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This study aimed to investigate the effects of inspiratory muscle training (IMT) on inspiratory muscle strength, dyspnea, and quality of life (QOL) in COPD patients. A comprehensive search was undertaken on the Web of Science, Scopus, Embase, Cochrane, and PubMed databases, encompassing data published up to 31 March 2024. A meta-analysis was subsequently conducted to quantify the standardized mean difference (SMD) and 95% confidence interval (CI) for the effects of IMT in COPD patients. Sixteen studies met the inclusion criteria. IMT significantly improved inspiratory muscle strength (SMD, 0.86, p < 0.00001), dyspnea (SMD = −0.50, p < 0.00001), and QOL (SMD = 0.48, p = 0.0006). Subgroup analysis showed that p = 0.005; dyspnea, SMD = −0.92, p < 0.0001), IMT conducted for ≤20 min (inspiratory muscle strength, SMD = 0.97, p = 0.008; dyspnea, SMD = −0.63, p = 0.007; QOL, SMD = 1.66, p = 0.007), and IMT conducted >3 times per week (inspiratory muscle strength, SMD = 1.06, p < 0.00001; dyspnea, SMD = −0.54, p < 0.00001; QOL, SMD = 0.48, p = 0.0009) had greater effects. This meta-analysis provides clinicians with evidence supporting the recommendation that COPD patients engage in IMT at

Accumulating evidence underscores exercise as a straightforward and cost-effective lifestyle intervention capable of mitigating the risk and slowing the emergence and progression of Alzheimer’s disease (AD). However, the intricate cellular and molecular mechanisms mediating these exercise-induced benefits in AD remain elusive. The present study delved into the impact of treadmill exercise on memory retrieval performance, hippocampal synaptic plasticity, synaptic morphology, and the expression and activity of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptors (AMPARs) in 6-month-old APP/PS1 mice. APP/PS1 mice (4-month-old males) were randomly assigned to either a treadmill exercise group or a sedentary group, with C57BL/6J mice (4-month-old males) as the control group (both exercise and sedentary). The exercise regimen spanned 8 weeks. Our findings revealed that 8-week treadmill exercise reversed memory retrieval impairment in step-down fear conditioning in 6-month-old APP/PS1 mice. Additionally, treadmill exercise enhanced basic synaptic strength, short-term potentiation (STP), and long-term potentiation (LTP) of the hippocampus in these mice. Moreover, treadmill exercise correlated with an augmentation in synapse numbers, refinement of synaptic structures, and heightened expression and activity of AMPARs. Our findings suggest that treadmill exercise improves behavioral performance and facilitates synaptic transmission by increasing structural synaptic plasticity and the activity of AMPARs in the hippocampus of 6-month-old APP/PS1 mice, which is involved in pre- and postsynaptic processes.

BackgroundA growing body of studies have examined the effect of exercise in people with multiple sclerosis (MS), while findings of available studies were conflicting. This meta-analysis aimed to explore the effects of exercise on balance, walking ability, walking endurance, fatigue, and quality of life in people with MS.MethodsWe searched PubMed, Web of Science, Scopus, and Cochrane databases, through March 1, 2024. Inclusion criteria were: (1) RCTs; (2) included an intervention and control group; (3) had people with MS as study subjects; (4) had balance, walking ability, walking endurance, fatigue, or quality of life as the outcome measures. Exclusion criteria were: (1) non-English publications; (2) animal model publications; (3) review articles; and (4) conference articles. A meta-analysis was conducted to calculate weighted mean difference (WMD) and 95% confidence interval (CI). Cochrane risk assessment tool and Physiotherapy Evidence Database (PEDro) scale were used to evaluate the methodological quality of the included studies.ResultsForty studies with a total of 56 exercise groups (n = 1,300) and 40 control groups (n = 827) were eligible for meta-analysis. Exercise significantly improved BBS (WMD, 3.77; 95% CI, 3.01 to 4.53, P < 0.00001), TUG (WMD, −1.33; 95% CI, −1.57 to −1.08, P < 0.00001), MSWS-12 (WMD, −2.57; 95% CI, −3.99 to −1.15, P = 0.0004), 6MWT (WMD, 25.56; 95% CI, 16.34 to 34.79, P < 0.00001), fatigue (WMD, −4.34; 95% CI, −5.83 to −2.84, P < 0.00001), and MSQOL-54 in people with MS (WMD, 11.80; 95% CI, 5.70 to 17.90, P = 0.0002) in people with MS. Subgroup analyses showed that aerobic exercise, resistance exercise, and multicomponent training were all effective in improving fatigue in people with MS, with resistance exercise being the most effective intervention type. In addition, a younger age was associated with a larger improvement in fatigue. Furthermore, aerobic exercise and multicomponent training were all effective in improving quality of life in people with MS, with aerobic exercise being the most effective intervention type.ConclusionExercise had beneficial effects in improving balance, walking ability, walking endurance, fatigue, and quality of life in people with MS. Resistance exercise and aerobic exercise are the most effective interventions for improving fatigue and quality of life in people with MS, respectively. The effect of exercise on improving fatigue was associated with the age of the participants, with the younger age of the participants, the greater the improvement in fatigue.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=371056, identifier: CRD42022371056.

IntroductionAn increasing number of studies have investigated the effect of exercise on flow-mediated dilation (FMD) in people with type 2 diabetes mellitus (T2DM), while the findings were controversial. The primary aim of this systematic review and meta-analysis was to investigate the effect of exercise on FMD in T2DM patients, and the secondary aim was to investigate the optimal type, frequency, session duration, and weekly time of exercise for T2DM patients.MethodsSearches were conducted in PubMed, Cochrane Library, Scopus, Web of Science, Embase and EBSCO databases. The Cochrane risk of bias tool (RoB2) in randomized trial and Physiotherapy Evidence Database (PEDro) scale were used to assess the methodological quality of the included studies.ResultsFrom the 3636 search records initially retrieved, 13 studies met the inclusion criteria. Our meta-analysis revealed that exercise had a significant effect on improving FMD in T2DM patients [WMD, 2.18 (95% CI, 1.78-2.58), p < 0.00001, I2 = 38%], with high-intensity interval training (HIIT) being the most effective intervention type [HIIT, 2.62 (1.42-3.82); p < 0.0001; aerobic exercise, 2.20 (1.29-3.11), p < 0.00001; resistance exercise, 1.91 (0.01-3.82), p = 0.05; multicomponent training, 1.49 (0.15-2.83), p = 0.03]. In addition, a higher frequency [> 3 times, 3.06 (1.94-4.19), p < 0.00001; ≤ 3 times, 2.02 (1.59-2.45), p < 0.00001], a shorter session duration [< 60 min, 3.39 (2.07-4.71), p < 0.00001; ≥ 60 min, 1.86 (1.32-2.40), p < 0.00001], and a shorter weekly time [≤ 180 min, 2.40 (1.63-3.17), p < 0.00001; > 180 min, 2.11 (0.82-3.40), p = 0.001] were associated with larger improvements in FMD.ConclusionThis meta-analysis provides clinicians with evidence to recommended that T2DM patients participate in exercise, especially HIIT, more than 3 times per week for less than 60 min, with a target of 180 min per week being reached by increasing the frequency of exercise.Systematic review registrationhttps://www.crd.york.ac.uk/prospero, identifier CRD42023466575.

Summary: Mutations of TRAPPC12 are associated with progressive childhood encephalopathy including abnormal white matter. However, the underlying pathogenesis is still unclear. Here, we found that Trappc12 deficiency in CG4 and oligodendrocyte progenitor cells (OPCs) affects their differentiation and maturation. In addition, TRAPPC12 interacts with Mea6/cTAGE5, and Mea6/cTAGE5 ablation in OPCs affects their proliferation and differentiation, leading to marked hypomyelination, compromised synaptic functionality, and aberrant behaviors in mice. We reveal that TRAPPC12 is associated with COPII components at ER exit site, and Mea6/cTAGE5 cKO disrupts the trafficking pathway by affecting the distribution and/or expression of TRAPPC12, SEC13, SEC31A, and SAR1. Moreover, we observed marked disturbances in the secretion of pleiotrophin (PTN) in Mea6-deficient OPCs. Notably, exogenous PTN supplementation ameliorated the differentiation deficits of these OPCs. Collectively, our findings indicate that the association between TRAPPC12 and MEA6 is important for cargo trafficking and white matter development.

The primary objective of this study was to assess the influence of exercise interventions on cancer-related fatigue (CRF), specifically in breast cancer patients, with the ultimate goal of establishing an optimal exercise prescription for breast cancer patients. A comprehensive search was undertaken across multiple databases, including Embase, PubMed, Cochrane Library, Web of Science, and Scopus, covering data published up to 1 September 2023. A meta-analysis was conducted to calculate the standardized mean difference (SMD) along with its corresponding 95% confidence interval (CI), thereby quantifying the effectiveness of exercise in alleviating CRF in the breast cancer patient population. Twenty-six studies met the inclusion criteria. Aerobic exercise (SMD, −0.17, p = 0.02), resistance exercise (SMD, −0.37, p = 0.0009), and combined exercise (SMD, −0.53, p < 0.0001) significantly improved CRF in breast cancer patients. In addition, exercise intervention conducted ≥3 times per week (SMD, −0.47, p = 0.0001) for >60 min per session (SMD, −0.63, p < 0.0001) and ≥180 min per week (SMD, −0.79, p < 0.0001) had greater effects on improving CRF in breast cancer patients, especially middle-aged patients (SMD, −0.42, p < 0.0001). Exercise is an effective approach to improving CRF in breast cancer patients. When devising an exercise program, the primary consideration should be the incorporation of combined exercise as the principal intervention. This entails ensuring that participants engage in the program at least three times weekly, with each session lasting for more than 60 min. The ultimate aim is to achieve a total weekly exercise duration of 180 min by progressively increasing the frequency of exercise sessions.

Summary: The purpose of the present study was to examine the effects of 6 weeks of 40-, 60-, or 80-cm drop jump (DJ) training on lower limb explosive and change of direction (CoD) performance in collegiate Sanda athletes. Repeated-measure ANOVA revealed that there was a significant group × time interaction for standing long jump test (p = 0.006), counter movement jump test (p = 0.026), Illinois agility test (p = 0.003), square test (p = 0.018), Nebraska test (p = 0.027), t test (p = 0.032), and hexagon test (p = 0.012) due to the best performance observed at post-test compared with pre-test for DJ60 (effect size = 0.89–2.89), and the improvement was higher than that of the other groups. These findings suggest that 6 weeks of DJ training could improve the lower limb explosive and CoD performance in collegiate Sanda athletes and that 60 cm may be the optimal drop height.

Abstract Previous studies have shown that aerobic exercise is an effective way to improve symptoms of Parkinson’s disease (PD). The aim of this study [PROSPERO CRD42022340730] was to explore the effects of aerobic exercises on balance, gait, motor function, and quality of life in PD patients. Searches were performed in PubMed, Web of Science, and EBSCO electronic databases. The Cochrane risk assessment tool was used to evaluate the methodological quality of the included literature. From 1287 search records initially identified, 20 studies were considered eligible for systematic review and meta-analysis. There was a significant effect of aerobic exercise on improving timed up and go test [standardized mean difference (SMD), −0.41 (95% CI, −0.61 to −0.22), p

Background: There is no clear agreement regarding the ideal rest interval and training intensity to optimize post-activation performance enhancement (PAPE) after barbell squat (BS). Therefore, the aim of this study was to investigate the effects of rest interval and training intensity on jumping performance due to PAPE.Methods: Searches were performed in PubMed, Web of Science, and EBSCO databases. We included studies that satisfied the following criteria: (1) eligible studies should be randomized controlled trials; (2) eligible studies should investigate the acute effect of barbell squat-induced PAPE on jump performance; (3) eligible studies should use countermovement jump, squat jump, or vertical jump as the outcome measure.Results: From 2518 search records initially identified, 19 studies were eligible for meta-analysis. Our meta-analysis results showed that BS had no significant effect on improving jumping performance due to PAPE (Cohen’s d = 0.09, p = 0.08). Subgroup analysis showed that rest interval between 0–1 min was detrimental to jumping performance (Cohen’s d = −0.33, p < 0.01), while rest intervals between 4–7 min (Cohen’s d = 0.31, p < 0.01) and 8-9 min (Cohen’s d = 0.26, p = 0.02) provided favorable jumping performance outcomes. In addition, low-intensity and moderate-intensity BS had no significant effect on jump performance, while high-intensity BS showed results consistent with rest interval.Conclusion: Our study indicated that both low-intensity and moderate-intensity BS failed to induce PAPE, and it is recommended that future studies use high-intensity BS to induce PAPE. A rest interval of 4–9 min had a beneficial impact on jump height, and an interval range of 4–7 min seems to be the best rest interval between conditioning activity and jumping performance.

This study aimed to determine whether drop jump height will affect the post-activation performance enhancement (PAPE) effect at room temperature (RT) and low temperature (LT) conditions. Twelve male strength-trained males participated in this study. Prior to warm-up, subjects underwent a 30 min period of environmental adaptation. Different warm-up protocols were used at different ambient temperatures to help subjects achieve a level of muscle activity and body temperature similar to their daily training. After the pre-test, each subject participated in six experimental sessions at either RT or LT conditions, respectively, which were separated by at least 72 h and conducted at the same time of day to control for circadian influences on metabolism. After the conditioning activities, vertical jump (VJ) performance was re-tested at 4 min, 8 min, and 12 min of passive recovery to assess transient potentiation effects. Under RT conditions, 60 cm and 90 cm drop jumps could induce PAPE, with the PAPE effect being most significant at 4 min (p < 0.01) and 8 min (p < 0.01), respectively, while a 30 cm drop jump could not induce PAPE. Under LT conditions, 30 cm and 90 cm drop jumps could not induce PAPE, and VJ performance gradually declined over time (p < 0.01). However, although a 60 cm drop jump could not induce PAPE, VJ performance was not affected by LT at 8 min and declined at 12 min (p < 0.05). This study demonstrated that 60 cm and 90 cm drop jumps can be used to induce PAPE at RT conditions. LT can impair PAPE induction, while a 60 cm drop jump can be utilized for warm-up at LT conditions to counteract the effects of LT on athletic performance.

Background: Current research suggests that continuous aerobic exercise can be effective in improving vascular endothelial function, while the effect between different intensities and durations of exercise is unclear. The aim of this study was to explore the effect of different durations and intensities of aerobic exercise on vascular endothelial function in different populations.Methods: Searches were performed in PubMed, Web of Science, and EBSCO databases. We included studies that satisfied the following criteria: 1) randomized controlled trials (RCTs); 2) including both an intervention and control group; 3) using flow-mediated dilation (FMD) as the outcome measure; and 4) testing FMD on the brachial artery.Results: From 3,368 search records initially identified, 41 studies were eligible for meta-analysis. There was a significant effect of continuous aerobic exercise on improving flow-mediated dilation (FMD) [weighted mean difference (WMD), 2.55, (95% CI, 1.93–3.16), p < 0.001]. Specifically, moderate-intensity [2.92 (2.02–3.825), p < 0.001] and vigorous-intensity exercise [2.58 (1.64–3.53), p < 0.001] significantly increased FMD. In addition, a longer duration [

The study investigated the effects of listening to self-selected music during a warm-up on brain wave synchronization/desynchronization and Wingate test performance. Seventeen healthy young men were required to complete a 10 min warm-up session with or without music intervention, followed by an electroencephalogram (EEG) or Wingate test, respectively. The ratings of perceived exertion (RPE) and heart rate (HR) were recorded immediately after the Wingate test. Compared with no music intervention, listening to self-selected music during a warm-up significantly increased peak power and mean power in the Wingate test (p < 0.05), upregulated the α energy percentage in the F3, C3, P3, O1, T3, F4, and Fp2 regions (p < 0.05) and β energy percentage in the F3, O1, and T5 regions (p < 0.05), while it downregulated the δ energy percentage in the F3, P3, O1, F4, and F8 regions (p < 0.05), θ/β in the F3 and O1 regions (p < 0.05), and (θ+α)/(α+β) in the F3 region (p < 0.05). However, there were no significant differences in the minimum power and fatigue index in the Wingate test between the music intervention and no music intervention, or in RPE and HR after the Wingate test (p > 0.05). This study demonstrated that listening to self-selected music during a warm-up enhances cortical excitability by upregulating the α and β energy percentages and downregulating the δ energy percentage, which may represent a potential mechanism by which listening to self-selected music during a warm-up improves anaerobic performance in healthy young men.

A growing body of research examines the effect of aerobic exercise on pulse wave velocity (PWV) in middle-aged and elderly people, while findings of available studies were conflicting. The aim of this study was to explore the effect of aerobic exercise on PWV in middle-aged and elderly people. Searches were performed in PubMed, Web of Science, and EBSCO databases. Cochrane risk assessment tool was used to evaluate the methodological quality of the included literature. We included studies that satisfied the following criteria: (1) eligible studies should be randomized controlled trials (RCTs); (2) eligible studies should include both an intervention and a control group; (3) eligible studies should use the middle-aged or elderly people as subjects; and (4) eligible studies should use PWV as the outcome measure. From 972 search records initially identified, 11 studies with a total of 12 exercise groups (n = 245) and 11 control groups (n = 239) were eligible for meta-analysis. There was a significant effect of aerobic exercise on reducing PWV in middle-aged and elderly people [weighted mean difference (WMD), –0.75 (95% CI, –1.21 to –0.28), p = 0.002]. Specifically, a higher intensity [vigorous-intensity, –0.74 (–1.34 to –0.14), p = 0.02; moderate-intensity, –0.68 (–1.49 to 0.12), p = 0.10], a younger age [45 years ≤ age < 60 years, –0.57 (–0.78 to –0.37), p < 0.00001; age ≥ 60 years, –0.91 (–2.10 to 0.27), p = 0.13], a better health status [healthy, –1.19 (–2.06 to –0.31), p = 0.008; diseased, –0.32 (–0.64 to –0.01), p = 0.04], and a lower basal body mass index (BMI) [BMI < 25, –1.19 (–2.06 to –0.31), p = 0.008; 25 ≤ BMI < 30, –0.52 (–0.92 to –0.12), p = 0.01; BMI ≥ 30, –0.09 (–0.93 to 0.76), p = 0.84] were associatedwith larger reductions in PWV. Aerobic exercise, especially vigorous-intensity aerobic exercise, contributed to reducing PWV in middle-aged and elderly people. The effect of aerobic exercise on improving PWV was associated with characteristics of the participants. Specifically, a younger age, a better health status, and a lower basal BMI contributed to more significant reductions in PWV.Systematic review registration[https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022337103], identifier [CRD42022337103].

BackgroundPrevious studies have found that aerobic exercise was more effective in improving vascular endothelial function than resistance training, high-intensity interval training (HIIT), and other types of exercise, while the effects between different intensities and durations of aerobic exercise were unclear. Therefore, we performed this meta-analysis to investigate the effects of different intensities and durations of aerobic exercise on the vascular endothelial function of middle-aged and elderly people.Methods:Databases were searched up to April 2021 for studies evaluating the influences of different intensities and durations of aerobic exercise on endothelial function assessed by flow-mediated dilation (FMD) among healthy middle-aged and elderly people. Data were pooled using random-effects models to obtain the weighted mean difference (WMD) and 95% confidence intervals (CIs).ResultsA total of 9 studies involving 221 participants fulfilled the inclusion criteria. Aerobic exercise improved the overall FMD of healthy middle-aged and elderly people [WMD, 1.33 (95% CI, 0.37–2.28), P < 0.05]. Specifically, vigorous-intensity exercise increased FMD significantly in healthy middle-aged and elderly people [WMD, 1.10 (95% CI, 0.27–1.93), P < 0.05], while moderate-intensity exercise had no significant association with FMD [WMD, 1.49 (95% CI, −0.62 to 3.60), P = 0.17]. In addition, long-term (8 weeks or above) aerobic exercise increased the FMD in healthy middle-aged and elderly people [WMD, 1.63 (95% CI, 0.61–2.66), P < 0.05], while one-time acute aerobic exercise had no significant association with FMD of healthy middle-aged and elderly people [WMD, 0.89 (95% CI, −1.47 to 3.24), P = 0.46]. Specifically, 8 weeks or above of vigorous-intensity exercise increased FMD significantly in healthy middle-aged and elderly people [WMD, 1.48 (95% CI, 1.06–1.90), P < 0.01], while 8 weeks or above of moderate aerobic exercise had no significant association with FMD [WMD, 1.49 (95% CI, −0.62 to 3.60), P = 0.17].ConclusionAerobic exercise, especially 8 weeks or above of vigorous-intensity aerobic exercise, improved the endothelial function in healthy middle-aged and elderly people.

Many studies have investigated the relationship between angiotensin-converting enzyme (ACE) D/I polymorphism and cardiovascular disease or endothelial dysfunction; however, hardly any of these studies has taken aging or menopause into consideration. Furthermore, despite that many studies have examined the regulatory effects of endothelial-released factors (ERFs) on endothelial function, no study has evaluated the relationship between ERFs and endothelial function with respect to ACE D/I polymorphism and menopause status. To answer these questions, 391 healthy Chinese women over a wide range of ages (22–75 years) were enrolled and divided into pre-menopause group and post-menopause group. After ACE D/I genotype being identified, the women were then classified into either DI/II or DD genotype. Flow-mediated dilatation (FMD) of brachial endothelium and plasma levels of ERFs: nitric oxide (NO), endothelin-1 (ET-1), and angiotensin II (Ang II) were measured. The results showed that frequencies of ACE D/I genotypes were in accordance with the Hardy-Weinberg equilibrium, and the frequency of I allele was higher than D allele. In pre-menopause group, FMD was significantly higher in women of DI/II than DD (P = 0.032), and age-dependent in both genotypes (DD, P = 0.0472; DI/II, P < 0.0001). In post-menopause group, FMD was similar between women of DI/II and DD, and age-dependent only in women of DI/II (P < 0.0001). In pre-menopause group, Ang II level was significantly higher in women of DD than DI/II (P = 0.029), and FMD was significantly correlated with all ERFs in women of DD (NO, P = 0.032; ET-1, P = 0.017; Ang II, P = 0.002), but only with Ang II in women of DI/II (P = 0.026). In post-menopause group, no significant difference was observed in any ERF between women of DI/II and DD, and FMD was only significantly correlated with ET-1 in women of DD (P = 0.010). In summary, FMD in women of DI/II was superior to DD in pre-menopause and more age-dependent than DD in post-menopause, and FMD was closely associated with ERFs. In conclusion, Chinese women of DI/II seem to have lower risk than DD in pre-menopause, but similar risk as DD in post-menopause in developing cardiovascular disease.

Alzheimer’s disease (AD) is characterized by deficits in learning and memory. A pathological feature of AD is the alterations in the number and size of synapses, axon length, dendritic complexity, and dendritic spine numbers in the hippocampus and prefrontal cortex. Treadmill exercise can enhance synaptic plasticity in mouse or rat models of stroke, ischemia, and dementia. The aim of this study was to examine the effects of treadmill exercise on learning and memory, and structural synaptic plasticity in 3×Tg-AD mice, a mouse model of AD. Here, we show that 12 weeks treadmill exercise beginning in three-month-old mice improves spatial working memory in six-month-old 3×Tg-AD mice, while non-exercise six-month-old 3×Tg-AD mice exhibited impaired spatial working memory. To investigate potential mechanisms for the treadmill exercise-induced improvement of spatial learning and memory, we examined structural synaptic plasticity in the hippocampus and prefrontal cortex of six-month-old 3×Tg-AD mice that had undergone 12 weeks of treadmill exercise. We found that treadmill exercise led to increases in synapse numbers, synaptic structural parameters, the expression of synaptophysin (Syn, a presynaptic marker), the axon length, dendritic complexity, and the number of dendritic spines in 3×Tg-AD mice and restored these parameters to similar levels of non-Tg control mice without treadmill exercise. In addition, treadmill exercise also improved these parameters in non-Tg control mice. Strengthening structural synaptic plasticity may represent a potential mechanism by which treadmill exercise prevents decline in spatial learning and memory and synapse loss in 3×Tg-AD mice.

Dopamine neurons in the ventral tegmental area (VTA) are powerful regulators of depression-related behavior. Dopamine neuron activity is altered in chronic stress-based models of depression, but the underlying mechanisms remain incompletely understood. Here, we show that mice subject to chronic mild unpredictable stress (CMS) exhibit anxiety- and depressive-like behavior, which was associated with decreased VTA dopamine neuron firing in vivo and ex vivo. Dopamine neuron firing is governed by voltage-gated ion channels, in particular hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Following CMS, HCN-mediated currents were decreased in nucleus accumbens-projecting VTA dopamine neurons. Furthermore, shRNA-mediated HCN2 knockdown in the VTA was sufficient to recapitulate CMS-induced depressive- and anxiety-like behavior in stress-naïve mice, whereas VTA HCN2 overexpression largely prevented CMS-induced behavioral deficits. Together, these results reveal a critical role for HCN2 in regulating VTA dopamine neuronal activity and depressive-related behaviors.

PURPOSE:The role of exercise to prevent or reverse aging-induced cognitive decline has been widely reported. This neuroprotection is associated with changes in the synaptic structure plasticity. However, the mechanisms of exercise-induced synaptic plasticity in the aging brain are still unclear. Thus, the aim of the present study is to investigate the aging-related alterations of Rho-GTPase and the modulatory influences of exercise training. METHODS:Young and old rats were used in this study. Old rats were subjected to different schedules of aerobic exercise (12 m/min, 60 min/d, 3d/w or 5d/w) or kept sedentary for 12 w. After 12 w of aerobic exercise, the synapse density in the cortex and hippocampus was detected with immunofluorescent staining using synaptophysin as a marker. The total protein levels of RhoA, Rac1, Cdc42 and cofilin in the cortex and hippocampus were detected with Western Blot. The activities of RhoA, Rac1 and Cdc42 were determined using a pull down assay. RESULTS:We found that synapse loss occurred in aging rats. However, the change of expression and activity of RhoA, Rac1 and Cdc42 was different in the cortex and hippocampus. In the cortex, the expression and activity of Rac1 and Cdc42 was greatly increased with aging, whereas there were no changes in the expression and activity of RhoA. In the hippocampus, the expression and activity of Rac1 and Cdc42 was greatly decreased and there were no changes in the expression and activity of RhoA. As a major downstream substrate of the Rho GTPase family, the increased expression of cofilin was only observed in the cortex. High frequency exercise ameliorated all aging-related changes in the cortex and hippocampus. CONCLUSIONS:These data suggest that aerobic exercise reverses synapse loss in the cortex and hippocampus in aging rats, which might be related to the regulation of Rho GTPases.

Diacylglycerol lipase-α (DAGL-α), the principal biosynthetic enzyme of the endogenous cannabinoid 2-arachidonylglycerol (2-AG) on neurons, plays a key role in CB1 receptor-mediated synaptic plasticity and hippocampal neurogenesis, but its contribution to global hippocampal-mediated processes remains unknown. Thus, the present study examines the role that DAGL-α plays on LTP in hippocampus, as well as in hippocampal-dependent spatial learning and memory tasks, and on the production of endocannabinoid and related lipids through the use of complementary pharmacologic and genetic approaches to disrupt this enzyme in male mice. Here we show that DAGL-α gene deletion or pharmacological inhibition disrupts LTP in CA1 of the hippocampus but elicits varying magnitudes of behavioral learning and memory deficits in mice. In particular, DAGL-α-/- mice display profound impairments in the Object Location assay and Morris Water Maze (MWM) acquisition engaging in nonspatial search strategies. In contrast, WT mice administered the DAGL-α inhibitor D034 show delays in MWM acquisition and reversal learning, but no deficits in expression, extinction, forgetting, or perseveration processes in this task, as well as no impairment in Object Location. The deficits in synaptic plasticity and MWM performance occur in concert with decreased 2-AG and its major lipid metabolite (arachidonic acid), but increases of a 2-AG diacylglycerol precursor in hippocampus, PFC, striatum, and cerebellum. These novel behavioral and electrophysiological results implicate a direct and perhaps selective role of DAGL-α in the integration of new spatial information. [ABSTRACT FROM AUTHOR]

Exchange protein directly activated by cAMP (Epac) is a direct effector for the ubiquitous second messenger cAMP. Epac activates the phospholipase Cε (PLCε) pathway. PLCβ has been linked to the synthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). Here, we report that Epac facilitates endocannabinoid-mediated retrograde synaptic depression through activation of PLCε. Intracellular loading of a selective Epac agonist 8-CPT-2Me-cAMP into ventral tegmental area (VTA) dopamine neurons enabled previously ineffective stimuli to induce depolarization-induced suppression of inhibition (DSI) and long-term depression of IPSCs (I-LTD) in the VTA. DSI and I-LTD are mediated by 2-AG since they were blocked by a diacylglycerol lipase inhibitor. The effects of 8-CPT-2Me-cAMP on DSI and I-LTD were absent in Epac2 and PLCε knock-out mice, but remained intact in Epac1 knock-out mice. These results identify a novel mechanism for on-demand synthesis of retrograde signaling 2-AG by the Epac2-PLCε pathway. We investigated the functional significance of Epac2-PLCε-2-AG signaling in regulating inhibitory synaptic plasticity in VTA dopamine neurons induced by in vivo cocaine exposure. We showed that cocaine place conditioning led to a decrease in the frequency and amplitude of spontaneous IPSCs and an increase in action potential firing in wild-type mice, but not in Epac2 or PLCε knock-out mice. Together, these results indicate that the Epac2-PLCε-2-AG signaling cascade contributes to cocaine-induced disinhibition of VTA dopamine neurons. [ABSTRACT FROM AUTHOR]