Chronic-Antibiotics Induced Gut Microbiota Dysbiosis Rescues Memory Impairment and Reduces ß-Amyloid Aggregation in a Preclinical Alzheimer's Disease Model.

Alzheimer's disease (AD) is a multifactorial pathology characterized by ß-amyloid (Aß) deposits, Tau hyperphosphorylation, neuroinflammatory response, and cognitive deficit. Changes in the bacterial gut microbiota (BGM) have been reported as a possible etiological factor of AD. We assessed in offspring (F1) 3xTg, the effect of BGM dysbiosisdysbiosis in mothers (F0) at gestation and F1 from lactation up to the age of 5 months on Aß and Tau levels in the hippocampus, as well as on spatial memory at the early symptomatic stage of AD. We found that BGM dysbiosisdysbiosis with antibiotics (Abx) treatment in F0 was vertically transferred to their F1 3xTg mice, as observed on postnatal day (PD) 30 and 150. On PD150, we observed a delay in spatial memory impairment and Aß deposits, but not in Tau and pTau protein in the hippocampus at the early symptomatic stage of AD. These effects are correlated with relative abundance of bacteria and alpha diversity, and are specific to bacterial consortia. Our results suggest that this specific BGM could reduce neuroinflammatory responses related to cerebral amyloidosis and cognitive deficit and activate metabolic pathways associated with the biosynthesis of triggering or protective molecules for AD.

Oxidative stress, the immune response, synaptic plasticity, and cognition in transgenic models of Alzheimer disease.

INTRODUCTION: Worldwide, approximately 50 million people have dementia, with Alzheimer disease (AD) being the most common type, accounting for 60%-70% of cases. Given its high incidence, it is imperative to design studies to expand our knowledge about its onset and development, and to develop early diagnosis strategies and/or possible treatments. One methodological strategy is the use of transgenic mouse models for the study of the factors involved in AD aetiology, which include oxidative stress and the immune response. DEVELOPMENT: We searched the PubMed, Scopus, and Google Scholar databases for original articles and reviews published between 2013 and 2019. In this review, we address 2 factors that have been studied independently, oxidative stress and the immune response, in transgenic models of AD, and discuss the relationship between these factors and their impact on the loss of synaptic and structural plasticity, resulting in cognitive impairment. CONCLUSION: This review describes possible mechanisms by which oxidative stress and the immune response participate in the molecular, cellular, and behavioural effects of AD, observing a close relationship between these factors, which lead to cognitive impairment.

Ozone pollution, oxidative stress, synaptic plasticity, and neurodegeneration.

INTRODUCTION: Overpopulation and industrial growth result in an increase in air pollution, mainly due to suspended particulate matter and the formation of ozone. Repeated exposure to low doses of ozone, such as on a day with high air pollution levels, results in a state of chronic oxidative stress, causing the loss of dendritic spines, alterations in cerebral plasticity and in learning and memory mechanisms, and neuronal death and a loss of brain repair capacity. This has a direct impact on human health, increasing the incidence of chronic and degenerative diseases. DEVELOPMENT: We performed a search of the PubMed, Scopus, and Google Scholar databases for original articles and reviews published between 2000 and 2018 and addressing the main consequences of ozone exposure on synaptic plasticity, information processing in cognitive processes, and the alterations that may lead to the development of neurodegenerative diseases. CONCLUSIONS: This review describes one of the pathophysiological mechanisms of the effect of repeated exposure to low doses of ozone, which causes loss of synaptic plasticity by producing a state of chronic oxidative stress. This brain function is key to both information processing and the generation of structural changes in neuronal populations. We also address the effect of chronic ozone exposure on brain tissue and the close relationship between ozone pollution and the appearance and progression of neurodegenerative diseases.

Spatial Memory and Gut Microbiota Alterations Are Already Present in Early Adulthood in a Pre-clinical Transgenic Model of Alzheimer's Disease.

The irreversible and progressive neurodegenerative Alzheimer's disease (AD) is characterized by cognitive decline, extracellular ß-amyloid peptide accumulation, and tau neurofibrillary tangles in the cortex and hippocampus. The triple-transgenic (3xTg) mouse model of AD presents memory impairment in several behavioral paradigms and histopathological alterations from 6 to 16 months old. Additionally, it seems that dysbiotic gut microbiota is present in both mouse models and patients of AD at the cognitive symptomatic stage. The present study aimed to assess spatial learning, memory retention, and gut microbiota alterations in an early adult stage of the 3xTg-AD mice as well as to explore its sexual dimorphism. We evaluated motor activity, novel-object localization training, and retention test as well as collected fecal samples to characterize relative abundance, alpha- and beta-diversity, and linear discriminant analysis (LDA) effect size (LEfSe) analysis in gut microbiota in both female and male 3xTg-AD mice, and controls [non-transgenic mice (NoTg)], at 3 and 5 months old. We found spatial memory deficits in female and male 3xTg-AD but no alteration neither during training nor in motor activity. Importantly, already at 3 months old, we observed decreased relative abundances of Actinobacteria and TM7 in 3xTg-AD compared to NoTg mice, while the beta diversity of gut microbiota was different in female and male 3xTg-AD mice in comparison to NoTg. Our results suggest that gut microbiota modifications in 3xTg-AD mice anticipate and thus could be causally related to cognitive decline already at the early adult age of AD. We propose that microbiota alterations may be used as an early and non-invasive diagnostic biomarker of AD.

Recruitment of neurons in basolateral amygdala after intense training produces a stronger memory trace.

Typical amnestic treatments are ineffective when administered to subjects trained in aversively-motivated tasks using relatively high foot-shock intensities. This effect has been found when treatments that disrupt neuronal activity are administered to different regions of the brain, including the amygdala. However, the molecular mechanisms induced by this intense training are unknown. We made a detailed mapping of c-Fos-expressing neurons in four regions of the amygdala after moderate and intense one-trial inhibitory avoidance training. Rats were sacrificed 90 min after training or after appropriate control procedures, and their brains were prepared for immunohistochemical c-Fos protein detection in the central, lateral, and in the anterior and posterior parts of the basolateral amygdaloid nucleus. We found a high percentage of neurons expressing c-Fos in the anterior part of the basolateral nucleus after moderate training, and this percentage increased further after intense training. Moderate and intense training did not induce changes in c-Fos expression in the other explored amygdaloid regions. These results show that inhibitory avoidance training produces a localized expression of c-Fos in the basolateral anterior nucleus of the amygdala, which is dependent upon the intensity of training, and indicate that synaptic plastic changes in this region may be required for the formation of memory of moderate and intense aversive learning.

Inhibition of transcription and translation in dorsal hippocampus does not interfere with consolidation of memory of intense training.

Findings of several experiments indicate that many treatments that typically interfere with memory consolidation are ineffective in preventing or attenuating memory induced by intense training. As extensive evidence suggests that the consolidation of newly acquired memories requires gene expression and de novo protein synthesis the present study investigated whether intense training prevents consolidation impairment induced by blockers of mRNA and protein synthesis. Rats were given a single inhibitory training trial using a moderate (1.0 mA) or a relatively intense (2.0 mA) foot-shock. Bilateral hippocampal infusions of the mRNA synthesis blocker DRB (10, 40 or 80 ng/0.5 µL/hemisphere) or the protein synthesis inhibitor anisomycin (ANI), an inhibitor de novo protein synthesis (15.62, 31.25, or 62.50 µg/0.5 µL/hemisphere) were administered 15 min prior to training. Retention was measured at 30 min or 48 h following training. DRB and ANI impaired memory of moderate training in a dose-dependent manner without affecting short-term memory. In contrast, memory consolidation was not impaired in the groups trained with 2.0 mA. The findings showed that: (1) inhibitors of transcription and translation in the hippocampus impair the consolidation of memory of inhibitory avoidance learning induced by moderate levels of aversive stimulation and (2) blocking of mRNA and protein synthesis does not prevent the consolidation of memory induced by relatively high levels of aversive stimulation. These findings do not support the hypothesis that gene expression and de novo protein synthesis are necessary steps for long-term memory formation as memory was not impaired if intense foot-shock was used in training.

Effect of Ozone Exposure on Dendritic Spines of CA1 Pyramidal Neurons of the Dorsal Hippocampus and on Object-place Recognition Memory in Rats.

The growth of many cities has generated an increase in the emission of environmental pollutants. Exposure to these pollutants has been associated with increased mortality worldwide. These pollutants, such as ozone, produce reactive oxygen species (ROS), which cause oxidative stress throughout the body. It has been observed that there is a relationship between chronic oxidative stress and the development of degenerative diseases typical of old age such as amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease. The purpose of this research was to evaluate whether chronic exposure to ozone produces a deleterious effect on density and morphology of dendritic spines in CA1 of dorsal hippocampus and on learning and memory of object-place recognition. Rats were exposed to ozone or to ozone-free air for a period of 15, 30, 60, or 90 days. The principal results indicate that chronic oxidative stress induced by ozone produces a decrease in the density of dendritic spines, a decrease in thin and mushroom spine ratios, and an increase in stubby spine ratio, as well as a deficit in learning and memory of the object-place recognition task. These results indicate that chronic ozone exposure produces a loss in the inputs of CA1 neurons of the dorsal hippocampus, which may be the source of the cognitive deficits observed in the object-place recognition task, as indicated by the decrease in density of dendritic spines; these alterations are similar to those reported in some neurodegenerative diseases such as Alzheimer's disease.

Mushroom spine dynamics in medium spiny neurons of dorsal striatum associated with memory of moderate and intense training.

A growing body of evidence indicates that treatments that typically impair memory consolidation become ineffective when animals are given intense training. This effect has been obtained by treatments interfering with the neural activity of several brain structures, including the dorsal striatum. The mechanisms that mediate this phenomenon are unknown. One possibility is that intense training promotes the transfer of information derived from the enhanced training to a wider neuronal network. We now report that inhibitory avoidance (IA) induces mushroom spinogenesis in the medium spiny neurons (MSNs) of the dorsal striatum in rats, which is dependent upon the intensity of the foot-shock used for training; that is, the effect is seen only when high-intensity foot-shock is used in training. We also found that the relative density of thin spines was reduced. These changes were evident at 6 h after training and persisted for at least 24 h afterward. Importantly, foot-shock alone did not increase spinogenesis. Spine density in MSNs in the accumbens was also increased, but the increase did not correlate with the associative process involved in IA; rather, it resulted from the administration of the aversive stimulation alone. These findings suggest that mushroom spines of MSNs of the dorsal striatum receive afferent information that is involved in the integrative activity necessary for memory consolidation, and that intense training facilitates transfer of information from the dorsal striatum to other brain regions through augmented spinogenesis.

Differential effects of spaced vs. massed training in long-term object-identity and object-location recognition memory.

Here we tested whether the well-known superiority of spaced training over massed training is equally evident in both object identity and object location recognition memory. We trained animals with objects placed in a variable or in a fixed location to produce a location-independent object identity memory or a location-dependent object representation. The training consisted of 5 trials that occurred either on one day (Massed) or over the course of 5 consecutive days (Spaced). The memory test was done in independent groups of animals either 24h or 7 days after the last training trial. In each test the animals were exposed to either a novel object, when trained with the objects in variable locations, or to a familiar object in a novel location, when trained with objects in fixed locations. The difference in time spent exploring the changed versus the familiar objects was used as a measure of recognition memory. For the object-identity-trained animals, spaced training produced clear evidence of recognition memory after both 24h and 7 days, but massed-training animals showed it only after 24h. In contrast, for the object-location-trained animals, recognition memory was evident after both retention intervals and with both training procedures. When objects were placed in variable locations for the two types of training and the test was done with a brand-new location, only the spaced-training animals showed recognition at 24h, but surprisingly, after 7 days, animals trained using both procedures were able to recognize the change, suggesting a post-training consolidation process. We suggest that the two training procedures trigger different neural mechanisms that may differ in the two segregated streams that process object information and that may consolidate differently.

Alternativas metodológicas para perfeccionar la adquisición de habilidades en residentes de Medicina Interna / Methodological alternative to improve the acquisition of abilities in the Internal Medicine residents

Se realizó una investigación de desarrollo con enfoque cualitativo en el Hospital Universitario "Arnaldo Milián Castro" de Villa Clara en el período comprendido entre septiembre del 2008 hasta julio del 2010, con el propósito de diseñar varias acciones metodológicas para perfeccionar la adquisición de habilidades del residente de Medicina Interna que se forma en esta institución. El proceso indagatorio fue concebido en tres etapas: diagnóstico, diseño de las acciones metodológicas y valoración por criterio de especialistas del producto final. Las principales dificultades detectadas en la adquisición de habilidades fueron: dificultad en la lectura de EKG, habilidades técnicas deficientes, dificultad en las habilidades diagnósticas y terapéuticas y bajo rigor en la evaluación del residente. A partir del diagnóstico realizado se diseñaron alternativas metodológicas que fueron valoradas como pertinentes por los especialistas seleccionados.

A qualitative study was carried out at "Arnaldo Milián Castro" University Hospital of Villa Clara from September 2008 to July 2010, with the purpose to design a series of methodological actions to improve the acquisition of abilities in the Internal Medicine residents which are formed in this institution. The process was organized in three stages: Diagnoses, designing of methodological actions and the valuation of the final product by the Specialists' Criteria Method. The principal difficulties detected in the acquisition of abilities were: Difficulties in the reading of EKGs, insufficiency in technical abilities, difficulties in the diagnosed and therapeutic abilities of the residents. A series of methodological actions were design according to the diagnoses, they were valued as pertinent by the selected specialists.