Sandra Sanchez-Roige

Long-term treadmill exercise induces neuroprotective molecular changes in rat brain.

Exercise enhances general health. However, its effects on neurodegeneration are controversial, and the molecular pathways in the brain involved in this enhancement are poorly understood. Here, we examined the effect of long-term moderate treadmill training on adult male rat cortex and hippocampus to identify the cellular mechanisms behind the effects of exercise. We compared three animal groups: exercised (30 min/day, 12 m/min, 5 days/wk, 36 wk), handled but nonexercised (treadmill handling procedure, 0 m/min), and sedentary (nonhandled and nonexercised). Moderate long-term exercise induced an increase in IGF-1 levels and also in energy parameters, such as PGC-1α and the OXPHOS system. Moreover, the sirtuin 1 pathway was activated in both the exercised and nonexercised groups but not in sedentary rats. This induction could be a consequence of exercise as well as the handling procedure. To determine whether the long-term moderate treadmill training had neuroprotective effects, we studied tau hyperphosphorylation and GSK3β activation. Our results showed reduced levels of phospho-tau and GSK3β activation mainly in the hippocampus of the exercised animals. In conclusion, in our rodent model, exercise improved several major brain parameters, especially in the hippocampus. These improvements induced the upregulation of sirtuin 1, a protein that extends life, the stimulation of mitochondrial biogenesis, the activation of AMPK, and the prevention of signs of neurodegeneration. These findings are consistent with other reports showing that physical exercise has positive effects on hormesis.

Exaggerated waiting impulsivity associated with human binge drinking, and high alcohol consumption in mice

There are well-established links between impulsivity and alcohol use in humans and animal models; however, whether exaggerated impulsivity is a premorbid risk factor or a consequence of alcohol intake remains unclear. In a first approach, human young (18–25 years) social binge and non-binge drinkers were tested for motor impulsivity and attentional abilities in a human version of the Five-Choice Serial Reaction Time Task (Sx-5CSRTT), modeled on the rodent 5CSRTT. Participants completed four variants of the Sx-5CSRT, in addition to being screened for impulsive traits (BIS-11 questionnaire) and impulsive behavior (by means of the Delay Discounting Questionnaire, Two-Choice Impulsivity Paradigm (TCIP), Stop Signal Reaction Time, and Time Estimation Task). Using a second approach, we compared one of these impulsivity measures, 5CSRTT performance, in two inbred strains of mice known to differ in alcohol intake. Compared with non-bingers (NBD; n=22), binge drinkers (BD, n=22) showed robust impairments in attention and premature responding when evaluated under increased attentional load, in addition to presenting deficits in decision making using the TCIP. The best predictors for high binge drinking score were premature responding in the Sx-5CSRTT, trait impulsivity in the BIS-11, and decision making in the TCIP. Alcohol-naïve C57BL/6J (B6) mice (alcohol preferring) were more impulsive in the 5CSRTT than DBA2/J (D2) mice (alcohol averse); the degree of impulsivity correlated with subsequent alcohol consumption. Homologous measures in animal and human studies indicate increased premature responding in young social BD and in the ethanol-preferring B6 strain of mice.

Measuring impulsivity in mice: the five-choice serial reaction time task

RationaleMice are useful tools for dissecting genetic and environmental factors in relation to the study of attention and impulsivity. The five-choice serial reaction time task (5CSRTT) paradigm has been well established in rats, but its transferability to mice is less well documented.ObjectivesThis study aims to summarise the main results of the 5CSRTT in mice, with special focus on impulsivity.MethodsThe 5CSRTT can be used to explore aspects of both attentional and inhibitory control mechanisms.ResultsDifferent manipulations of the task parameters can lead to different results; adjusting the protocol as a function of the main variable of interest or the standardisation of the protocol to be applied to a large set of strains will be desirable.ConclusionsThe 5CSRTT has proven to be a useful tool to investigate impulsivity in mice.

Epigenetic alterations in hippocampus of SAMP8 senescent mice and modulation by voluntary physical exercise.

The senescence-accelerated SAMP8 mouse model displays features of cognitive decline and Alzheimers disease. With the purpose of identifying potential epigenetic markers involved in aging and neurodegeneration, here we analyzed the expression of 84 mature miRNAs, the expression of histone-acetylation regulatory genes and the global histone acetylation in the hippocampus of 8-month-old SAMP8 mice, using SAMR1 mice as control. We also examined the modulation of these parameters by 8 weeks of voluntary exercise. Twenty-one miRNAs were differentially expressed between sedentary SAMP8 and SAMR1 mice and seven miRNAs were responsive to exercise in both strains. SAMP8 mice showed alterations in genes involved in protein acetylation homeostasis such as Sirt1 and Hdac6 and modulation of Hdac3 and Hdac5 gene expression by exercise. Global histone H3 acetylation levels were reduced in SAMP8 compared with SAMR1 mice and reached control levels in response to exercise. In sum, data presented here provide new candidate epigenetic markers for aging and neurodegeneration and suggest that exercise training may prevent or delay some epigenetic alterations associated with accelerated aging.

Long-term physical exercise induces changes in sirtuin 1 pathway and oxidative parameters in adult rat tissues

The protein deacetylase, sirtuin 1, is suggested as a master regulator of exercise-induced beneficial effects. Sirtuin 1 modulates mitochondrial biogenesis, primarily via its ability to deacetylate and activate proliferator-activated receptor-γ coactivator-1α (PGC-1α), interacting with AMPK kinase. Redox cell status can also influence this regulatory axis and together they form an important convergence point in hormesis during the aging process. Here, we tested whether treadmill training (36weeks), as a paradigm of long-term moderate exercise, modifies the AMPK-sirtuin 1-PGC-1α axis and redox balance in rat gastrocnemius muscle, liver and heart. Physical activity induced increases in sirtuin 1 protein levels in all the aged rat tissues studied, as well as total PGC-1α levels. However, no changes in AMPK activation or significant differences in mitochondrial biogenesis (by measuring electron transport chain protein content) were found after exercise training. Parallel to these changes, we observed an improvement of oxidative stress defenses, mainly in muscle, with modification of the antioxidant enzyme machinery resulting in a reduction in lipid peroxidation and protein carbonylation. Thus, we demonstrate that moderate long-term exercise promotes tissue adaptations, increasing muscle, liver and heart sirtuin 1 protein content and activity and increasing PGC-1α protein expression. However, AMPK activation or mitochondrial biogenesis is not modified, but it cannot be discarded that its participation in the adaptive mechanism which prevents the development of the deleterious effects of age.

Long-Term Exercise Modulates Hippocampal Gene Expression in Senescent Female Mice

The senescence-accelerated SAMP8 mouse is considered a useful non-transgenic model for studying aspects of progressive cognitive decline and Alzheimers disease (AD). Using SAMR1 mice as controls, here we explored the effects of 6 months of voluntary wheel running in 10-month-old female SAMP8 mice. Exercise in SAMP8 mice improved phenotypic features associated with premature aging (i.e., skin color and body tremor) and enhanced vascularization and BDNF gene expression in the hippocampus compared with controls. With the aim of identifying genes involved in brain aging responsive to long-term exercise, we performed whole genome microarray studies in hippocampus from sedentary SAMP8 (P8sed), SAMR1 (R1sed), and exercised SAMP8 (P8run) mice. The genes differentially expressed in P8sed versus R1sed were considered as putative aging markers (i) and those differentially expressed in P8run versus P8sed were considered as genes modulated by exercise (ii). Genes differentially expressed in both comparisons (i and ii) were considered as putative aging genes responsive to physical exercise. We identified 34 genes which met both criteria. Gene ontology analysis revealed that they are mainly involved in functions related to extracellular matrix maintenance. Selected genes were validated by real-time quantitative PCR assays, i.e., collagen type 1 alpha 1 (col1a1), collagen type 1 alpha 2 (col1a2), fibromodulin (fmod), prostaglandin D(2) synthase (ptgds), and aldehyde dehydrogenase (Aldh1a2). As a whole, our study suggests that exercise training during adulthood may prevent or delay gene expression alterations and processes associated with hippocampal aging in at-risk subjects.

Wnt pathway regulation by long-term moderate exercise in rat hippocampus.

An active lifestyle involving regular exercise reduces the deleterious effects of the aging process. At the cerebral level, both synaptic plasticity and neurogenesis are modulated by exercise, although the molecular mechanisms underlying these effects are not clearly understood. In the mature nervous system, the canonical Wnt (Wnt/β-catenin) signaling pathway is implicated in neuroprotection and synaptic plasticity. Here, we examined whether the Wnt pathway could be modulated in adult male rat hippocampus by long-term moderate exercise (treadmill running) or enrichment (handling/environmental stimulation). Sedentary animals showed higher protein levels of the Wnt antagonist, Dkk-1, the lowest levels being found in the exercised group. Although there was no evidence of any changes in activation of the LRP6 receptor, the total levels of LRP6 were higher in exercised and enriched animals. Analysis of some of the components implicated in the phosphorylation of β-catenin, which leads ultimately to its proteasomal degradation, revealed higher levels and activation of Axin1 and GSK-3α/β respectively in sedentary animals. However neither different phosphorylated forms nor total β-catenin protein levels differed between the experimental groups. Higher protein levels of Axin2 and the antiapoptotic protein, Bcl-2, were found with exercise and handling, whereas the proapototic, Bax, was unaffected. Thus, our results suggest activation of the Wnt pathway not only with moderate exercise, but also with the handling of the animals.

Physiological and behavioural consequences of long-term moderate treadmill exercise

The benefits of long-term moderate exercise for health are widely accepted in humans, but few animal studies have been undertaken to characterize the effects of such activity on emotionality and responsiveness to stress. The present study describes the effects of long-term moderate forced treadmill training (36 weeks) on exploratory activity, anxiety-like behaviour, and the resting or stress levels of some physiological variables, including pituitary-adrenal (PA) hormones. Five-week-old male Sprague-Dawley rats were trained on the treadmill (TM) for 36 weeks, using a more moderate training (12m/min, 30min/day, 4-5 days/week) than that currently used in the literature. Two groups were used as controls: a non-handled sedentary (SED) group, receiving no manipulation, and a control (CON) group exposed to a stationary treadmill for the same amount of time as the TM group. In accordance with literature data, TM rats showed lower resting levels of glucose, triglycerides and cholesterol than the other two groups. The TM and CON groups both showed higher ambulation than the SED group in some behavioural tests, without evidence for altered anxiety. Resting levels of adrenocorticotropin (ACTH) and corticosterone did not differ among the groups, but a reduced ACTH response to both a novel environment (mild stressor) and an active escape-avoidance task (severe stressor) was observed in TM rats, whereas changes in corticosterone were modest. The results support the view that the physiological consequences of long-term moderate training are beneficial, including reduced PA responsiveness to stress, even though exercise training did not affect anxiety-like behaviour.

Alpha-synuclein deletion decreases motor impulsivity but does not affect risky decision making in a mouse Gambling Task

RationaleThere is evidence to support the role of alpha-synuclein in motor impulsivity, but the extrapolation of this finding to other types of impulsivity remains to be elucidated.ObjectiveThis study aims to investigate the role of alpha-synuclein in choice impulsivity/risky decision-making by means of a mouse version of the Iowa Gambling Task (mIGT).MethodsTwo strains of mice that differ in the expression of the alpha-synuclein gene, the C57BL/6JOlaHsd (HA) and C57BL/6J (CR), were tested in the mIGT. HA mice differ from their CR ancestors in possessing a chromosomal deletion resulting in the loss of two genes: snca, encoding alpha-synuclein and mmrn1, encoding multimerin-1. Mice were trained in the mIGT until a stable pattern of responding was achieved and then the acute effects of ethanol and cocaine in choice preference were investigated.ResultsNo differences between the strains were evident in risky decision-making in any of the experiments, but HA mice showed consistently reduced levels of premature responding in comparison with CR mice, confirming the reduced motor impulsivity found in a previous study. Ethanol did not modify the percentage of advantageous choices in either strain, while cocaine increased the risky choice behaviour by increasing the percentage of disadvantageous choices in both strains.ConclusionsWe provide further evidence for the involvement of alpha-synuclein in motor impulsivity and suggest that alpha-synuclein does not play a role in risky decision-making as evaluated in the mIGT.

Voluntary exercise promotes beneficial anti-aging mechanisms in SAMP8 female brain.

Regular physical exercise mediates health and longevity promotion involving Sirtuin 1 (SIRT1)-regulated pathways. The anti-aging activity of SIRT1 is achieved, at least in part, by means of fine-tuning the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway by preventing the transition of an originally pro-survival program into a pro-aging mechanism. Additionally, SIRT1 promotes mitochondrial function and reduces the production of reactive oxygen species (ROS) through regulating peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), the master controller of mitochondrial biogenesis. Here, by using senescence-accelerated mice prone 8 (SAMP8) as a model for aging, we determined the effect of wheel-running as a paradigm for long-term voluntary exercise on SIRT1-AMPK pathway and mitochondrial functionality measured by oxidative phosphorylation (OXPHOS) complex content in the hippocampus and cortex. We found differential activation of SIRT1 in both tissues and hippocampal-specific activation of AMPK. These findings correlated well with significant changes in OXPHOS in the hippocampal, but not in the cerebral cortex, area. Collectively, the results revealed greater benefits of the exercise in the wheel-running intervention in a murine model of senescence, which was directly related with mitochondrial function and which was mediated through the modulation of SIRT1 and AMPK pathways.