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Resistance-exercise training ameliorates LPS-induced cognitive impairment concurrent with molecular signaling changes in the rat dentate gyrus
Abstract
Effective treatments preventing brain neuroinflammatory diseases are lacking. Resistance-exercise training (RT) ameliorates mild cognitive impairment (MCI), a forerunner to neuroinflammatory diseases. However, few studies have addressed the molecular basis by which RT abates MCI. Thus, experiments were performed to identify some molecular changes occurring in response to RT in young, female Wistar rats. To induce MCI, intraventricular lipopolysaccharide (LPS) injections were used to increase dentate gyrus inflammation, reflected by significantly increased TNFα (~400%) and IL-1β (~1,500%) mRNA (p<0.0001) after 6-weeks. Five days after LPS injections, half of LPS injected rats either performed 3 days/week of RT by ladder climbing for 6-weeks, while half remained without ladders. RT for 6-weeks increased lean body mass percentage (p<0.05), individual muscle masses (gastrocnemius and tibialis anterior) (p<0.05), and maximum lifting capacity (p<0.001). The RT group, compared to sedentary controls, had: 1) ameliorated spatial learning deficits (p<0.05), 2) increased dentate gyrus phosphorylation of IGF-1R, AKT and GSK3β proteins (p<0.05), components of downstream IGF-I signaling, and 3) increased dentate gyrus synaptic-plasticity-marker SYN1 protein (p<0.05). Two follow-up experiments (without LPS) characterized dentate gyrus signaling during short-term RT. Twenty-four hours following the third workout in a 1-week training duration, phosphorylation of ERK1/2 and GSK3β proteins, as well as proliferation-marker protein, PCNA, were significantly increased (p < 0.05). Similar changes did not occur in a separate group of rats following a single RT workout. Taken together, these data indicate that RT ameliorates LPS-induced MCI after RT, possibly mediated by increased IGF-1 signaling pathway components within the dentate gyrus.
... We excluded 11 studies because they did not meet the eligibility criteria, eight of which were of the wrong population (30)(31)(32)(33)(34)(35)(36)(37), one presented wrong outcomes (38), one performed wrong intervention (39), and one study was not found (40). We included in this review the remaining 11 studies that met the inclusion criteria and used different instruments and ways of presenting the same outcome (7,19,(41)(42)(43)(44)(45)(46)(47)(48)(49). For the metaanalysis, we excluded 2 studies (44,47), one (44) after sensitivity analysis, and another (47) because overlapping population with study in 2019 (46). ...
... We included in this review the remaining 11 studies that met the inclusion criteria and used different instruments and ways of presenting the same outcome (7,19,(41)(42)(43)(44)(45)(46)(47)(48)(49). For the metaanalysis, we excluded 2 studies (44,47), one (44) after sensitivity analysis, and another (47) because overlapping population with study in 2019 (46). The Kappa test (1.0 in the first step and 1.0 in the second step) indicates an almost perfect agreement between the researchers. ...
... Studies that met the eligibility criteria included 550 adult and older animals weighing 25-280g. Eight studies did not report the weight (7, 41, 42, 44,46-49) and three studies did not report the number of animals (44,47,48). All details are shown in Table 1. ...
Alzheimer’s disease (AD) is among common cause of dementia. Complementary therapies, such as resistance exercise (RE), have been proposed as an alternative for the treatment of AD. We performed a systematic review and meta-analysis to investigate the effects of RE on the cognitive function of AD animal models and their physiological mechanisms.
This review was submitted to PROSPERO (CRD42019131266) and was done according to PRISMA checklist. Four databases were used in the search: MEDLINE/PUBMED, SCOPUS, Web of Science and Google Scholar. We used SYRCLE and CAMAREDES to assess the risk of bias and methodological quality. We calculated the standardized mean difference using 95% confidence intervals and considered the random effects model and p < 0.05 to determine significance.
A total of 1,807 studies were founded, and after the selection process, only 11 studies were included in this review and 8 studies were included for meta-analysis. Four studies applied RE before AD induction, 7 studies applied RE after AD induction or in the AD condition. All studies included 550 adult and older animals weighing 25–280g. Our analysis revealed that RE had a positive effect on memory in AD animal models but did not show a significant impact on anxiety.
RE performed four or six weeks, more than three days a week, had a significant protective effect on memory. The included studies had a high risk of bias and moderate methodological quality. Therefore, RE can be a potential strategy for preventing cognitive decline in animal models.
... The RET protocol this study stimulated protein synthesis, resulting in morphological changes l fiber CSA in the short term. The morphophysiological changes during hyp well documented in RET protocols, such as climbing [4,8,[47][48][49]. ...
... The RET protocol employed in this study stimulated protein synthesis, resulting in morphological changes like increased fiber CSA in the short term. The morphophysiological changes during hypertrophy are well documented in RET protocols, such as climbing [4,8,[47][48][49]. ...
... The Akt signaling regulates protein synthesis and controls FOXO expression [18,48], regulating the expression of E3 ligases MAFbx/atrogin-1 and MuRF-1, involved in protein degradation via the ubiquitin-proteasome system (UPS) that designates target proteins for degradation. MuRF-1 and atrogin-1 reportedly increase in skeletal muscles under protein catabolic conditions such as fasting, cancer, diabetes, and muscle immobilization [32]. ...
Aim: To evaluate the effects of resistance exercise training (RET) and/or glutamine supplementation (GS) on signaling protein synthesis in adult rat skeletal muscles. Methods: The following groups were studied: (1) control, no exercise (C); (2) exercise, hypertrophy resistance exercise training protocol (T); (3) no exercise, supplemented with glutamine (G); and (4) exercise and supplemented with glutamine (GT). The rats performed hypertrophic training, climbing a vertical ladder with a height of 1.1 m at an 80° incline relative to the horizontal with extra weights tied to their tails. The RET was performed three days a week for five weeks. Each training session consisted of six ladder climbs. The extra weight load was progressively increased for each animal during each training session. The G groups received daily L-glutamine by gavage (one g per kilogram of body weight per day) for five weeks. The C group received the same volume of water during the same period. The rats were euthanized, and the extensor digitorum longus (EDL) muscles from both hind limbs were removed and immediately weighed. Glutamine and glutamate concentrations were measured, and histological, signaling protein contents, and mRNA expression analyses were performed. Results: Supplementation with free L-glutamine increased the glutamine concentration in the EDL muscle in the C group. The glutamate concentration was augmented in the EDL muscles from T rats. The EDL muscle mass did not change, but a significant rise was reported in the cross-sectional area (CSA) of the fibers in the three experimental groups. The levels of the phosphorylated proteins (pAkt/Akt, pp70S6K/p70S6K, p4E-BP1/4E-BP1, and pS6/S6 ratios) were significantly increased in EDL muscles of G rats, and the activation of p4E-BP1 was present in T rats. The fiber CSAs of the EDL muscles in T, G, and GT rats were increased compared to the C group. These changes were accompanied by a reduction in the 26 proteasome activity of EDL muscles from T rats. Conclusion: Five weeks of GS and/or RET induced muscle hypertrophy, as indicated by the increased CSAs of the EDL muscle fibers. The increase in CSA was mediated via the upregulated phosphorylation of Akt, 4E-BP1, p70S6k, and S6 in G animals and 4E-BP1 in T animals. In the EDL muscles from T animals, a decrease in proteasome activity, favoring a further increase in the CSA of the muscle fibers, was reported.
... To the best of our knowledge, there are only two studies that examined the effect of acute resistance exercise on brain IGF-1 levels and signaling. One studied male rats (Fernandes et al., 2016) while the other used female rats (Kelty et al., 2019). Both failed to find an effect. ...
... Fernandes et al. (2016) indicated that this may have been caused by the time of sample collection, which was 24 h after exercise, while circulating IGF-1 levels after acute exercise typically return back to baseline after 15 to 30 min post-exercise (Rubin et al., 2005;West et al., 2009;Rojas Vega et al., 2010;Tsai et al., 2015). Also in the study of Kelty et al. (2019), rats were killed and brain tissue was collected only 24 h after the resistance exercise session. ...
... Finally, evidence from animal models suggests that physical exercise training had no differential effect on the levels of IGF-1 in the brain as a function of gender. Specifically, it was found that hippocampal IGF-1 levels increased both in male and female rats following chronic cardiovascular training (Ding et al., 2006;Gomes et al., 2009;Wong-Goodrich et al., 2010;Cassilhas et al., 2012) and resistance (Cassilhas et al., 2012;Kelty et al., 2019) exercise. ...
Physical exercise may improve cognitive function by modulating molecular and cellular mechanisms within the brain. We propose that the facilitation of long-term synaptic potentiation (LTP)-related pathways, by products induced by physical exercise (i.e., exerkines), is a crucial aspect of the exercise-effect on the brain. This review summarizes synaptic pathways that are activated by exerkines and may potentiate LTP. For a total of 16 exerkines, we indicated how blood and brain exerkine levels are altered depending on the type of physical exercise (i.e., cardiovascular or resistance exercise) and how they respond to a single bout (i.e., acute exercise) or multiple bouts of physical exercise (i.e., chronic exercise). This information may be used for designing individualized physical exercise programs. Finally, this review may serve to direct future research towards fundamental gaps in our current knowledge regarding the biophysical interactions between muscle activity and the brain at both cellular and system levels.
... To test spatial memory, a gray Barnes maze circular platform (122 cm in diameter) with 20 holes (each being 10.2 cm in diameter) was used similarly to our previous publications (Kelty et al., 2019;Mao et al., 2021). Briefly, the circular platform contained an escape box (28 cm in length, 12.7 cm width, 7.6 cm height) located such that the rat could climb down and in. ...
... cDNA from each sample was assayed in duplicate for the target genes in Table 1 using iTaq Universal SYBR green Supermix (Bio-Rad Laboratories, Hercules, CA). mRNA expression values were quantified by the 2 (−delta delta CT) (Kelty et al., 2019(Kelty et al., , 2022Grigsby et al., 2020;Mao et al., 2021) method normalized to Pgk1. ...
Physical inactivity is the 4th leading cause of death globally and has been shown to significantly increase the risk for developing Alzheimer's Disease (AD). Recent work has demonstrated that exercise prior to breeding produces heritable benefits to the brains of offspring, suggesting that the physical activity status of previous generations could play an important role in one's brain health and their subsequent risk for neurodegenerative diseases. Thus, our study aimed to test the hypothesis that selective breeding for physical inactivity, or for high physical activity, preference produces heritable deficits and enhancements to brain health, respectively. To evaluate this hypothesis, male and female sedentary Low Voluntary Runners (LVR), wild type (WT), and High Voluntary Runner (HVR) rats underwent cognitive behavioral testing, analysis of hippocampal neurogenesis and mitochondrial respiration, and molecular analysis of the dentate gyrus. These analyses revealed that selecting for physical inactivity preference has produced major detriments to cognition, brain mitochondrial respiration, and neurogenesis in female LVR while female HVR display enhancements in brain glucose metabolism and hippocampal size. On the contrary, male LVR and HVR showed very few differences in these parameters relative to WT. Overall, we provide evidence that selective breeding for physical inactivity has a heritable and detrimental effect on brain health and that the female brain appears to be more susceptible to these effects. This emphasizes the importance of remaining physically active as chronic intergenerational physical inactivity likely increases susceptibility to neurodegenerative diseases for both the inactive individual and their offspring.
... Herein, we utilized an LPS-induced rodent MCI model, which exhibits impaired spatial and recognition memory, published previously by our laboratory [19], to examine potential cognitive effects of Cr supplementation. Furthermore, we examined neuro-molecular mechanisms in the dentate gyrus resulted from and associated with Cr supplementation, this being a sub-region of hippocampus known to play a fundamental role in hippocampusdependent learning and memory [20,21]. ...
... The MCI model is discussed in greater detail elsewhere [19,23] and involves intracerebroventricular (i.c.v.) injections of LPS (Sigma, St. Louis, MO, USA). Briefly, rats were anesthetized with 2% isoflurane and positioned into a stereotaxic frame (David Kopf Instruments, Tunjunga, CA, USA). ...
Mild cognitive impairment (MCI) designates the boundary area between cognitive function in natural aging and dementia, and this is viewed as a therapeutic window to prevent the occurrence of dementia. The current study investigated the neurocognitive effects of oral creatine (Cr) supplementation in young female Wistar rats that received intracerebroventricular injections of lipopolysaccharide (LPS) to mimic MCI. Neuromolecular changes within the dentate gyrus were analyzed following behavioral testing. We also investigated both neurocognitive and neuromolecular changes following Cr supplementation in the absence of LPS in young female Wistar rats to further investigate mechanisms. Interestingly, based on trial 2 of Barnes maze test, Cr supplementation ameliorated spatial learning and memory deficit induced by LPS, shown by decreased latency time and errors to reach the escape box (p < 0.0001, n = 12). Cr supplementation also attenuated recognition memory deficit induced by LPS, shown by increased amount of time taken to explore the new object (p = 0.002, n = 12) during novel object recognition testing. Within the dentate gyrus, Cr supplementation in LPS injected rats upregulated mTORC1 signaling (p = 0.026 for mTOR phosphorylation, p = 0.002 for p70S6K phosphorylation, n = 8) as well as the synapsin (p = 0.008) and PSD-95 synaptic proteins (p = 0.015), in comparisons to LPS injected rats. However, Cr supplementation failed to further enhance spatial memory and recognition memory in the absence of LPS. In conclusion, Cr ameliorates LPS-induced cognitive impairment in a rodent MCI model. Mechanistically, these phenotypic effects may, in part, be mitigated via an upregulation of mTORC1 signaling, and an enhancement in synaptogenesis in the dentate gyrus. While preliminary, these findings may inform future research investigating neurocognitive effects of Cr for MCI patients.
... These pleiotropic factors promote neurogenesis, neuronal survival and neuroplasticity (Pedersen and Febbraio, 2012;Jin et al., 2018;Lourenco et al., 2019;Martínez Muñoz et al., 2019), and cognitive abilities (Cotman et al., 2007;Lee et al., 2012). Several studies have shown that strength training increase BDNF and IGF-1 (Hess and Smart, 2017;Kelty et al., 2019;Quiles et al., 2019;Mckay et al., 2020), more so than aerobic exercise in the CNS, shown by studies in rodents, and in the circulation, shown in studies in humans (De Souza Vale et al., 2009;Chen et al., 2017;Hess and Smart, 2017;Kelty et al., 2019). Strength training and HIIT were both shown to exert positive effects on various types of cognitive abilities (Cassilhas et al., 2007;Tsukamoto et al., 2016;Fiorelli et al., 2019;Landrigan et al., 2019). ...
... These pleiotropic factors promote neurogenesis, neuronal survival and neuroplasticity (Pedersen and Febbraio, 2012;Jin et al., 2018;Lourenco et al., 2019;Martínez Muñoz et al., 2019), and cognitive abilities (Cotman et al., 2007;Lee et al., 2012). Several studies have shown that strength training increase BDNF and IGF-1 (Hess and Smart, 2017;Kelty et al., 2019;Quiles et al., 2019;Mckay et al., 2020), more so than aerobic exercise in the CNS, shown by studies in rodents, and in the circulation, shown in studies in humans (De Souza Vale et al., 2009;Chen et al., 2017;Hess and Smart, 2017;Kelty et al., 2019). Strength training and HIIT were both shown to exert positive effects on various types of cognitive abilities (Cassilhas et al., 2007;Tsukamoto et al., 2016;Fiorelli et al., 2019;Landrigan et al., 2019). ...
Aerobic, anaerobic, and strength exercises are known to improve various cognitive functions, such as executive functions, pattern separation, and working memory. High-intensity functional training (HIFT) is a form of physical activity that can be modified to any fitness level and elicits greater muscle recruitment than repetitive aerobic exercises, thereby improving cardiovascular endurance, strength, and flexibility. HIFT emphasizes functional, multi-joint movements via high-intensity interval training (HIIT) and muscle-strengthening exercises. It is yet unknown, however, whether HIFT affects cognitive functions in adolescents. To address this question, we subjected adolescents to 3 × 20 min training sessions/week of HIFT for 3 months. The effects of HIFT were tested on performance in: (1) virtual reality (VR)-based spatial learning task; (2) computerized visual pattern separation; and (3) attention span. The control group performed a typical physical class three times per week. The effects on cognition were tested at baseline and following 3 months of HIFT. Three months into the intervention, the HIFT group achieved higher scores in the spatial learning task, pattern separation task, and in the attention span test, compared with controls. These data suggest that HIFT can potentially translate into improving school performance in adolescents.
... Previous studies have not sufficiently examined the effects of social isolation on the body and the effectiveness of environmental changes for rats of any age. Studies with older rats are needed; however, as in similar studies [17,18], we chose to study young rats first as a preliminary study. ...
Social isolation affects physical functioning owing to psychological stress. We constructed a rat model to clarify the unexplored effects of social isolation and to determine whether environmental changes as an intervention against social isolation can reduce the stress-inducing effects of social isolation on physiological factors. Eight-week-old male rats were divided into three groups: group-housed, isolated, and intervention. Group-housed rats were kept 2 animals per cage. Isolated rats were kept 1 rat per cage. The intervention group alternated between the isolation and group-housed conditions. All rats were euthanized after 21 days. Their plasma, masseter muscles, and lower limb muscles were collected. Body weight, food intake, locomotor activity, muscle weight, and plasma corticosterone, ghrelin, and myostatin levels were measured. The results indicated that there were no significant differences between the group-housed and intervention groups for all outcomes. However, weight gain, food intake, and plasma corticosterone levels were higher in the isolated group than in the group-housed group. Plasma myostatin levels were higher in the isolated group than in the intervention group. Plasma ghrelin concentrations were lower in the isolated group than in the group-housed or intervention groups. In the isolated group, locomotor activity decreased compared to that in the intervention group. The lower limb muscle weight ratio also decreased in the isolated group compared to that in the group-housed and intervention groups. In conclusion, isolation decreased physical activity and affected body weight, food intake, and muscle weight; these changes were associated with corticosterone as a stress marker, ghrelin as an appetite-related factor, and myostatin, which is a growth inhibitor of skeletal muscles. Moreover, these changes were suppressed when the isolation time was reduced in the intervention group. The present study suggests that intermittent breaking of isolation may reduce the physical effects of isolation.
... Reasonable physical exercise can provide a valuable means of inhibiting inflammation and microglial activation (Wang et al., 2016), with confirmatory indicating that exercise can prevent and treat neurological diseases by inhibiting inflammationmediated insulin resistance. For example, studies have established that swimming can lower insulin resistance in the mouse hippocampus by decreasing nervous system inflammation (Zhang H. et al., 2022), whereas resistance exercise training has been reported to effectively alleviate neuroinflammation in the mouse brain (Kelty et al., 2019). Furthermore, exercise-induced suppression of inflammation has yielded positive effects in the context of neurodegenerative diseases, such as AD and PD, and these benefits are closely related to the mitigation of insulin resistance (Li et al., 2022;Wang et al., 2023). ...
Neurodegenerative diseases are debilitating nervous system disorders attributed to various conditions such as body aging, gene mutations, genetic factors, and immune system disorders. Prominent neurodegenerative diseases include Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and multiple sclerosis. Insulin resistance refers to the inability of the peripheral and central tissues of the body to respond to insulin and effectively regulate blood sugar levels. Insulin resistance has been observed in various neurodegenerative diseases and has been suggested to induce the occurrence, development, and exacerbation of neurodegenerative diseases. Furthermore, an increasing number of studies have suggested that reversing insulin resistance may be a critical intervention for the treatment of neurodegenerative diseases. Among the numerous measures available to improve insulin sensitivity, exercise is a widely accepted strategy due to its convenience, affordability, and significant impact on increasing insulin sensitivity. This review examines the association between neurodegenerative diseases and insulin resistance and highlights the molecular mechanisms by which exercise can reverse insulin resistance under these conditions. The focus was on regulating insulin resistance through exercise and providing practical ideas and suggestions for future research focused on exercise-induced insulin sensitivity in the context of neurodegenerative diseases.
... In 3×Tg AD model mice (a transgenic mouse AD model), short-term resistance exercise reduces Aβ load, tau hyperphosphorylation, reactive astrogliosis, and inflammatory responses in the frontal cortex and hippocampus; this effect also correlated with improved synaptic plasticity and cognitive functions, including shortterm memory and working memory functions (Liu et al., 2020). Resistance exercise can also reverse cognitive dysfunction from neuroinflammation via insulin-like growth factor 1 (IGF-1) signaling in the hippocampal dentate gyrus region (Kelty et al., 2019). Long-term resistance training in APP/PS1 mice can also activate microglia recruitment, without enhancing inflammatory responses, but increasing elimination of Aβ deposition (Hashiguchi et al., 2020). ...
Alzheimer’s disease (AD) is a progressive and degenerative neurological disease characterized by the deterioration of cognitive functions. While a definitive cure and optimal medication to impede disease progression are currently unavailable, a plethora of studies have highlighted the potential advantages of exercise rehabilitation for managing this condition. Those studies show that exercise rehabilitation can enhance cognitive function and improve the quality of life for individuals affected by AD. Therefore, exercise rehabilitation has been regarded as one of the most important strategies for managing patients with AD. Herein, we provide a comprehensive analysis of the currently available findings on exercise rehabilitation in patients with AD, with a focus on the exercise types which have shown efficacy when implemented alone or combined with other treatment methods, as well as the potential mechanisms underlying these positive effects. Specifically, we explain how exercise may improve the brain microenvironment and neuronal plasticity. In conclusion, exercise is a cost-effective intervention to enhance cognitive performance and improve quality of life in patients with mild to moderate cognitive dysfunction. Therefore, it can potentially become both a physical activity and a tailored intervention. This review may aid the development of more effective and individualized treatment strategies to address the challenges imposed by this debilitating disease, especially in low-and middle-income countries.
... According to the study of Yu et al., 15 days of voluntary exercise increased the expression of IGF-1 and promoted hippocampal neurogenesis in healthy adult mice compared with the non-exercise group, but the expression of IGF-1 only increased in the DG region (Yu et al., 2014). In addition, it has been shown that 6 weeks of resistance exercise (ladder climbing) can activate the IGF-1 downstream signaling pathways external-signal regulated kinase 1/2 (ERK1/2) and glycogen synthase kinase 3β (GSK-3β) in the DG region and enhance cell proliferation in the DG, improving lipopolysaccharide-induced spatial learning deficits in rats (Kelty et al., 2019). It has also been shown that exercise training promoted neural progenitor cell proliferation by activating the IGF-1/protein kinase B (protein kinase B, PKB, or Akt) pathway (Zheng et al., 2014). ...
Obesity is an important factor that threatens human health. The occurrence of many chronic diseases is related to obesity, and cognitive function decline often occurs with the onset of obesity. With the further prevalence of obesity, it is bound to lead to a wider range of cognitive dysfunction (ORCD). Therefore, it is crucial to suppress ORCD through intervention. In this regard, exercise has been shown to be effective in preventing obesity and improving cognitive function as a non-drug treatment. There is sufficient evidence that exercise has a regulatory effect on a growth factor closely related to cognitive function—insulin-like growth factor 1 (IGF-1). IGF-1 may be an important mediator in improving ORCD through exercise. This article reviews the effects of obesity and IGF-1 on cognitive function and the regulation of exercise on IGF-1. It analyzes the mechanism by which exercise can improve ORCD by regulating IGF-1. Overall, this review provides evidence from relevant animal studies and human studies, showing that exercise plays a role in improving ORCD. It emphasizes the importance of IGF-1, which helps to understand the health effects of exercise and promotes research on the treatment of ORCD.
... Moreover, exercise can improve outcomes in neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD) [6,7]. The effects of exercise on the brain are most pronounced in the hippocampus and dentate gyrus, which are important brain regions involved in learning and memory [8]. The benefits of exercise include increased hippocampal size and blood flow, morphological changes in the dendrites and dendritic spines, and increased synaptic plasticity and the induction of myokines [9,10]. ...
Parkinson’s disease with cognitive impairment (PD-CI) results in several clinical outcomes for which specific treatment is lacking. Although the pathogenesis of PD-CI has not yet been fully elucidated, it is related to neuronal plasticity decline in the hippocampus region. The dopaminergic projections from the substantia nigra to the hippocampus are critical in regulating hippocampal plasticity. Recently, aerobic exercise has been recognized as an effective therapeutic strategy for enhancing plasticity through the secretion of various muscle factors. The exact role of FNDC5—an upregulated, newly identified myokine produced after exercise—in mediating hippocampal plasticity and regional dopaminergic projections in PD-CI remains unclear. In this study, the effect of treadmill exercise on hippocampal synaptic plasticity was evaluated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced chronic PD models. The results showed that treadmill exercise substantially alleviated the motor dysfunction, cognition disorder, and dopaminergic neuron degeneration induced by MPTP. Here, we discovered that the quadriceps, serum, and brain FNDC5 levels were lower in PD mice and that intervention with treadmill exercise restored FNDC5 levels. Moreover, treadmill exercise enhanced the synaptic plasticity of hippocampal pyramidal neurons via increased dopamine levels and BDNF in the PD mice. The direct protective effect of FNDC5 is achieved by promoting the secretion of BDNF in the hippocampal neurons via binding the integrin αVβ5 receptor, thereby improving synaptic plasticity. Regarding the indirect protection effect, FNDC5 promotes the dopaminergic connection from the substantia nigra to the hippocampus by mediating the interaction between the integrin αVβ5 of the hippocampal neurons and the CD90 molecules on the membrane of dopaminergic terminals. Our findings demonstrated that treadmill exercise could effectively alleviate cognitive disorders via the activation of the FNDC5–BDNF pathway and enhance the dopaminergic synaptic connection from SNpc to the hippocampus in the MPTP-induced chronic PD model.
... Aerobic and resistance exercise improve aerobic fitness and muscular strength and endurance. These changes in muscle function are clinically relevant because they are associated with decreased cognitive decline and brain degeneration (e.g., decreased gray matter volume) (73)(74)(75)(76)(77)(78). In fact, slower walking speed is associated with hypoperfusion in adults with T2D and can predict cognitive impairment (58,79). ...
Exercise has systemic health benefits in people, in part, through improving whole-body insulin sensitivity. The brain is an insulin sensitive organ that is often underdiscussed relative to skeletal muscle, liver, and adipose tissue. While brain insulin action may have only subtle impacts on peripheral regulation of systemic glucose homeostasis, it is important for weight regulation as well as mental health. In fact, brain insulin signaling is also involved in processes that support healthy cognition. Furthermore, brain insulin resistance has been associated with age-related declines in memory and executive function as well as Alzheimer's disease pathology. Herein, we provide an overview of brain insulin sensitivity in relation to cognitive function from animal and human studies, with particular emphasis placed on the impact exercise may have on brain insulin sensitivity. Mechanisms discussed include mitochondrial function, brain growth factors, and neurogenesis, which collectively help combat obesity-related metabolic disease and Alzheimer's dementia.
... These pleiotropic factors trigger neurogenesis, lead to the survival of neurons, enhance neural flexibility [57,58], and improve cognitive ability [59]. Previous studies have demonstrated that strength training exercises have more positive effects on BDNF and IGF-1 as compared to aerobic exercises [60,61]. Studies also suggest that resistance training exercises and high-intensity periodic exercises induce positive effects on cognitive abilities [62,63]. ...
Obesity is the underlying cause of various health conditions such as hypertension, diabetes, and respiratory diseases. It is associated with low self-confidence, emotional disorder, anxiety, depression, social isolation, and suicide. In the present study, we investigated the effect of functional training on obese women's brain-derived neurotrophic factor (BDNF) and executive functioning. To this end, 25 obese women were randomly assigned to 3 different groups labelled as active obese women-functional training, inactive obese women-functional training, and control group. The subjects performed 24 one-hour-long sessions of functional training three times a week. The intensity of activity for the research groups was moderate, which was equivalent to a level of 6-7 on the Borg scale. The analysis of intragroup results indicated that functional training increased serum BDNF significantly in both active and inactive obese women. It was also observed to improve executive functioning in both groups of the obese women via decreasing the number of errors, increasing the number of true responses, and reducing reaction time. The analysis of intergroup results, on the other hand, revealed that there were no significant differences between active and inactive obese women in terms of serum BDNF and executive functioning after functional training. Training promotes cognitive health, and this study adds that functional training may be important for improvement and maintenance of brain health and functional performance. Therefore, by increasing BDNF level through functional exercises, it is possible to help improve the cognitive functions of obese women.
... The results from this study showed that resistance training reduced the number of seizures, improved memory and increased both IGF-1 and BDNF concentrations within the hippocampus. This was supported by more recent findings from Kelty et al. [64] that demonstrated that 6 weeks of resistance training (ladder climbing, 3 × /week) ameliorated cognitive impairments in rats with intraventricular liposaccharide-induced mild cognitive impairments. Additionally, rats that underwent resistance training showed increased IGF-1 signalling within the dentate gyrus. ...
Resistance exercise is used extensively in athletic and general populations to induce neuromuscular adaptations to increase muscle size and performance. Exercise parameters such as exercise frequency, intensity, duration and modality are carefully manipulated to induce specific adaptations to the neuromuscular system. While the benefits of resistance exercise on the neuromuscular system are well documented, there is growing evidence to suggest that resistance exercise, even when performed acutely, can lead to neuroplastic changes within the central nervous system (CNS) and improve cognitive functioning. As such, resistance exercise has been proposed as a novel adjuvant rehabilitation strategy in populations that suffer from neurological or neurocognitive impairments (i.e. Parkinson’s and Alzheimer’s dementia) or even to attenuate age-related declines in cognitive health. In this review, we present evidence for the neuroplastic effects and cognitive benefits of resistance exercise and propose some of the underlying mechanisms that drive neuroplasticity following resistance training. We will further discuss the effects of exercise parameters, in particular exercise frequency, intensity, duration and modality to improve cognitive health. Lastly, we will highlight some of the existing limitations in the literature surrounding the use of resistance exercise to improve cognitive function and propose considerations to improve future studies in this field. In summary, the current evidence supports the role of resistance exercise, as a stand alone or in combination with aerobic exercise, for benefiting cognitive health and that it should be considered as an adjuvant therapy to treat age- or disease-related cognitive declines.
... Interestingly, it was demonstrated that progressively weighted ladder climbing as a rodent model of resistance-exercise training (RT) ameliorated LPS(UO)-induced cognitive impairment, a forerunner to neuroinflammatory diseases. These improvements in cognitive function occurred in concert with RT-induced IGF-1R/Akt/ GSK3b signaling (93). ...
Knowledge of glycogen synthase kinase 3β (GSK3β) activity and the molecules identified that regulate its function in infections caused by pathogenic microorganisms is crucial to understanding how the intensity of the inflammatory response can be controlled in the course of infections. In recent years many reports have described small molecular weight synthetic and natural compounds, proteins, and interference RNA with the potential to regulate the GSK3β activity and reduce the deleterious effects of the inflammatory response. Our goal in this review is to summarize the most recent advances on the role of GSK3β in the inflammatory response caused by bacteria, bacterial virulence factors (i.e. LPS and others), viruses, and parasites and how the regulation of its activity, mainly its inhibition by different type of molecules, modulates the inflammation.
... One study suggested that LPS-induced neuroinflammation results in cognitive impairment by controlling betaamyloid generation [28]. A recent study demonstrated that LPS stimulated brain undergoes changes in molecular signaling and shows memory dysfunction in hippocampal formation regions [29]. Inflammation is associated with decreased neuronal connectivity in CNS diseases [30]. ...
Resistance exercise training (RET) is considered an excellent tool for preventing diseases with an inflammatory background. Its neuroprotective, antioxidant, and anti‐inflammatory properties are responsible for positively modulating cholinergic and oxidative systems, promoting neurogenesis, and improving memory. However, the mechanisms behind these actions are largely unknown. In order to investigate the pathways related to these effects of exercise, we conducted a 12‐week long‐term exercise training protocol and used lipopolysaccharide (LPS) to induce damage to the cortex and hippocampus of male Wistar rats. The cholinergic system, oxidative stress, and histochemical parameters were analyzed in the cerebral cortex and hippocampus, and memory tests were also performed. It was observed that LPS: (1) caused memory loss in the novel object recognition (NOR) test; (2) increased the activity of acetylcholinesterase (AChE) and Iba1 protein density; (3) reduced the protein density of brain‐derived neurotrophic factor (BDNF) and muscarinic acetylcholine receptor M1 (CHRM1); (4) elevated the levels of lipid peroxidation (TBARS) and reactive species (RS); and (5) caused inflammatory damage to the dentate gyrus. RET, on the other hand, was able to prevent all alterations induced by LPS, as well as increase per se the protein density of the alpha‐7 nicotinic acetylcholine receptor (nAChRα7) and Nestin, and the levels of protein thiols (T‐SH). Overall, our study elucidates some mechanisms that support resistance physical exercise as a valuable approach against LPS‐induced neuroinflammation and memory loss.
Exercise has well-recognized beneficial effects on the whole body. Previous studies suggest that exercise could promote tissue regeneration and repair in various organs. In this review, we have summarized the major effects of exercise on tissue regeneration primarily mediated by stem cells and progenitor cells in skeletal muscle, nervous system, and vascular system. The protective function of exercise-induced stem cell activation under pathological conditions and aging in different organs have also been discussed in detail. Moreover, we have described the primary molecular mechanisms involved in exercise-induced tissue regeneration, including the roles of growth factors, signaling pathways, oxidative stress, metabolic factors, and non-coding RNAs. We have also summarized therapeutic approaches that target crucial signaling pathways and molecules responsible for exercise-induced tissue regeneration, such as IGF1, PI3K, and microRNAs. Collectively, the comprehensive understanding of exercise-induced tissue regeneration will facilitate the discovery of novel drug targets and therapeutic strategies.
Neuroinflammation is an early detectable marker of mild cognitive impairment, the transition state between normal cognition and dementia. Resistance-exercise training can attenuate the cognitive decline observed in patients with mild cognitive impairment. However, the underlying mechanisms of resistance training effects are largely unknown. To further elucidate mechanisms of the known cognitive health benefits from resistance-exercise training, we tested if three weeks of resistance-exercise training could ameliorate lipopolysaccharide-induced neuroinflammation. Five-week-old female Wistar rats received intracerebroventricular injections of lipopolysaccharides to induce neuroinflammation and cognitive impairment. Rats then underwent three weeks of progressive ladder climbing to recapitulate resistance-exercise training in humans. Cognition was assessed towards the end of the training period by novelty object recognition testing. Neuroinflammation was measured one and 24-hours after the last resistance-exercise training workout. Resistance-exercise training ameliorated cognitive impairment, diminished lipopolysaccharide-induced neuroinflammatory cytokine expression, and attenuated astrocyte remodeling in the dentate gyrus 24-hours post exercise. Here, we provide evidence that the ladder-climbing model of resistance-exercise training in rats can improve cognition as early as three weeks. Additionally, these data support the hypothesis that resistance exercise can reduce lipopolysaccharide-induced neuroinflammation in the dentate gyrus.
Physical inactivity is positively associated with anxiety and depression. Considering physical inactivity, anxiety, and depression each have a genetic basis for inheritance, our lab used artificial selectively bred low-voluntary running (LVR) and wild type (WT) female Wistar rats to test if physical inactivity genes selected over multiple generations would lead to an anxiety or depressive-like phenotype. We performed next generation RNA sequencing and immunoblotting on the dentate gyrus to reveal key biological functions from heritable physical inactivity. LVR rats did not display depressive-like behavior. However, LVR rats did display anxiogenic behavior with gene networks associated with reduced neuronal development, proliferation, and function compared to WT counterparts. Additionally, immunoblotting revealed LVR deficits in neuronal development and function. To our knowledge, this is the first study to show that by selectively breeding for physical inactivity genes, anxiety-like genes were co-selected. The study also reveals molecular insights to the genetic influences that physical inactivity has on anxiety-like behavior.
Blog Post for the 'Swiss Junior Doctors and Undergraduate Perspective on Sport and Exercise Medicine Blog Series' from the British Journal of Sports Medicine. - 5 minute read -
Exercise medicine has influential rehabilitative, preventive and curative potential.
Promotion of physical activity to improve the health of patients suffering from dementia seems meaningful. Increasing evidence demonstrates the positive effects of physical activity on brains of healthy and demented persons. Physical activity and especially exercise may have better treatment effects for cognitive impairment in patients suffering from dementia compared to pharmaceutical therapy.
In this study, we investigated lipopolysaccharide (LPS)-induced cognitive impairment and neuroinflammation in C57BL/6J mice by using behavioral tests, immunofluorescence, enzyme-linked immunosorbent assay (ELISA) and Western blot. We found that LPS treatment leads to sickness behavior and cognitive impairment in mice as shown in the Morris water maze and passive avoidance test, and these effects were accompanied by microglia activation (labeled by ionized calcium binding adaptor molecule-1, IBA-1) and neuronal cell loss (labeled by microtubule-associated protein 2, MAP-2) in the hippocampus. The levels of interleukin-4 (IL-4) and interleukin-10 (IL-10) in the serum and brain homogenates were reduced by the LPS treatment, while the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), prostaglandin E2 (PGE2) and nitric oxide (NO) were increased. In addition, LPS promoted the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in the brain homogenates. The Western blot analysis showed that the nuclear factor kappa B (NF-κB) signaling pathway was activated in the LPS groups. Furthermore, VIPER, which is a TLR-4-specific inhibitory peptide, prevented the LPS-induced neuroinflammation and cognitive impairment. These data suggest that LPS induced cognitive impairment and neuroinflammation via microglia activation by activating the NF-kB signaling pathway; furthermore, we compared the time points, doses, methods and outcomes of LPS administration between intraperitoneal and intracerebroventricular injections of LPS in LPS-induced neuroinflammation and cognitive impairment, and these data may provide additional insight for researchers performing neuroinflammation research.
The global population is aging at an unprecedented rate giving rise to a greater prevalence of age-related illnesses such as dementia and vascular disease. Dementia affects approximately 47 million individuals globally with projections of 130 million by the year 2050. Late-onset Alzheimer’s disease is the most common form of dementia, accounting for approximately 75% of all cases and is characterized by a progressive decline in cognitive function, memory, and cerebral volume. The pathogenesis of Alzheimer’s disease is poorly understood; however, aging, genetics, and an individual’s diet and lifestyle over several decades appear to be key determinants. As there is no current cure for Alzheimer’s disease, postponing or preventing the onset of Alzheimer’s disease and dementia through therapeutic methods should, therefore, be targeted at individuals decades prior to an individual showing signs or symptoms of decline. As a preventative tool, resistance exercise improves memory, attention, spatial awareness, reaction time, planning, and information processing. Improvements in cognitive performance following resistance exercise and training may be mediated by peripheral elevations in the physiological biomarkers (i.e., neural and vascular) explored in this review. The purpose of this review is to discuss vascular and neuronal degeneration as a cause or consequence of dementia and Alzheimer’s disease, and the biological markers of neurogenesis and blood vessel growth, function, and regulation. We will also explore the merits of acute and chronic resistance training as a strategy to postpone the onset of cognitive decline, dementia, and Alzheimer’s disease.
Vascular insulin resistance often precedes endothelial dysfunction in type 1 diabetes mellitus. Strategies to limit vascular dysfunction include intensive insulin therapy (4–9 mM) and aerobic training. To avoid the risk of hypoglycaemia, individuals often prescribed conventional insulin therapy (9–15 mM) and participate in resistance training. In a model of type 1 diabetes mellitus, this study examined insulin-induced vasomotor function in the aorta and femoral artery to determine (1) whether resistance training with conventional insulin therapy provides the same benefits as aerobic training with conventional insulin therapy, (2) whether aerobic training or resistance training, when paired with conventional insulin therapy, results in superior vasomotor function compared to intensive insulin therapy alone and (3) whether vessel-specific adaptations exist. Groups consisted of conventional insulin therapy, intensive insulin therapy, aerobic training with conventional insulin therapy and resistance training with conventional insulin therapy. Following multiple low doses of streptozotocin, male Sprague-Dawley rats were supplemented with insulin to maintain blood glucose concentrations (9–15 mM: conventional insulin therapy, aerobic training and resistance training; 4–9 mM: intensive insulin therapy) for 12 weeks. Aerobic training performed treadmill exercise and resistance training consisted of weighted climbing. Coinciding with increased Akt signalling, aerobic training resulted in enhanced insulin-induced vasorelaxation in the femoral artery. Intensive insulin therapy displayed increased mitogen-activated protein kinase signalling and no improvement in insulin-stimulated vasorelaxation compared to all other groups. These data suggest that aerobic training may be more beneficial for limiting the pathogenesis of vascular disease in type 1 diabetes mellitus than merely intensive insulin therapy.
We examined the effects of resistance training (RT) frequency performed 3 times per week (RT3) versus RT performed 6 times per week (RT6) under volume-equated conditions in resistance-trained men. Twenty-seven men were randomly allocated to RT3 (n = 14) or RT6 (n = 13). The supervised training intervention lasted for 6-weeks. Upper and lower-body strength were assessed using the one-repetition maximum (1RM) test. Also, muscular endurance (60% 1RM performed to momentary failure), and muscle thickness (elbow flexors, elbow extensors, rectus femoris, and vastus intermedius) were measured pre and post-intervention. Pre-to-post intervention, both groups increased upper-body strength (RT3: +4%; RT6: +6%) and lower-body strength (RT3: +22%; RT6: +18%) with no significant between-group differences. No significant pre-to-post intervention increases in muscular endurance were seen in either of the training groups. Both groups increased elbow extensor thickness (RT3: +14%; RT6: +11%), rectus femoris thickness (RT3: +5%; RT6: +6%), and vastus intermedius thickness (RT3: +10%; RT6: +11%) with no significant between-group differences. Only the RT3 group significantly increased elbow flexor thickness from pre-to-post intervention (+7%). When training volume is equated, it seems that RT performed either 3 or 6 times per week can result in similar strength gains over a 6-week training period. Furthermore, under volume-equated conditions, comparable hypertrophy results may also be expected with both RT frequencies. Finally, no changes were seen in muscular endurance possibly because of the considerable inter-individual variability in the responses. The findings presented herein might be of interest to coaches, exercise practitioners, athletes, and recreational trainees.
A gene was sought that could reverse low voluntary running distances in a model of low voluntary wheel-running behavior. In order to confirm the low motivation to wheel-run in our model does not result from defects in reward valuation, we employed sucrose preference and conditioned place preference for voluntary wheel-access. We observed no differences between our model and wild-type rats regarding the aforementioned behavioral testing. Instead, low voluntary runners seemed to require less running to obtain similar rewards for low voluntary running levels compared to wild-type rats. Previous work in our lab identified protein kinase inhibitor alpha as being lower in low voluntary running than wild-type rats. Next, nucleus accumbens injections of an adenoviral-associated virus that overexpressed the protein kinase inhibitor alpha gene increased running distance in low voluntary running, but not wild-type rats. Endogenous mRNA levels for protein kinase inhibitor alpha, dopamine receptor D1, dopamine receptor D2, and Fos were all only lower in wild-type rats following overexpression compared to low voluntary runners, suggesting a potential molecular and behavioral resistance in wild-type rats. Utilizing a nucleus accumbens preparation, three intermediate early gene mRNAs increased in low voluntary running slices after dopamine receptor agonist SKF-38393 exposure, while wild-type had no response. In summary, the results suggest that protein kinase inhibitor alpha is a promising gene candidate to partially rescue physical activity in the polygenic model of low voluntary running. Importantly, there were divergent molecular responses to protein kinase inhibitor alpha overexpression in low voluntary runners compared to wild-type rats.
Neurodegenerative diseases are increasing in number, given that the general global population is becoming older. They manifest themselves through mechanisms that are not fully understood, in many cases, and impair memory, cognition and movement. Currently, no neurodegenerative disease is curable, and the treatments available only manage the symptoms or halt the progression of the disease. Therefore, there is an urgent need for new treatments for this kind of disease, since the World Health Organization has predicted that neurodegenerative diseases affecting motor function will become the second-most prevalent cause of death in the next 20 years. New therapies can come from three main sources: synthesis, natural products, and existing drugs. This last source is known as drug repurposing, which is the most advantageous, since the drug’s pharmacokinetic and pharmacodynamic profiles are already established, and the investment put into this strategy is not as significant as for the classic development of new drugs. There have been several studies on the potential of old drugs for the most relevant neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Multiple Sclerosis and Amyotrophic Lateral Sclerosis.
Anesthesia/surgery could be associated with cognitive impairment and Alzheimer’s disease neuropathogenesis. However, whether surgery under different anesthetics has different effects on cognitive function remains largely unknown. We therefore set out to compare effects of anesthetic isoflurane or desflurane plus surgery on cognitive function and hippocampus levels of synaptic marker (postsynaptic density-95 and synaptophysin) and ATP. Five-month-old AD Transgenic (Tg) (FAD5X) and wild-type male mice received isoflurane or desflurane plus abdominal surgery. We assessed cognitive function in Barnes maze and measured hippocampus levels of postsynaptic density-95, synaptophysin, and ATP in the mice. We determined whether vitamin K2 could mitigate these anesthesia/surgery-induced changes. Isoflurane, but not desflurane, plus surgery increased escape latency and escape distance in Barnes maze probe test and reduced postsynaptic density-95, synaptophysin, and ATP levels as compared to control condition in AD Tg mice. Vitamin K2 attenuated the anesthesia/surgery-induced changes in the AD Tg mice. These findings suggest that isoflurane, but not desflurane, plus surgery might induce cognitive impairment via causing brain energy deficits. Pending confirmative studies in both animals and humans suggest desflurane could be a better choice for AD patients when surgery is needed. Moreover, vitamin K2 could treat cognitive deficiency associated with anesthesia and surgery.
Alzheimer's disease (AD) is a primary cause of dementia in the middle-aged and elderly worldwide. Animal models for AD are widely used to study the disease mechanisms as well as to test potential therapeutic agents for disease modification. Among the non-genetically manipulated neuroinflammation models for AD, lipopolysaccharide (LPS)-induced animal model is commonly used. This review paper aims to discuss the possible factors that influence rats' response following LPS injection. Factors such as dose of LPS, route of administration, nature and duration of exposure as well as age and gender of animal used should be taken into account when designing a study using LPS-induced memory impairment as model for AD.
Epilepsy is a disease characterized by recurrent, unprovoked seizures. Cognitive impairment is an important comorbidity of chronic epilepsy. Human and animal model studies of epilepsy have shown that aerobic exercise induces beneficial structural and functional changes and reduces the number of seizures. However, little is yet understood about the effects of resistance exercise on epilepsy. We evaluated the effects of a resistance exercise program on the number of seizures, long-term memory and expression/activation of signaling proteins in rats with epilepsy. The number of seizures was quantified by video-monitoring and long-term memory was assessed by an inhibitory avoidance test. Using western blotting, multiplex and enzyme-linked immunosorbent assays, we determined the effects of a 4-week resistance exercise program on IGF-1 and BDNF levels and ERK, CREB, mTOR activation in the hippocampus of rats with epilepsy. Rats with epilepsy submitted to resistance exercise showed a decrease in the number of seizures compared to non-exercised epileptic rats. Memory deficits were attenuated by resistance exercise. Rats with epilepsy showed an increase in IGF-1 levels which were restored to control levels by resistance exercise. BDNF levels and ERK and mTOR activation were decreased in rats with epilepsy and resistance exercise restored these to control levels. In conclusion, resistance exercise reduced seizure occurrence and mitigated memory deficits in rats with epilepsy. These resistance exercise-induced beneficial effects can be related to changes in IGF-1 and BDNF levels and its signaling protein activation. Our findings indicate that the resistance exercise might be included as complementary therapeutic strategy for epilepsy treatment.
Physical exercise is known to be a beneficial factor by increasing the cellular stress tolerance. In ischemic stroke, physical exercise is suggested to both limit the brain injury and facilitate behavioral recovery. In this study we investigated the effect of physical exercise on brain damage following global cerebral ischemia in mice. We aimed to study the effects of 4.5 weeks of forced treadmill running prior to ischemia on neuronal damage, neuroinflammation and its effect on general stress by measuring corticosterone in feces. We subjected C57bl/6 mice (n = 63) to either treadmill running or a sedentary program prior to induction of global ischemia. Anxious, depressive, and cognitive behaviors were analyzed. Stress levels were analyzed using a corticosterone ELISA. Inflammatory and neurological outcomes were analyzed using immunohistochemistry, multiplex electrochemoluminescence ELISA and Western blot. To our surprise, we found that forced treadmill running induced a stress response, with increased anxiety in the Open Field test and increased levels of corticosterone. In accordance, mice subjected to forced exercise prior to ischemia developed larger neuronal damage in the hippocampus and showed higher cytokine levels in the brain and blood compared to non-exercised mice. The extent of neuronal damage correlated with increased corticosterone levels. To compare forced treadmill with voluntary wheel running, we used a different set of mice that exercised freely on running wheels. These mice did not show any anxiety or increased corticosterone levels. Altogether, our results indicate that exercise pre-conditioning may not be beneficial if the animals are forced to run as it can induce a detrimental stress response.
Radial glial-like cells (RGLs) in the adult dentate gyrus (DG) function as progenitor cells for adult hippocampal neurogenesis, a process involved in the stress-related pathophysiology and treatment efficiency of depression. Resveratrol (RSV) has been demonstrated to be a potent activator of neurogenesis. The present study investigated whether chronic RSV treatment has antidepressant potential in relation to hippocampal neurogenesis. Mice received two weeks of RSV (20 mg/kg) or dimethylsulfoxide (DMSO) treatment, followed by lipopolysaccharide (LPS; 1 mg/kg) or saline injections for 5 days. We found that RSV treatment abrogated the increased immobility in the forced swimming test and tail suspension test induced by LPS. Immunohistochemical staining revealed that RSV treatment reversed the increase in microglial activation and the inhibition in DG neurogenesis. RSV treatment also attenuated LPS-induced defects in the expanding of RGLs through promoting symmetric division. In addition, RSV ameliorated LPS-induced NF-κB activation in the hippocampus coincides with the up-regulation levels of Sirt1 and Hes1. Taken together, these data indicated that RSV-induced Sirt1 activation counteracts LPSinduced depression-like behaviors via a neurogenic mechanism. A new model to understand the role of RSV in treating depression may result from these findings.
Alzheimer's disease is one of the most significant healthcare problems nationally and globally. Recently, the first description of the reversal of cognitive decline in patients with early Alzheimer's disease or its precursors, MCI (mild cognitive impairment) and SCI (subjective cognitive impairment), was published [1]. The therapeutic approach used was programmatic and personalized rather than monotherapeutic and invariant, and was dubbed metabolic enhancement for neurodegeneration (MEND). Patients who had had to discontinue work were able to return to work, and those struggling at work were able to improve their performance. The patients, their spouses, and their co-workers all reported clear improvements. Here we report the results from quantitative MRI and neuropsychological testing in ten patients with cognitive decline, nine ApoE4+ (five homozygous and four heterozygous) and one ApoE4-, who were treated with the MEND protocol for 5-24 months. The magnitude of the improvement is unprecedented, providing additional objective evidence that this programmatic approach to cognitive decline is highly effective. These results have far-reaching implications for the treatment of Alzheimer's disease, MCI, and SCI; for personalized programs that may enhance pharmaceutical efficacy; and for personal identification of ApoE genotype.
We investigated the change in myokine expression related to hypertrophy (IL-4, IL-6, IL-10) and atrophy (TNF-α, NFκB, IL-1β) in middle-aged rats after resistance exercise with ladder climbing. 50- and 10-week-old male Wistar rats were randomly assigned to two groups: the sedentary and exercise groups. The exercise groups underwent a ladder-climbing exercise for 8 weeks. While the tibialis anterior muscle mass in the young group significantly increased after the ladder-climbing exercise, the middle-aged group did not show any changes after undergoing the same exercise. To understand the molecular mechanism causing this difference, we analyzed the change in hypertrophy- and atrophy-related myokine levels from the tibialis anterior muscle. After 8 weeks of ladder-climbing exercise, the IL-4 and IL-10 protein levels did not change. However, the IL-6 level significantly increased after exercise training, but the amount of increase in the young training group was higher than in the middle-aged training group. IL-1β and TNF-α as well as NFκB protein levels were significantly higher in the middle-aged group than in the young group. Except for TNF-α, exercise training did not affect IL-1β and NFκB protein levels. The TNF-α level significantly decreased in the middle-aged exercise training group. AMPK and PGC-1α levels also significantly increased after exercise training, but there was no difference between age-related groups. Therefore, 8-week high-intensity exercise training using ladder climbing downregulates the skeletal muscle production of myokine involved in atrophy and upregulates hypertrophic myokine. However, the extent of these responses was lower in the middle-aged than young group.
Background
Mild cognitive impairment (MCI) increases dementia risk with no pharmacologic treatment available.
Methods
The Study of Mental and Resistance Training was a randomized, double-blind, double-sham controlled trial of adults with MCI. Participants were randomized to 2 supervised interventions: active or sham physical training (high intensity progressive resistance training vs seated calisthenics) plus active or sham cognitive training (computerized, multidomain cognitive training vs watching videos/quizzes), 2–3 days/week for 6 months with 18-month follow-up. Primary outcomes were global cognitive function (Alzheimer's Disease Assessment Scale-cognitive subscale; ADAS-Cog) and functional independence (Bayer Activities of Daily Living). Secondary outcomes included executive function, memory, and speed/attention tests, and cognitive domain scores.
Results
One hundred adults with MCI [70.1 (6.7) years; 68% women] were enrolled and analyzed. Resistance training significantly improved the primary outcome ADAS-Cog; [relative effect size (95% confidence interval) −0.33 (−0.73, 0.06); P < .05] at 6 months and executive function (Wechsler Adult Intelligence Scale Matrices; P = .016) across 18 months. Normal ADAS-Cog scores occurred in 48% (24/49) after resistance training vs 27% (14/51) without resistance training [P < .03; odds ratio (95% confidence interval) 3.50 (1.18, 10.48)]. Cognitive training only attenuated decline in Memory Domain at 6 months (P < .02). Resistance training 18-month benefit was 74% higher (P = .02) for Executive Domain compared with combined training [z-score change = 0.42 (0.22, 0.63) resistance training vs 0.11 (−0.60, 0.28) combined] and 48% higher (P < .04) for Global Domain [z-score change = .0.45 (0.29, 0.61) resistance training vs 0.23 (0.10, 0.36) combined].
Conclusions
Resistance training significantly improved global cognitive function, with maintenance of executive and global benefits over 18 months.
It has been demonstrated that resistance exercise improves cognitive functions in humans. Thus, an animal model that mimics this phenomenon can be an important tool for studying the underlying neurophysiological mechanisms. Here, we tested if an animal model for resistance exercise was able to improve the performance in a hippocampus-dependent memory task. In addition, we also evaluated the level of insulin-like growth factor 1/insulin growth factor receptor (IGF-1/IGF-1R), which plays pleiotropic roles in the nervous system. Adult male Wistar rats were divided into three groups (N = 10 for each group): control, SHAM, and resistance exercise (RES). The RES group was submitted to 8 weeks of progressive resistance exercise in a vertical ladder apparatus, while the SHAM group was left in the same apparatus without exercising. Analysis of a cross-sectional area of the flexor digitorum longus muscle indicated that this training period was sufficient to cause muscle fiber hypertrophy. In a step-through passive avoidance task (PA), the RES group presented a longer latency than the other groups on the test day. We also observed an increase of 43 and 94% for systemic and hippocampal IGF-1 concentration, respectively, in the RES group compared to the others. A positive correlation was established between PA performance and systemic IGF-1 (r = 0.46, P < 0.05). Taken together, our data indicate that resistance exercise improves the hippocampus-dependent memory task with a concomitant increase of IGF-1 level in the rat model. This model can be further explored to better understand the effects of resistance exercise on brain functions.
Correspondence: Dr Liu-Ambrose, Department of Physical Therapy, University of British Columbia, 212-2177 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada (tlambrose@exchange.ubc.ca).
Author Contributions: All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Voss and Liu-Ambrose. Acquisition of data: Nagamatsu, Hsu, and Liu-Ambrose. Analysis and interpretation of data: Nagamatsu, Handy, Voss, and Liu-Ambrose. Drafting of the manuscript: Nagamatsu, Handy, and Liu-Ambrose. Critical revision of the manuscript for important intellectual content: Nagamatsu, Handy, Hsu, Voss, and Liu-Ambrose. Statistical analysis: Nagamatsu, Voss, and Liu-Ambrose. Obtained funding: Liu-Ambrose. Administrative, technical, and material support: Nagamatsu, Hsu, Voss, and Liu-Ambrose. Study supervision: Handy and Liu-Ambrose.
Financial Disclosure: None reported.
Funding/Support: The Pacific Alzheimer's Research Foundation provided funding for this study (Dr Liu-Ambrose).
Previous Presentation: Data from this manuscript were presented as a podium presentation at the International Society for Neuroimaging in Psychiatry; September 9, 2011; Heidelberg, Germany.
Additional Information: Ms Nagamatsu is a Michael Smith Foundation for Health Research Senior Graduate trainee and a Natural Sciences and Engineering Research Council of Canada Doctoral trainee. Dr Liu-Ambrose is a Michael Smith Foundation for Health Research Scholar, a Canadian Institutes of Health Research New Investigator, and a Heart and Stroke Foundation of Canada's Henry J. M. Barnett's Scholarship recipient.
Additional Contributions: Alison Chan, BSc, Jennifer C. Davis, PhD, B. Lynn Beattie, MD, and Peter Graf, PhD, made significant contributions to this study. We thank the instructors for their commitment to the participants' health and safety.
This article was corrected for errors on July 10, 2013.
A growing body of scientific evidence indicates that exercise has a positive impact on human health, including neurological health. Aerobic exercise, which is supposed to enhance cardiovascular functions and metabolism, also induces neurotrophic factors that affect hippocampal neurons, thereby improving spatial learning and memory. Alternatively, little is known about the effect of resistance exercise on hippocampus-dependent memory, although this type of exercise is increasingly recommended to improve muscle strength and bone density and to prevent age-related disabilities. Therefore, we evaluated the effects of resistance training on spatial memory and the signaling pathways of brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1), comparing these effects with those of aerobic exercise. Adult male Wistar rats underwent 8 weeks of aerobic training on a treadmill (AERO group) or resistance training on a vertical ladder (RES group). Control and sham groups were also included. After the training period, both AERO and RES groups showed improved learning and spatial memory in a similar manner. However, both groups presented distinct signaling pathways. Although the AERO group showed increased level of IGF-1, BDNF, TrkB, and β-CaMKII (calcium/calmodulin-dependent kinase II) in the hippocampus, the RES group showed an induction of peripheral and hippocampal IGF-1 with concomitant activation of receptor for IGF-1 (IGF-1R) and AKT in the hippocampus. These distinct pathways culminated in an increase of synapsin 1 and synaptophysin expression in both groups. These findings demonstrated that both aerobic and resistance exercise can employ divergent molecular mechanisms but achieve similar results on learning and spatial memory.
Background:
Stroke rehabilitation with different exercise paradigms has been investigated, but which one is more effective in facilitating motor recovery and up-regulating brain neurotrophic factor (BDNF) after brain ischemia would be interesting to clinicians and patients. Voluntary exercise, forced exercise, and involuntary muscle movement caused by functional electrical stimulation (FES) have been individually demonstrated effective as stroke rehabilitation intervention. The aim of this study was to investigate the effects of these three common interventions on brain BDNF changes and motor recovery levels using a rat ischemic stroke model.
Methodology/principal findings:
One hundred and seventeen Sprague-Dawley rats were randomly distributed into four groups: Control (Con), Voluntary exercise of wheel running (V-Ex), Forced exercise of treadmill running (F-Ex), and Involuntary exercise of FES (I-Ex) with implanted electrodes placed in two hind limb muscles on the affected side to mimic gait-like walking pattern during stimulation. Ischemic stroke was induced in all rats with the middle cerebral artery occlusion/reperfusion model and fifty-seven rats had motor deficits after stroke. Twenty-four hours after reperfusion, rats were arranged to their intervention programs. De Ryck's behavioral test was conducted daily during the 7-day intervention as an evaluation tool of motor recovery. Serum corticosterone concentration and BDNF levels in the hippocampus, striatum, and cortex were measured after the rats were sacrificed. V-Ex had significantly better motor recovery in the behavioral test. V-Ex also had significantly higher hippocampal BDNF concentration than F-Ex and Con. F-Ex had significantly higher serum corticosterone level than other groups.
Conclusion/significance:
Voluntary exercise is the most effective intervention in upregulating the hippocampal BDNF level, and facilitating motor recovery. Rats that exercised voluntarily also showed less corticosterone stress response than other groups. The results also suggested that the forced exercise group was the least preferred intervention with high stress, low brain BDNF levels and less motor recovery.
Cognitive decline among seniors is a pressing health care issue. Specific exercise training may combat cognitive decline. We compared the effect of once-weekly and twice-weekly resistance training with that of twice-weekly balance and tone exercise training on the performance of executive cognitive functions in senior women.
In this single-blinded randomized trial, 155 community-dwelling women aged 65 to 75 years living in Vancouver were randomly allocated to once-weekly (n = 54) or twice-weekly (n = 52) resistance training or twice-weekly balance and tone training (control group) (n = 49). The primary outcome measure was performance on the Stroop test, an executive cognitive test of selective attention and conflict resolution. Secondary outcomes of executive cognitive functions included set shifting as measured by the Trail Making Tests (parts A and B) and working memory as assessed by verbal digit span forward and backward tests. Gait speed, muscular function, and whole-brain volume were also secondary outcome measures.
Both resistance training groups significantly improved their performance on the Stroop test compared with those in the balance and tone group (P < or = .03). Task performance improved by 12.6% and 10.9% in the once-weekly and twice-weekly resistance training groups, respectively; it deteriorated by 0.5% in the balance and tone group. Enhanced selective attention and conflict resolution was significantly associated with increased gait speed. Both resistance training groups demonstrated reductions in whole-brain volume compared with the balance and tone group at the end of the study (P < or = .03).
Twelve months of once-weekly or twice-weekly resistance training benefited the executive cognitive function of selective attention and conflict resolution among senior women.
clinicaltrials.gov Identifier: NCT00426881.
Multiple sclerosis (MS) is a progressive disease of the CNS that is characterised by widespread lesions in the brain and spinal cord. MS results in motor, cognitive, and neuropsychiatric symptoms, all of which can occur independently of one another. The common cognitive symptoms include deficits in complex attention, efficiency of information processing, executive functioning, processing speed, and long-term memory. These deficits detrimentally affect many aspects of daily life, such as the ability to run a household, participate fully in society, and maintain employment--factors that can all affect the overall quality of life of the patient. The increased use of neuroimaging techniques in patients with MS has advanced our understanding of structural and functional changes in the brain that are characteristic of this disease, although much remains to be learned. Moreover, examination of efforts to treat the cognitive deficits in MS is still in the early stages.
This study was undertaken to evaluate the relationship between physical performance capacity and the mitochondrial content of skeletal muscle. Four groups of rats were trained by means of treadmill running 5 days/wk for 13 wk. One group ran 10 min/day, a second group ran 30 min/day, a third group ran 60 min/day, and a fourth group ran 120 min/day. The magnitude of the exercise-induced adaptive increase in gastrocnemius muscle respiratory capacity varied over a twofold range in the four groups. There were significant correlations between the levels of three mitochondrial markers (cytochrome c, citrate synthase, respiratory capacity) in the animals' gastrocnemius muscles and the duration of a run to exhaustion. There was also a significant correlation between the amounts of glycogen remaining in liver and skeletal muscle after a 30-min-long exercise test and the respiratory capacity of the animal's leg muscles. These findings are compatible with the interpretation that a close relationshiop exists between skeletal muscle mitochondrial content and the capacity to perform endurance exercise.
Only a small fraction of neurotransmitter-containing synaptic vesicles (SVs), the readily releasable pool, is available for fast Ca(2+)-induced release at any synapse. Most SVs are sequestered at sites away from the plasma membrane and cannot be exocytosed directly. Recruitment of SVs to the releasable pool is thought to be an important component of short-term synaptic facilitation by serotonin (5-HT) at Aplysia sensorimotor synapses. Synapsins are associated with SVs and hypothesized to play a central role in the regulation of SV mobilization in nerve terminals. Aplysia synapsin was cloned to examine its role in synaptic plasticity at the well characterized sensorimotor neuron synapse of this animal. Acute 5-HT treatment of ganglia induced synapsin phosphorylation. Immunohistochemical analyses of cultured Aplysia neurons revealed that synapsin is distributed in distinct puncta in the neurites. These puncta are rapidly dispersed after treatment of the neurons with 5-HT. The dispersion of synapsin puncta by 5-HT was fully reversible after washout of the modulator. Both 5-HT-induced phosphorylation and dispersion of synapsin were mediated, at least in part, by cAMP-dependent protein kinase and mitogen-activated protein kinase. These experiments indicate that synapsin and its regulation by 5-HT may play an important role in the modulation of SV trafficking in short-term synaptic plasticity.
Although the synapsin phosphoproteins were discovered more than 30 years ago and are known to play important roles in neurotransmitter release and synaptogenesis, a complete picture of their functions within the nerve terminal is lacking. It has been shown that these proteins play an important role in the clustering of synaptic vesicles (SVs) at active zones and function as modulators of synaptic strength by acting at both pre- and postdocking levels. Recent studies have demonstrated that synapsins migrate to the endocytic zone of central synapses during neurotransmitter release, which suggests that there are additional functions for these proteins in SV recycling.
We discuss the factors that encouraged us to examine the question of whether exercise training has a positive influence on cognitive health of older adults in 2003. At that time there was a substantial literature on exercise and cognition. However, cognitive assessment instruments, exercise protocols (including type of exercise, length, and intensity of exercise programs), and subject-selection criteria differed widely. Our meta-analysis enabled us to examine both the main question under study—exercise effects on cognition—and potential moderators of this effect. Several interesting findings, which are briefly detailed in the present article, were revealed by our analyses. The current article also examines where the literature has gone since our 2003 article.
Twenty young women (20.3+1.5 years, 164+6 cm, 68.7+13.8 kg) without prior structured resistance training experience were recruited for this study. Body composition (BodPod), compartmental water (Bioelectrical Impedance), 7-site skinfold, and arm and thigh CSA were assessed pre- and post- 8 week training. Performance testing consisted of vertical jump, 3 kg chest pass initial velocity, squat 1RM and overhead press 1RM. Following 2 weeks of familiarization training, subjects were matched for body composition and relative squat strength, and randomly assigned to either a high- (HL: n=10; 4 sets of 5-7 repetitions) or moderate-load (ML: n=10; 2 sets of 10-14 repetitions) group that completed 6-7 exercises per day performed to momentary muscular failure. Training was divided into two lower and one upper body training sessions per week performed on non-consecutive days for 8 weeks. There were no statistically significant main effects for group or group x time interactions for any variable assessed. Both HL and ML resulted in similar significant increases in lean body mass (1.5 + .83 kg), lean dry mass (1.32 + 0.62 kg), thigh CSA (6.6 + 5.6 cm), vertical jump (2.9 + 3.2 cm), chest pass velocity (0.334 + 1.67 m/s), back squat 1 RM (22.5 + 8.1 kg), and overhead press (3.0 + 0.8 kg). HL and ML also both resulted in significant decreases in percent body fat (1.3 + 1.3 %), total body water (0.73 + 0.70 L), and intracellular water (0.43 + 0.38 L). The results of this study indicate that both moderate- and high-load training are effective at improving muscle growth, body composition, strength and power in untrained young women.
This study tested the hypotheses that obesity-induced decrements in insulin-stimulated cerebrovascular vasodilation would be normalized with acute endothelin-1a receptor antagonism, and treatment with a physical activity intervention restores vasoreactivity to insulin through augmented nitric oxide synthase (NOS)-dependent dilation. Otsuka Long-Evans Tokushima Fatty rats were divided into the following groups; 20-wk old food-controlled (CON-20); 20-wk old free-food access (model of obesity, OB-20); 40-wk old food-controlled (CON-40); 40-wk old free-food access (OB-40); and 40-wk old free-food access+RUN (RUN-40; wheel-running access from 20-40 wk). Rats underwent Barnes maze testing and a euglycemic hyperinsulinemic clamp (EHC). In the 40-wk cohort, cerebellum and hippocampus blood flow (BF) were examined (microsphere-infusion). Vasomotor responses (pressurized myography) to insulin were assessed in untreated, endothelin-1a receptor antagonism and NOS inhibition conditions in posterior cerebral arteries. Insulin-stimulated vasodilation was attenuated in the OB vs. CON and RUN groups (P≤0.04). Dilation to insulin was normalized with endothelin-1a receptor antagonism in the OB groups (between groups, P≥0.56) and insulin-stimulated NOS-mediated dilation was greater in the RUN-40 vs. OB-40 group (P<0.01). At 40-wk of age, cerebellum BF decreased during the EHC in the OB-40 group (P=0.02), but not CON or RUN groups (P≥0.36). Barnes maze testing revealed increased entry errors and latencies in the RUN-40 vs. CON and OB groups (P<0.01). These findings indicate OB-induced impairments in vasoreactivity to insulin involve increased endothelin-1 and decreased NO signaling. Chronic spontaneous physical activity, initiated after disease onset, reversed impaired vasodilation to insulin and decreased Barnes maze performance, possibly because of increased exploratory behavior.
Objectives:
To determine whether improvements in aerobic capacity (VO2peak ) and strength after progressive resistance training (PRT) mediate improvements in cognitive function.
Design:
Randomized, double-blind, double-sham, controlled trial.
Setting:
University research facility.
Participants:
Community-dwelling older adults (aged ≥55) with mild cognitive impairment (MCI) (N = 100).
Intervention:
PRT and cognitive training (CT), 2 to 3 days per week for 6 months.
Measurements:
Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog); global, executive, and memory domains; peak strength (1 repetition maximum); and VO2peak .
Results:
PRT increased upper (standardized mean difference (SMD) = 0.69, 95% confidence interval = 0.47, 0.91), lower (SMD = 0.94, 95% CI = 0.69-1.20) and whole-body (SMD = 0.84, 95% CI = 0.62-1.05) strength and percentage change in VO2peak (8.0%, 95% CI = 2.2-13.8) significantly more than sham exercise. Higher strength scores, but not greater VO2peak , were significantly associated with improvements in cognition (P < .05). Greater lower body strength significantly mediated the effect of PRT on ADAS-Cog improvements (indirect effect: β = -0.64, 95% CI = -1.38 to -0.004; direct effect: β = -0.37, 95% CI = -1.51-0.78) and global domain (indirect effect: β = 0.12, 95% CI = 0.02-0.22; direct effect: β = -0.003, 95% CI = -0.17-0.16) but not for executive domain (indirect effect: β = 0.11, 95% CI = -0.04-0.26; direct effect: β = 0.03, 95% CI = -0.17-0.23).
Conclusion:
High-intensity PRT results in significant improvements in cognitive function, muscle strength, and aerobic capacity in older adults with MCI. Strength gains, but not aerobic capacity changes, mediate the cognitive benefits of PRT. Future investigations are warranted to determine the physiological mechanisms linking strength gains and cognitive benefits.
Inflammation influences chronic neurodegeneration but its precise roles are not yet clear. Systemic inflammation caused by infection, trauma or co-morbidity can alter the brain’s inflammatory status, produce acute cognitive impairments, such as delirium, and drive new pathology and accelerated decline. Consistent with this, elevated systemic TNF-α is associated with more rapid cognitive decline over 6 months in Alzheimer’s disease patients. In the current study we challenged normal animals and those with existing progressive neurodegeneration (ME7 prion disease) with TNF-α (i.p.) to test the hypothesis that this cytokine has differential effects on cognitive function, sickness behavior and features of underlying pathology contingent on the animals’ baseline condition. TNF-α (50 μg/kg) had no impact on performance of normal animals (normal brain homogenate; NBH) on working memory (T-maze) but produced acute impairments in ME7 animals similarly challenged. Plasma TNF-α and CCL2 levels were equivalent in NBH and ME7 TNF-challenged animals but hippocampal and hypothalamic transcription of IL-1β, TNF-α and CCL2 and translation of IL-1β were higher in ME7+TNF-α than NBH+TNF-α animals. TNF-α produced an exaggerated sickness behavior response (hypothermia, weight loss, inactivity) in ME7 animals compared to than in NBH animals. However a single challenge with this dose was not sufficient to produce de novo neuronal death, synaptic loss or tau hyperphosphorylation that was distinguishable from that arising from ME7 alone. The data indicate that acutely elevated TNF-α has robust acute effects on brain function, selectively in the degenerating brain, but more sustained levels may be required to significantly impact on underlying neurodegeneration.
Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal lobar dementia are among the most pressing problems of developed societies with aging populations. Neurons carry out essential functions such as signal transmission and network integration in the central nervous system and are the main targets of neurodegenerative disease. In this Review, I address how the neuron's environment also contributes to neurodegeneration. Maintaining an optimal milieu for neuronal function rests with supportive cells termed glia and the blood-brain barrier. Accumulating evidence suggests that neurodegeneration occurs in part because the environment is affected during disease in a cascade of processes collectively termed neuroinflammation. These observations indicate that therapies targeting glial cells might provide benefit for those afflicted by neurodegenerative disorders.
Methods:
Male Wistar rats were familiarised with climbing a ladder without a load for three days and randomly assigned into control (CTL) and resistance exercise (RES) groups. The RES group was subjected to a single bout of resistance exercise applied immediately after fear conditioning training. Subsequently, the animals were tested for contextual (24h) and tone (48h) fear memory. Another group of animals were subjected to a single bout of resistance exercise and euthanised 24 hours later for hippocampal analysis of IGF-1 and synaptic proteins (synapsin I, synaptophysin, and PSD-95).
Results:
The exercised rats improved contextual but not tone fear memory. Hippocampal IGF-1 was not altered by resistance exercise. However, the levels of synapsin I, synaptophysin, and PSD-95 increased significantly in the RES group.
Conclusion:
Our results suggest that a single bout of resistance exercise applied immediately after fear conditioning can improve contextual memory, probably through the activation of pre- and postsynaptic machinery required for memory consolidation. This article is protected by copyright. All rights reserved.
The neurotrophic factor insulin-like growth factor (IGF)-1 promotes neurogenesis in the mammalian brain and provides protection against brain injury. However, Studies regarding the effects of IGF-1 on cognitive function in aged mice remain limited. We investigated the effects of overexpression of IGF-1 specifically in neural stem cells of the hippocampal dentate gyrus on the recognitive function in 18-month-old transgenic mice. Immunohistocytochemistry and Nissl staining revealed the increased population of BrdU-positive cells as well as the upregulated expression of Nestin and neuronal nuclei (NeuN), respective markers for neural progenitors and neurons, in the hippocampus of the aged IGF-1 transgenic mice versus the wild-type, suggesting that IGF-1 overexpression promotes neurogenesis. In addition, the IGF-1 receptor (IGF-1R), the phosphorylation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) were enhanced in the transgenic mice than in the wild-type. Transgenic mice also showed superior performance in the Morris water maze and step-down memory tests to their wild-type counterparts. Moreover, the learning and memory abilities of transgenic mice were significantly undermined with the blockage of CaMKII and ERK signaling pathway. Accordingly, our findings indicated that IGF-1 may mitigate the aged-associated cognitive decline via promoting neurogenesis in the hippocampus and activating CaMKII and ERK signaling by binding with IGF-1R.
The purpose of this study was to examine whether exercise training reduced inflammation and symptomology in a mouse model of colitis. We hypothesized that moderate forced treadmill running (FTR) or voluntary wheel running (VWR) would reduce colitis symptoms and colon inflammation in response to dextran sodium sulfate (DSS). Male C57Bl/6J mice were randomized to sedentary, moderate intensity FTR (8-12 m/min, 40 min, 6 weeks, 5x/week), or VWR (30 days access to wheels). DSS was given at 2% (w/v) in drinking water over 5 days. Mice discontinued exercise 24 h prior to and during DSS treatment. Colons were harvested on Days 6, 8 and 12 in FTR and Day 8 post-DSS in VWR experiments. Contrary to our hypothesis, we found that moderate FTR exacerbated colitis symptomology and inflammation as measured by significant (p⩽0.05) increases in diarrhea and IL-6, IL-1β, IL-17 colon gene expression. We also observed higher mortality (3/10 died vs. 0/10, p = 0.07) in the FTR/DSS group. In contrast, VWR alleviated colitis symptoms and reduced inflammatory gene expression in the colons of DSS-treated mice (p⩽0.05). While DSS treatment reduced food/fluid intake and body weight, there was a tendency for FTR to exacerbate, and for VWR to attenuate, this effect. FTR (in the absence of DSS) increased gene expression of the chemokine and antibacterial protein CCL6 suggesting that FTR altered gut homeostasis that may be related to the exaggerated response to DSS. In conclusion, we found that FTR exacerbated, whereas VWR attenuated, symptoms and inflammation in response to DSS.
Using genomic microarray analysis, our objective was to identify and annotate differences in the pre-training skeletal muscle transcriptomes among human subjects clustered as non-responders (Non), modest responders (Mod), and extreme responders (Xtr) based on differential magnitudes of myofiber hypertrophy in response to progressive resistance training (RT) (Non -16μm(2), Mod 1,111μm(2), or Xtr 2,475μm(2)). In prior work, we noted differences among clusters in the prevalence of myogenic stem cells prior to and during RT (35), and in the translational signaling responses to the first bout of resistance exercise (30). Here we identified remarkable differences in the pre-training transcript profiles among clusters (8026 genes differentially expressed between Xtr and Non; 2463 between Xtr and Mod; and 1294 between Mod and Non). Annotated functions and networks of differentially expressed genes suggest Xtr were "primed" to respond to RT through transcriptional regulation, along with a uniquely expressed network of genes involved in skeletal muscle development, while the failed response in Non may have been driven by excessive pro-inflammatory signaling. Protein follow-up analysis revealed higher basal levels of acetylated histone H3 (K36) in the two responder clusters (Mod, Xtr) compared to Non, and only the responders experienced alterations in the muscle content of select proteins (e.g., α-tubulin, p27(kip)) in response to the first resistance exercise stimulus. Overall, the widely disparate transcriptomes identified prior to RT among the three clusters support the notion that at least some of the inter-individual heterogeneity in propensity for RT-induced myofiber hypertrophy is likely pre-determined.
Brain inflammation plays a pivotal role in the pathogenesis of chronic neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. We investigated the effects of treadmill exercise and wheel exercise on spatial learning ability in relation with long-term potentiation (LTP) using lipopolysaccharide-induced brain inflammation in the rats. Brain inflammation was induced by an injection of LPS into the cerebral ventricle. We found that brain inflammation impaired spatial learning ability and suppressed the induction of LTP in the hippocampus, as well as weakening expressions of brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B (Trk-B) with the phosphorylated cyclic AMP response element binding protein (p-CREB). Both treadmill exercise and wheel exercise significantly improved spatial learning ability deteriorated by brain inflammation. These effects can be ascribed to the long-lasting effect of exercise on LTP through enhancement of the expressions regarding BDNF, TrkB, and p-CREB. Treadmill exercise and wheel exercise exerted similar effects on these factors. We infer that exercise may alleviate brain inflammation-induced learning impairment.
Glycogen synthase kinase-3 (GSK3) is implicated in the regulation of several physiological processes, including the control of glycogen and protein synthesis by insulin, modulation of the transcription factors AP-1 and CREB, the specification of cell fate in Drosophila and dorsoventral patterning in Xenopus embryos. GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors and in vitro by either MAP kinase-activated protein (MAPKAP) kinase-1 (also known as p90rsk) or p70 ribosomal S6 kinase (p70S6k). Here we show, however, that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3. Another insulin-stimulated protein kinase inactivates GSK3 under these conditions, and we demonstrate that it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC). Like the inhibition of GSK3 (refs 10, 14), the activation of PKB is prevented by inhibitors of phosphatidylinositol (PI) 3-kinase.
The endogenous cannabinoid system participates in oligodendrocyte progenitor differentiation in vitro. To determine the effect of synthetic cannabinoids on oligodendrocyte differentiation, we exposed differentiating cultures of oligodendrocytes with cannabinoid CB(1), CB(2) and CB(1)/CB(2) receptor agonists and antagonists. The response of the PI3K/Akt and the mammalian target of rapamycin (mTOR) signalling pathways were studied as effectors of cannabinoid activity.
Purified oligodendrocyte progenitor cells (OPC) obtained from primary mixed glial cell cultures were treated for 48 h with CB(1), CB(2) and CB(1) /CB(2) receptor agonists (ACEA, JWH133 and HU210, respectively) in the presence or absence of the antagonists AM281 (CB(1) receptor) and AM630 (CB(2) receptor). Moreover, inhibitors of the phosphatidylinositol 3-kinase (PI3K)/Akt and mTOR pathways (LY294002 and rapamycin, respectively) were used to study the involvement of these pathways on cannabinoid-induced OPC maturation.
ACEA, JWH133 and HU-210 enhanced OPC differentiation as assessed by the expression of stage specific antigens and myelin basic protein (MBP). Moreover, this effect was blocked by the CB receptor antagonists. ACEA, JWH133 and HU210 induced a time-dependent phosphorylation of Akt and mTOR, whereas the inhibitors of PI3K/Akt (LY294002) or of mTOR (rapamycin) reversed the effects of HU-210 on oligodendrocyte differentiation and kinase activation.
Activation of cannabinoid CB(1) or CB(2) receptors with selective agonists accelerated oligodendrocyte differentiation through the mTOR and Akt signalling pathways.
In the present study, neuroinflammation was induced by bilateral intracerebroventricular (ICV) administration of Lipopolysaccharide (LPS). Proinflammatory cytokines (TNF-alpha and IL-1beta), acetylcholinesterase (AChE) activity, malondialdehyde (MDA) and reduced glutathione (GSH) were studied as markers for neuroinflammation, cholinergic activity and oxidative stress respectively in different brain regions at different time points after LPS injection. LPS produced increase in proinflammatory cytokines, MDA and the decrease in level of GSH at 24 h indicating a state of inflammation in brain regions, which was significantly blocked by Ibuprofen, a non steroidal anti-inflammatory drug. Enhanced AChE activity with these inflammatory markers after LPS administration indicates a possible relationship between neuroinflammation and cholinergic system during the development of neurodegenerative diseases.
The persistent diarrhoea of greater than 14 days' duration in 17 infants, comprising 1% of 1672 patients who were admitted to a South African Hospital during January 1985-July 1987 for a study on acute gastroenteritis, is described. The age of the patients was between 20 days and 31 months (7.4 +/- 7.8 months), 11 of whom were of less than 6 months and the majority (13) were boys. Fifteen had the nutritional status below the 3rd weight-for-age centile. On admission, gastroenteritis was graded as mild in three patients, moderate in nine and severe in five. Seven, six and four patients had mild, moderate and severe dehydration respectively. Twelve patients required infusion of intravenous (i.v.) fluids for greater than or equal to 14 days to maintain hydration. Complications, such as bronchopneumonia and septicaemia, were present in five and three patients respectively. Nine of the 17 patients shed rotavirus in their stools, 7 of whom continued to do so for 10 to 18 days, and 3 of whom had associated infections either with Salmonella or with enteropathogenic Escherichia coli or both. Any causal agent was not detected in six patients. The mainstay of treatment was oral rehydration therapy with i.v. fluid when necessary and a normal diet of cow's milk-based formula to all except the two breast-fed infants. A failure to improve patients' condition led to the following graded additions to the treatment regimen: lactose-free soya diet, administration of oral gentamicin plus cholestyramine and feeding of semi-elemental formula ("Alfaré," R). The last one gave encouraging results, though the study was not a controlled therapeutic trial.
The expression of proliferating cell nuclear antigen (PCNA), also called cyclin, was quantified in the cell lines SP2/0 and MOLT-4 and in mouse splenocytes induced to proliferate in vitro with mitogens. Autoantibody from a patient with systemic lupus erythematosus was used to label PCNA in cell suspensions after the cells had been fixed and permeabilized. In the same cells DNA was stained by propidium iodide. The cells were then analysed by flow cytometry for PCNA and DNA content. The PCNA profiles in proliferating spleen cells and the cell lines were similar. Most G0-G1 cells did not express significant amount of PCNA. A dramatic increase in PCNA immunofluorescence was observed in late G1 cells, and further increases were observed in S-phase cells. G2-M cells showed a reduced level of PCNA immunofluorescence relative to S-phase cells but were still elevated relative to G0-G1 cells. Proliferating cells arrested at the G1-S boundary by exposure to cytosine arabinoside showed an increased PCNA immunofluorescence as compared to unstimulated cells.
Cell-free extracts prepared from human 293 cells, supplemented with purified SV40 large-T antigen, support replication of plasmids containing the SV40 origin of DNA replication. A cellular protein (Mr approximately 36,000) that is required for efficient SV40 DNA synthesis in vitro has been purified from these extracts. This protein is recognized by human autoantibodies and is identified as the cell-cycle regulated protein known as proliferating cell nuclear antigen (PCNA) or cyclin.
Proliferating cell nuclear antigen (PCNA)/cyclin is an intranuclear polypeptide antigen that is found in both normal and transformed proliferating cells. We have recently described two mouse monoclonal antibodies reacting with PCNA. In this report we describe the application of these antibodies to the study of proliferating human cells by indirect immunofluorescence microscopy and by flow cytometry. A fixation/permeation procedure was developed in order to obtain satisfactory binding of monoclonal PCNA-specific antibodies to proliferating cells. This method involved fixation with 1% paraformaldehyde followed by methanol treatment. For the staining of cells in suspension with the IgM type monoclonal antibodies lysolecithin was added to the paraformaldehyde solution to achieve a better permeation by the antibody molecules. This procedure gave a good ratio of specific staining relative to the background staining. It also preserved the shape and normal architecture of the cells as judged by visual microscopic observation and by light scatter measurements using a flow cytometer. Furthermore, this fixation technique permits simultaneous labeling of DNA by propidium iodide and PCNA by monoclonal antibodies. PCNA was detected in various types of normal and transformed proliferating cells by indirect immunofluorescence. Quiescent peripheral blood mononuclear cells were PCNA-negative whereas a fraction of lectin-stimulated lymphocytes became PCNA-positive. Similarly, early passages of fetal skin fibroblasts were PCNA-positive but non-proliferating senescent fibroblasts of later passages were PCNA-negative. The association of PCNA-staining by monoclonal antibodies with cell proliferation was confirmed by flow cytometry. Simultaneous labeling of PCNA and DNA showed that the PCNA signal increased during the G1 phase of the cell cycle, reached its maximum in the S-phase, and declined during the G2/M phase. Using cell sorting we demonstrated that mitotic cells had a very low PCNA signal. Thus, monoclonal PCNA-specific antibodies offer a convenient tool for the detection of human cell proliferation by immunofluorescence microscopy and by flow cytometry.
Strength gains with resistance training are due to muscle hypertrophy and nervous system adaptations. The contribution of either factor may be related to the complexity of the exercise task used during training. The purpose of this investigation was to measure the degree to which muscle hypertrophy contributes to gains in strength during exercises of varying complexity. Nineteen young women resistance trained twice a week for 20 weeks, performing exercises designed to provide whole-body training.
The lean mass of the trunk, legs and arms was measured by dual energy x-ray absorptiometry and compared to strength gains (measured as the 1-repetition maximum) in bench press, leg press and arm curl exercises, pre-, mid- (10 weeks) and post-training. No changes were found in a control group of ten women. For the exercise group, increases in bench press, leg press and arm curl strength were significant from pre- to mid-, and from mid- to post-training (P < 0.05). In contrast, increases in the lean mass of the body segments used in these exercises followed a different pattern. Increases in the lean mass of the arms were significant from pre- to mid-training, while increases in the lean mass of the trunk and legs were delayed and significant from mid- to post-training only (P < 0.05). It is concluded that a more prolonged neural adaptation related to the more complex bench and leg press movements may have delayed hypertrophy in the trunk and legs. With the simpler arm curl exercise, early gains in strength were accompanied by muscle hypertrophy and, presumably, a faster neural adaptation.
Proliferating cell nuclear antigen (PCNA) is essential for the function of DNA polymerases delta and epsilon. Because proliferating cell nuclear antigen is required for DNA replication and repair, PCNA is abundantly expressed in proliferating cells. Interestingly, PCNA mRNA has also been detected in the adult mouse brain by Northern blot analysis. In this study, two monoclonal antibodies against PCNA, PC10 and 19F4, were used for Western blot analysis. Monoclonal antibody PC10, but not 19F4, detected a band in the adult mouse brain extract. This PC10-reactive protein in the brain displayed a more acidic isoelectric point than PCNA by two-dimensional gel electrophoresis. In situ hybridization showed that PCNA mRNA was abundantly expressed in the adult mouse subventricular zone. Additionally, relatively low levels of PCNA mRNA expression were also found in neurons throughout the central nervous system, however, no hybridization was observed in the white matter. Immunohistochemistry was also performed using 19F4 and PC10, and staining of progenitor cell nuclei in the subventricular zone was observed with both antibodies. Whereas 19F4 immunostaining was restricted to progenitor cells, PC10 immunostaining was also found in postmitotic nonproliferating cell nuclei. In the cortical neuroepithelium of developing mice, the distribution of PC10 immunoreactivity was wider than that of 19F4 immunoreactivity and PCNA mRNA expression. These results suggest that proliferating cell nuclear antigen mRNA is expressed not only in proliferating cells but also in nonproliferating cells such as neurons. The protein recognized only with PC10 may be a modified, most probably a phosphorylated PCNA.
Exercise training produces a vast array of physiological adaptations, ranging from changes in metabolism to muscle mitochondrial biogenesis. Researchers studying the physiological effects of exercise often use animal models that employ forced exercise regimens that include aversive motivation, which could activate the stress response. This study examined the effect of forced treadmill running (8 wk) on several physiological systems that are sensitive to training and stress. Forced treadmill running produced both positive and negative physiological adaptations. Indicative of positive training adaptations, exercised male Sprague-Dawley rats had a decrease in body weight gain and an increase in muscle citrate synthase activity compared with sedentary controls. In contrast, treadmill running also resulted in the potentially negative adaptations of adrenal hypertrophy, thymic involution, decreased serum corticosteroid binding globulin, elevated lymphocyte nitrite concentrations, suppressed lymphocyte proliferation, and suppressed antigen-specific IgM. Such alterations in neuroendocrine tissues and immune responses are commonly associated with chronic stress. Thus treadmill running produces both positive training adaptations and potentially negative adaptations that are indicative of chronic stress. Researchers employing forced activity need to be aware that this type of exercise procedure also produces physiological adaptations indicative of chronic stress and that these changes could potentially impact other measures of interest.
Dementia affects about 40% of patients with Parkinson's disease; the incidence of dementia in these patients is up to six times that in healthy people. Clinically, the prototype of dementia in PD is a dysexecutive syndrome. Loss of cholinergic, dopaminergic, and noradrenergic innervation has been suggested to be the underlying neurochemical deficits. Nigral pathology alone is probably not sufficient for the development of dementia. Although there is some controversy with regard to the site and type of pathology involved, dementia is likely to be associated with the spread of pathology to other subcortical nuclei, the limbic system, and the cerebral cortex. On the basis of more recent studies, the main pathology seems to be Lewy-body-type degeneration with associated cellular and synaptic loss in cortical and limbic structures. Alzheimer's disease-type pathology is commonly associated with dementia but less predictive. Recent evidence from small studies suggests that cholinesterase inhibitors may be effective in the treatment of dementia associated with PD.
On cell maturation following culture in medium containing 26 mM potassium (high K+; HK), a change to medium containing 5 mM potassium (low K+; LK) rapidly induces apoptosis in rat cerebellar granule neurons. Brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1) have survival-promoting effects on the neurons via PI3-K. However, it remains unclear how they prevent the apoptosis in the pathway downstream of phosphatidylinositol-3 kinase (PI3-K). Recently, we have reported that PI3-K-ASK1 pathway is involved in signal-transduction to p38 MAPK (p38)-c-Jun pathway. Here we found that IGF-1 had a greater survival-promoting effect than BDNF, and activated PI3-K to a higher level and maintained the level for a longer time. BDNF and IGF-1 suppressed the activation of p38 and c-Jun, but not of c-Jun N-terminal kinase (JNK), caused by lowering the potassium concentration. The inhibitory effects of IGF-1 were much greater than those of BDNF. In addition, LY294002, a specific inhibitor of PI3-K, cancelled the inhibitory effects of BDNF and IGF-1. These results suggest that the greater inhibitory effects of IGF-1 than BDNF, on activation of p38 and c-Jun and apoptosis, are caused by the higher level of PI3-K activation during LK-induced apoptosis of cultured cerebellar granule neurons.
Insulin-like growth factor-1 (IGF-1) and brain-derived neurotrophic factor (BDNF) are trophic factors required for the viability and normal functions of various neuronal cells. However, the detailed intracellular mechanism(s) involved in these effects in neuronal cells remains to be fully elucidated. In present study, the respective intracellular signaling pathway induced by IGF-1 and BDNF and their possible role in neuronal survival were investigated. Both IGF-1 and BDNF protected hippocampal neurons from serum deprivation-induced death with IGF-1 apparently being more potent. Western blot analyses showed that both IGF-1 and BDNF induced the activation of the phosphatidylinositide 3 kinase (PI3)/Akt (protein kinase B) kinase and the mitogen-activated protein kinase (MAPK) pathways. The phosphorylation of Akt and its downstream target, FKHRL1, induced by IGF-1 was rapid and sustained while that of MAPK was transient. The reverse situation was observed for BDNF. Moreover, IGF-1 potently induced the tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and its association with PI3 kinase while BDNF was weak in these assays. In contrast, the tyrosine phosphorylation of Shc proteins was dramatically stimulated by BDNF, with IGF-1 having only a minimal effect. Most interestingly, only the inhibitor of the PI3K/Akt pathway, LY294002, was able to block the survival effects of both IGF-1 and BDNF; an inhibitor of the MAPK pathway inhibitor, PD98059, being ineffective. Taken together, these data reveal that the survival properties of both IGF-1 and BDNF against serum deprivation are mediated by the activation of the PI3K/Akt, but not the MAPK, pathway in hippocampal neurons.
The phosphoinositide 3-kinase (PI3K)/Akt signalling cascade has classically been implicated in promoting cell survival but more recently has been shown to regulate a number of other cellular functions. In particular, studies have suggested that PI3K contributes to mechanisms associated with synaptic plasticity and memory processes but the function of this cascade in forms of synaptic plasticity, such as long-term potentiation, remains controversial and the PI3K substrates which mediate these effects are poorly understood. Here we report that the PI3K inhibitor LY294002 infused i.c.v. in vivo blocked maintenance of long-term potentiation induced in the dentate gyrus with a single tetanus to the perforant path but not with repeated tetani. This pattern of stimulation led to rapid and transient phosphorylation of the PI3K substrate Akt at Ser473 but not at Thr308. Functional readout of partial activation of Akt was demonstrated by an increase in phosphorylation of two downstream substrates, Forkhead (FKHR) and mammalian target of rapamycin (mTOR), in a delayed and prolonged manner at Akt-specific phosphorylation sites. LY294002 blocked phosphorylation of Akt and the prolonged phosphorylation of FKHR and mTOR but did not impair long-term potentiation-induced phosphorylation of extracellular receptor kinase. In addition, the same i.c.v. concentration of LY294002 impaired long-term consolidation of recognition memory but not short-term recognition memory or spatial learning and repeated training in the recognition memory task overcame the deficit in consolidation. These results suggest that activation of the PI3K/Akt pathway may contribute to the mechanisms of synaptic plasticity and memory consolidation by promoting cell survival via FKHR and protein synthesis via mTOR. Importantly, only partial activation of Akt at its Ser473 residue was necessary to mediate these effects.
Cognitive impairment in multiple sclerosis
- N D Chiaravalloti
- J Deluca
Chiaravalloti ND, DeLuca J. Cognitive impairment in multiple sclerosis. Lancet Neurol 7: 1139 -1151, 2008. doi:10.1016/S1474-4422(08)
70259-X.