneous locomotor activities were recorded. Spatial learning and memory functions were analyzed by Morris Water Maze (MWM) test. Total volumetric changes of hippocampal subfields were estimated by Cavalieri method. HFD exposure produced sex-dependent alterations in BMI, serum lipid and activity levels. MWM results showed no significant difference among groups. However, retrieval indexes were higher in HFD-fed males. Total volumetric analysis of the dentate gyrus was comparable, but the pyramidal cell layer volume of HFD-fed males was lower than those of SD-fed males. Despite alterations in some growth and lipid parameters, maternal and perinatal exposure to HFD did not markedly affect cognitive functions and hippocampal morphology of offspring.
La nutrición desequilibrada durante el período perinatal causa diversos grados de perturbaciones en el metabolismo y las funciones cognitivas en neonatos. El objetivo de este estudio fue investigar los efectos de la exposición a una dieta alta en grasas (HFD) materna y posdestete en los parámetros de crecimiento, las funciones del hipocampo y la morfología de neonatos de una manera dependiente del sexo. Ratas SpragueDawley fueron alimentadas con dieta estándar (10 % grasa) o grasa saturada (65 % grasa) durante su período de gestación y lactancia. Después del destete, las crías se mantuvieron en la misma dieta durante 6 semanas. El índice de masa corporal (IMC) de las crías se controló semanalmente, luego se registraron las actividades locomotoras espontáneas. El aprendizaje espacial y las funciones de memoria se analizaron mediante la prueba Morris Water Maze (MWM). Los cambios volumétricos totales de los subcampos del hipocampo se estimaron mediante el método de Cavalieri. La exposición a HFD produjo alteraciones dependientes del sexo en el IMC, los niveles de lípidos séricos y los niveles de actividad. Los resultados de MWM no mostraron diferencias significativas entre los grupos. Sin embargo, los índices de recuperación fueron más altos en machos alimentados con HFD. El análisis volumétrico total del giro dentado fue comparable, pero el volumen de la capa de células piramidales de los machos alimentados con HFD fue menor que el de los machos alimentados con SD. A pesar de las alteraciones en algunos parámetros lipídicos y de crecimiento, la exposición materna y perinatal a HFD no afectó marcadamente las funciones cognitivas y la morfología del hipocampo de la descendencia.
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Animales , Masculino , Femenino , Embarazo , Ratas , Efectos Tardíos de la Exposición Prenatal , Grasas de la Dieta/efectos adversos , Hipocampo/fisiopatología , Hipocampo/patología , Tamaño de los Órganos , Ratas Sprague-Dawley , Aprendizaje por Laberinto , Fenómenos Fisiologicos de la Nutrición Prenatal , Animales Recién NacidosRESUMEN
Early life exposure to environmental pollutants and toxic chemicals has been linked to learning and behavioral alterations in children. iAs exposure is associated with different types neurological disorders such as memory and learning impairment. iAs is methylated in the brain by the arsenic III-methyltransferase in a process that requires glutathione (GSH). The xCT-antiporter cell membrane transporter participates in the influx of cystine for GSH synthesis in exchange for glutamate in a 1:1 ratio. In CD-1 mice gestationally exposed to 20 ppm of sodium arsenite in drinking water, we have previously observed up-regulation of xCT in the male mouse hippocampus which caused glutamatergic synapse alterations affecting learning and memory processes. Here, we used the same gestational iAs exposure model to investigate whether the up-regulation of xCT and down-regulation of GLT-1 transporters were associated with higher levels of extracellular glutamate and changes in the expression of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor, responsible for excitatory fast synaptic transmission. The induction of LTP in the perforant-dentate gyrus pathway (PP-DG) of the hippocampus was also studied, as well as learning and memory formation using the water maze test. Changes in GSH levels were also tested in the hippocampus of animals exposed to iAs. Results showed increased GSH synthesis (p < 0.05), associated with significantly higher extracellular glutamate levels in iAs exposed mice. Exposure was also significantly associated with AMPA subunits down-regulation, deficient LTP induction, and lower excitability of the PP-DG pathway. In addition, animals showed deficient learning and memory in the Morris Water Maze test.
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Arsénico/toxicidad , Ácido Glutámico/metabolismo , Hipocampo/efectos de los fármacos , Trastornos de la Memoria/inducido químicamente , Efectos Tardíos de la Exposición Prenatal , Receptores de Glutamato/metabolismo , Animales , Giro Dentado/efectos de los fármacos , Giro Dentado/metabolismo , Femenino , Glutatión/metabolismo , Hipocampo/metabolismo , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Trastornos de la Memoria/etiología , Ratones Endogámicos , Vía Perforante/efectos de los fármacos , Embarazo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/metabolismoRESUMEN
As early protein malnutrition has a critically long-lasting impact on the hippocampal formation and its role in learning and memory, and environmental enrichment has demonstrated great success in ameliorating functional deficits, here we ask whether exposure to an enriched environment could be employed to prevent spatial memory impairment and neuroanatomical changes in the hippocampus of adult rats maintained on a protein deficient diet during brain development (P0-P35). To elucidate the protective effects of environmental enrichment, we used the Morris water task and neuroanatomical analysis to determine whether changes in spatial memory and number and size of CA1 neurons differed significantly among groups. Protein malnutrition and environmental enrichment during brain development had significant effects on the spatial memory and hippocampal anatomy of adult rats. Malnourished but non-enriched rats (MN) required more time to find the hidden platform than well-nourished but non-enriched rats (WN). Malnourished but enriched rats (ME) performed better than the MN and similarly to the WN rats. There was no difference between well-nourished but non-enriched and enriched rats (WE). Anatomically, fewer CA1 neurons were found in the hippocampus of MN rats than in those of WN rats. However, it was also observed that ME and WN rats retained a similar number of neurons. These results suggest that environmental enrichment during brain development alters cognitive task performance and hippocampal neuroanatomy in a manner that is neuroprotective against malnutrition-induced brain injury. These results could have significant implications for malnourished infants expected to be at risk of disturbed brain development.
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Desnutrición/metabolismo , Memoria Espacial/fisiología , Animales , Encéfalo/crecimiento & desarrollo , Encéfalo/fisiopatología , Ambiente , Hipocampo/crecimiento & desarrollo , Hipocampo/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/fisiopatología , Neuronas , Ratas , Ratas Wistar , Aprendizaje Espacial/fisiología , Lóbulo Temporal/fisiopatologíaRESUMEN
Glutamate is involved in excitotoxic mechanisms by interacting with different receptors. Such interactions result in neuronal death associated with several neurodegenerative disorders of the central nervous system (CNS). The aim of this work was to study the time course of changes in the expression of GluR1 and GluR2 subunits of glutamate amino-acid-3-hydroxy-5-methyl-isoxazol-4-propionic acid (AMPA) receptors in rat hippocampus induced by NMDA intrahippocampal injection. Rats were submitted to stereotaxic surgery for NMDA or saline (control) microinjection into dorsal hippocampus and the parameters were evaluated 24 h, 1, 2, and 4 weeks after injection. The extension and efficacy of the NMDA-induced injury were evaluated by Morris water maze (MWM) behavioral test and Nissl staining. The expression of GluR1 and GluR2 receptors, glial fibrillary acidic protein (GFAP), and neuronal marker (NeuN) was analyzed by immunohistochemistry. It was observed the impairment of learning and memory functions, loss of neuronal cells, and glial proliferation in CA1 area of NMDA compared with control groups, confirming the injury efficacy. In addition, NMDA injection induced distinct changes in GluR1 and GluR2 expression over the time. In conclusion, such changes may be related to the complex mechanism triggered in response to NMDA injection resulting in a local injury and in the activation of neuronal plasticity.
RESUMEN
Alzheimer's disease is a neurodegenerative disease associated with progressive memory and cognitive decline. Previous studies have identified the benefits of cognitive enrichment on reducing disease pathology. Additionally, epidemiological and clinical data suggest that repeated exercise, and cognitive and social enrichment, can improve and/or delay the cognitive deficiencies associated with aging and neurodegenerative diseases. In the present study, 3xTg-AD mice were exposed to a rigorous training routine beginning at 3 months of age, which consisted of repeated training in the Morris water maze spatial recognition task every 3 months, ending at 18 months of age. At the conclusion of the final Morris water maze training session, animals subsequently underwent testing in another hippocampus-dependent spatial task, the Barnes maze task, and on the more cortical-dependent novel object recognition memory task. Our data show that periodic cognitive enrichment throughout aging, via multiple learning episodes in the Morris water maze task, can improve the memory performance of aged 3xTg-AD mice in a separate spatial recognition task, and in a preference memory task, when compared to naïve aged matched 3xTg-AD mice. Furthermore, we observed that the cognitive enrichment properties of Morris water maze exposer, was detectable in repeatedly trained animals as early as 6 months of age. These findings suggest early repeated cognitive enrichment can mitigate the diverse cognitive deficits observed in Alzheimer's disease.