Influence of Sex and Sedentary Conditions on Sympathetic Burst Characteristics in Prepubertal, Post-Pubertal and Young Adult Rats.

Recent evidence indicates that sex-based differences in cardiovascular disease (CVD) begin early in life, particularly when associated with risks factors such as a sedentary lifestyle. CVD is associated with elevated sympathetic nerve activity (SNA), quantified as increased SNA bursting activity in humans. Whether burst characteristics are influenced by sex- and (in)activity at younger ages is unknown. The purpose of our study is to compare SNA bursts in active and sedentary female and male rats at ages including pre-puberty into young adulthood. We hypothesized that burst characteristics and blood pressure are higher under sedentary conditions and lower in female rats compared to males. We analyzed splanchnic SNA recordings from Inactin-anesthetized male and female rats at 4-, 8-, and 16-weeks of age. Physically active and sedentary rats were each housed in separate, environmentally-controlled chambers where physically active rats had free access to an in-cage running wheel. Sympathetic bursts were obtained by rectifying and integrating the raw SSNA signal. Burst frequency, burst height, and burst width were calculated using the Peak Parameters extension in LabChart. Our results showed that sedentary conditions produced a greater burst width in 8-and 16-week-old rats compared to 4-week-old rats in both males and female (p<0.001 for both). Burst frequency and incidence were both higher in 16-week-old males compared to 16-week-old females (p<0.001 for both). Our results suggest that there are (in)activity- and sex-related mechanisms, which impact sympathetic regulation of blood pressure at ages that include pre-puberty into young adulthood.

Controlled Formation of Protonated and Radical Cation Precursor Ions by Atmospheric Pressure Photoionization with µLC-MS Enables Electron Ionization and MS/MS Library Search.

Atmospheric pressure photoionization (APPI) was developed as an alternative to electrospray ionization (ESI) for the generation of protonated molecules using liquid chromatography and optimized using dopants such as toluene, which predominantly forms protonated molecules, and chlorobenzene, which favors the formation of radical cations, although the latter has not been fully exploited. Based on 40 diverse low-molecular-weight compounds and micro liquid chromatography (µLC) coupled with APPI tandem mass spectrometry (APPI-MS/MS), the potential of radical cations was investigated. Chromatographic and ionization conditions were decoupled by post-column addition of methanol, allowing separate study and optimization. Due to the mass flow sensitive behavior of APPI, sensitivity is not affected by post-column dilution, and for 8 of 35 analytes, the radical cation response with µLC-APPI is better than for protonated molecules using µLC-ESI. Collision-induced fragmentation (CID) of radical cations produced within a collision energy range from 10-115 eV have, in the median, 65% of the fragments found in electron ionization (EI) spectra. This similarity allowed identification of 86% of the analytes using data-dependent acquisition (DDA) of radical cations and NIST EI library searches. We propose a workflow that uses multimodal DDA of protonated precursor molecules using ESI or APPI with toluene as a dopant, and radical cations produced by chlorobenzene-assisted µLC-APPI with post-column addition of methanol. This increases the confidence of molecular identification by allowing orthogonal library searches using MS/MS libraries for protonated precursor CID spectra and EI libraries for radical cation CID spectra.

Age-related cognitive effects of the COVID-19 pandemic restrictions and associated mental health changes in Germans.

Restrictive means to reduce the spread of the COVID-19 pandemic have not only imposed broad challenges on mental health but might also affect cognitive health. Here we asked how restriction-related changes influence cognitive performance and how age, perceived loneliness, depressiveness and affectedness by restrictions contribute to these effects. 51 Germans completed three assessments of an online based study during the first lockdown in Germany (April 2020), a month later, and during the beginning of the second lockdown (November 2020). Participants completed nine online cognitive tasks of the MyBrainTraining and online questionnaires about their perceived strain and impact on lifestyle factors by the situation (affectedness), perceived loneliness, depressiveness as well as subjective cognitive performance. The results suggested a possible negative impact of depressiveness and affectedness on objective cognitive performance within the course of the lockdown. The younger the participants, the more pronounced these effects were. Loneliness and depressiveness moreover contributed to a worse evaluation of subjective cognition. In addition, especially younger individuals reported increased distress. As important educational and social input has partly been scarce during this pandemic and mental health problems have increased, future research should also assess cognitive long-term consequences.

Revisiting differential control of sympathetic outflow by the rostral ventrolateral medulla.

The rostral ventrolateral medulla (RVLM) is an important brain region involved in both resting and reflex regulation of the sympathetic nervous system. Anatomical evidence suggests that as a bilateral structure, each RVLM innervates sympathetic preganglionic neurons on both sides of the spinal cord. However, the functional importance of ipsilateral versus contralateral projections from the RVLM is lacking. Similarly, during hypotension, the RVLM is believed to rely primarily on withdrawal of tonic gamma aminobutyric acid (GABA) inhibition to increase sympathetic outflow but whether GABA withdrawal mediates increased activity of functionally different sympathetic nerves is unknown. We sought to test the hypothesis that activation of the ipsilateral versus contralateral RVLM produces differential increases in splanchnic versus adrenal sympathetic nerve activities, as representative examples of functionally different sympathetic nerves. We also tested whether GABA withdrawal is responsible for hypotension-induced increases in splanchnic and adrenal sympathetic nerve activity. To test our hypothesis, we measured splanchnic and adrenal sympathetic nerve activity simultaneously in Inactin-anesthetized, male Sprague-Dawley rats during ipsilateral or contralateral glutamatergic activation of the RVLM. We also produced hypotension (sodium nitroprusside, i.v.) before and after bilateral blockade of GABAA receptors in the RVLM (bicuculline, 5 mM 90 nL). Glutamate (100 mM, 30 nL) injected into the ipsilateral or contralateral RVLM produced equivalent increases in splanchnic sympathetic nerve activity, but increased adrenal sympathetic nerve activity by more than double with ipsilateral injections versus contralateral injections (p < 0.05; n = 6). In response to hypotension, increases in adrenal sympathetic nerve activity were similar after bicuculline (p > 0.05), but splanchnic sympathetic nerve activity responses were eliminated (p < 0.05; n = 5). These results provide the first functional evidence that the RVLM has predominantly ipsilateral innervation of adrenal nerves. In addition, baroreflex-mediated increases in splanchnic but not adrenal sympathetic nerve activity are mediated by GABAA receptors in the RVLM. Our studies provide a deeper understanding of neural control of sympathetic regulation and insight towards novel treatments for cardiovascular disease involving sympathetic nervous system dysregulation.

Globally altered sleep patterns and physical activity levels by confinement in 5056 individuals: ECLB COVID-19 international online survey.

Symptoms of psychological distress and disorder have been widely reported in people under quarantine during the COVID-19 pandemic; in addition to severe disruption of peoples' daily activity and sleep patterns. This study investigates the association between physical-activity levels and sleep patterns in quarantined individuals. An international Google online survey was launched in April 6th, 2020 for 12-weeks. Forty-one research organizations from Europe, North-Africa, Western-Asia, and the Americas promoted the survey through their networks to the general society, which was made available in 14 languages. The survey was presented in a differential format with questions related to responses "before" and "during" the confinement period. Participants responded to the Pittsburgh Sleep Quality Index (PSQI) questionnaire and the short form of the International Physical Activity Questionnaire. 5056 replies (59.4% female), from Europe (46.4%), Western-Asia (25.4%), America (14.8%) and North-Africa (13.3%) were analysed. The COVID-19 home confinement led to impaired sleep quality, as evidenced by the increase in the global PSQI score (4.37 ± 2.71 before home confinement vs. 5.32 ± 3.23 during home confinement) (p < 0.001). The frequency of individuals experiencing a good sleep decreased from 61% (n = 3063) before home confinement to 48% (n = 2405) during home confinement with highly active individuals experienced better sleep quality (p < 0.001) in both conditions. Time spent engaged in all physical-activity and the metabolic equivalent of task in each physical-activity category (i.e., vigorous, moderate, walking) decreased significantly during COVID-19 home confinement (p < 0.001). The number of hours of daily-sitting increased by ~2 hours/days during home confinement (p < 0.001). COVID-19 home confinement resulted in significantly negative alterations in sleep patterns and physical-activity levels. To maintain health during home confinement, physical-activity promotion and sleep hygiene education and support are strongly warranted.

Sedentary Conditions Promote Subregionally Specific Changes in Brain-Derived Neurotrophic Factor in the Rostral Ventrolateral Medulla.

A sedentary lifestyle is the top preventable cause of death and accounts for substantial socioeconomic costs to society. The rostral ventrolateral medulla regulates blood pressure under normal and pathophysiological states, and demonstrates inactivity-related structural and functional neuroplasticity, which is subregionally specific. The purpose of this study was to examine pro- and mature forms of brain-derived neurotrophic factor (BDNF) and their respective receptors in the male rat rostral ventrolateral medulla (RVLM) and its rostral extension following sedentary vs. active (running wheels) conditions (10-12weeks). We used subregionally specific Western blotting to determine that the mature form of BDNF and its ratio to its pro-form were lower in more caudal subregions of the rostral ventrolateral medulla of sedentary rats but higher in the rostral extension when both were compared to active rats. The full-length form of the tropomyosin receptor kinase B receptor and the non-glycosylated form of the 75 kilodalton neurotrophin receptor were lower in sedentary compared to active rats. The rostrocaudal patterns of expression of the mature form of BDNF and the full-length form of the tropomyosin receptor kinase B receptor were remarkably similar to the subregionally specific patterns of enhanced dendritic branching, neuronal activity, and glutamate-mediated increases in sympathetic nerve activity observed in previous studies performed in sedentary rats. Our studies suggest signaling pathways related to BDNF within subregions of both the rostral ventrolateral medulla and its rostral extension contribute to cardiovascular disease and premature death related to a sedentary lifestyle.

Sex-dependent development of enhanced sympathoexcitation in sedentary versus physically active rats.

KEY POINTS: The rostral ventrolateral medulla (RVLM) may contribute to sex-based differences in cardiovascular disease (CVD) based on overactivation of the sympathetic nervous system observed in sedentary male rats; however, the added influence of the reproductive cycle in females is currently unknown. To our knowledge this is the first study to demonstrate greater increases in sympathetic nerve activity in response to direct activation of the RVLM in female versus male rats prior to the onset of the reproductive cycle, which persisted after the onset of the reproductive cycle. Lower resting blood pressures in females also suggest peripheral adaptations contribute to sex-based differences in CVD. Sedentary versus physically active conditions appear to promote higher resting sympathetic outflow independent of age and sex. Our results demonstrate the importance of examining sedentary conditions in the context of sex differences and the reproductive cycle in contributing to sympathetic overactivity associated with cardiovascular disease. ABSTRACT: Female reproductive hormones are considered cardioprotective based on higher risks of cardiovascular disease (CVD) in post- versus pre-menopausal women. Similarly, based on epidemiological studies, a sedentary lifestyle is also a major risk factor for CVD. The mechanisms by which sedentary conditions contribute to CVD, and their influences in the presence and absence of female reproductive hormones are unknown. We hypothesized that sexually immature male and female rats would have similar centrally mediated regulation of blood pressure, but upon sexual maturation, female rats would have lower resting blood pressure and centrally-mediated sympathoexcitation compared to age-matched males. We also predicted resting sympathetic activity would increase upon exposure to sedentary versus active conditions (voluntary wheel running) in males but not in females. We recorded splanchnic sympathetic nerve activity (SSNA) and blood pressure in 4-, 8- and 16-week-old male and female rats under Inactin anaesthesia before and during microinjections of glutamate (1-100 mM) into the rostral ventrolateral medulla (RVLM). Four-week-old female rats had lower resting blood pressure and greater sympathoexcitation following activation of the RVLM, as did 8- and 16-week-old female rats, independent of age or activity condition. Sedentary animals had higher baseline SSNA compared to active animals, independent of sex or age. Our results reveal a complex influence of the interactions between the female reproductive cycle and sedentary conditions. They also demonstrate the importance of examining sedentary conditions in the context of sex- and female reproductive cycle-dependent incidences of cardiovascular disease.

Effects of home confinement on mental health and lifestyle behaviours during the COVID-19 outbreak: insights from the ECLB-COVID19 multicentre study.

Although recognised as effective measures to curb the spread of the COVID-19 outbreak, social distancing and self-isolation have been suggested to generate a burden throughout the population. To provide scientific data to help identify risk factors for the psychosocial strain during the COVID-19 outbreak, an international cross-disciplinary online survey was circulated in April 2020. This report outlines the mental, emotional and behavioural consequences of COVID-19 home confinement. The ECLB-COVID19 electronic survey was designed by a steering group of multidisciplinary scientists, following a structured review of the literature. The survey was uploaded and shared on the Google online survey platform and was promoted by thirty-five research organizations from Europe, North Africa, Western Asia and the Americas. Questions were presented in a differential format with questions related to responses "before" and "during" the confinement period. 1047 replies (54% women) from Western Asia (36%), North Africa (40%), Europe (21%) and other continents (3%) were analysed. The COVID-19 home confinement evoked a negative effect on mental wellbeing and emotional status (P < 0.001; 0.43 ≤ d ≤ 0.65) with a greater proportion of individuals experiencing psychosocial and emotional disorders (+10% to +16.5%). These psychosocial tolls were associated with unhealthy lifestyle behaviours with a greater proportion of individuals experiencing (i) physical (+15.2%) and social (+71.2%) inactivity, (ii) poor sleep quality (+12.8%), (iii) unhealthy diet behaviours (+10%), and (iv) unemployment (6%). Conversely, participants demonstrated a greater use (+15%) of technology during the confinement period. These findings elucidate the risk of psychosocial strain during the COVID-19 home confinement period and provide a clear remit for the urgent implementation of technology-based intervention to foster an Active and Healthy Confinement Lifestyle AHCL).

Sleep Quality and Physical Activity as Predictors of Mental Wellbeing Variance in Older Adults during COVID-19 Lockdown: ECLB COVID-19 International Online Survey.

BACKGROUND: The COVID-19 lockdown could engender disruption to lifestyle behaviors, thus impairing mental wellbeing in the general population. This study investigated whether sociodemographic variables, changes in physical activity, and sleep quality from pre- to during lockdown were predictors of change in mental wellbeing in quarantined older adults. METHODS: A 12-week international online survey was launched in 14 languages on 6 April 2020. Forty-one research institutions from Europe, Western-Asia, North-Africa, and the Americas, promoted the survey. The survey was presented in a differential format with questions related to responses "pre" and "during" the lockdown period. Participants responded to the Short Warwick-Edinburgh Mental Wellbeing Scale, the Pittsburgh Sleep Quality Index (PSQI) questionnaire, and the short form of the International Physical Activity Questionnaire. RESULTS: Replies from older adults (aged >55 years, n = 517), mainly from Europe (50.1%), Western-Asia (6.8%), America (30%), and North-Africa (9.3%) were analyzed. The COVID-19 lockdown led to significantly decreased mental wellbeing, sleep quality, and total physical activity energy expenditure levels (all p < 0.001). Regression analysis showed that the change in total PSQI score and total physical activity energy expenditure (F(2, 514) = 66.41 p < 0.001) were significant predictors of the decrease in mental wellbeing from pre- to during lockdown (p < 0.001, R2: 0.20). CONCLUSION: COVID-19 lockdown deleteriously affected physical activity and sleep patterns. Furthermore, change in the total PSQI score and total physical activity energy expenditure were significant predictors for the decrease in mental wellbeing.

Association of adipocytokines serum levels with left atrial thrombus formation in atrial fibrillation patients on oral anticoagulation (Alert) - A cross-sectional study.

BACKGROUND AND AIMS: Oral anticoagulation is effective for stroke prevention in atrial fibrillation (AF). However, strokes may still occur in high-risk individuals. We conducted a prospective trial to assess the association between adipocytokine serum levels and surrogate parameters for thromboembolic events. METHODS AND RESULTS: In this cross-sectional multicenter trial, we enrolled 189 patients with AF who were on oral anticoagulation. The primary endpoint was defined as either the presence of spontaneous echo contrast (SEC), a left atrial appendage (LAA), or a left atrial (LA) thrombus on transesophageal echocardiography. We investigated the association of adipocytokine serum levels with the combined endpoint using logistic regression analysis. Forty-eight individuals (25%) were assigned to group 1 (G1) due to the occurrence of at least one of the components of the combined endpoint (41 [21.7%] SEC, 3 [1.6%] LA thrombus, 13 [6.9%] LAA thrombus), whereas the remaining patients formed group 2 (G2). The BMI, logarithmized (loge) leptin (G1: 2.0 ± 1.3 µg/ml, G2: 2.0 ± 1.1 µg/ml, p = 0.746) and visfatin serum levels (G1: 3.4 ± 0.3 ng/ml, G2: 3.4 ± 0.5 ng/ml, p = 0.900) did not significantly differ between the groups. Conversely, logarithmized adiponectin (G1: 3.3 ± 0.6 ng/ml, G2: 3.1 ± 0.7 ng/ml, p = 0.036) and resistin levels (G1: 1.8 ± 0.5 ng/ml, G2: 1.6 ± 0.5 ng/ml, p = 0.009) were higher in patients with the primary endpoint. Multivariate logistic regression analysis using a score that combined the individual adiponectin and resistin values in each patient corroborated this association. CONCLUSIONS: Our results suggest that adiponectin and resistin may act as potential biomarkers to identify individuals with AF who are at high thromboembolic risk.

Neuroplasticity in N-methyl-d-aspartic acid receptor signaling in subregions of the rat rostral ventrolateral medulla following sedentary versus physically active conditions.

The rostral ventrolateral medulla (RVLM) is a brain region involved in normal regulation of the cardiovascular system and heightened sympathoexcitatory states of cardiovascular disease (CVD). Among major risk factors for CVD, sedentary lifestyles contribute to higher mortality than other modifiable risk factors. Previous studies suggest excessive glutamatergic excitation of presympathetic neurons in the RVLM occurs in sedentary animals. Therefore, the purpose of this study was to examine neuroplasticity in the glutamatergic system in the RVLM of sedentary and physically active rats. We hypothesized that relative to active rats, sedentary rats would exhibit higher expression of glutamate N-methyl-d-aspartic acid receptor subunits (GluN), phosphoGluN1, and the excitatory scaffold protein postsynaptic density 95 (PSD95), while achieving higher glutamate levels. Male Sprague-Dawley rats (4 weeks old) were divided into sedentary and active (running wheel) conditions for 10-12 weeks. We used retrograde tracing/triple-labeling techniques, western blotting, and magnetic resonance spectroscopy. We report in sedentary versus physically active rats: 1) fewer bulbospinal non-C1 neurons positive for GluN1, 2) significantly higher expression of GluN1 and GluN2B but lower levels of phosphoGluN1 (pSer896) and PSD95, and 3) higher levels of glutamate in the RVLM. Higher GluN expression is consistent with enhanced sympathoexcitation in sedentary animals; however, a more complex neuroplasticity occurs within subregions of the ventrolateral medulla. Our results in rodents may also indicate that alterations in glutamatergic excitation of the RVLM contribute to the increased incidence of CVD in humans who lead sedentary lifestyles. Thus, there is a strong need to further pursue mechanisms of inactivity-related neuroplasticity in the RVLM.

Structural and functional brain signatures of endurance runners.

Although endurance running (ER) seems to be a simple repetitive exercise, good ER performance also requires and relies on multiple cognitive and motor control processes. Most of previous neuroimaging studies on ER were conducted using a single MRI modality, yet no multimodal study to our knowledge has been performed in this regard. In this study, we used multimodal MRI data to investigate the brain structural and functional differences between endurance runners (n = 22; age = 26.27 ± 6.07 years; endurance training = 6.23 ± 2.41 years) and healthy controls (HCs; n = 20; age = 24.60 ± 4.14 years). Compared with the HCs, the endurance runners showed greater gray matter volume (GMV) and cortical surface area in the left precentral gyrus, which at the same time had higher functional connectivity (FC) with the right postcentral and precentral gyrus. Subcortically, the endurance runners showed greater GMV in the left hippocampus and regional inflation in the right hippocampus. Using the bilateral hippocampi as seeds, further seed-based FC analyses showed higher hippocampal FC with the supplementary motor area, middle cingulate cortex, and left posterior lobe of the cerebellum. Moreover, compared with the HCs, the endurance runners also showed higher fractional anisotropy in several white matter regions, involving the corpus callosum, left internal capsule, left corona radiata, left external capsule, left posterior lobe of cerebellum and bilateral precuneus. Taken together, our findings provide several lines of evidence for the brain structural and functional differences between endurance runners and HCs. The current data suggest that these brain characteristics may have arisen as a result of regular ER training; however, whether they represent the neural correlates underlying the good ER performances of the endurance runners requires further investigations.

Psychological consequences of COVID-19 home confinement: The ECLB-COVID19 multicenter study.

BACKGROUND: Public health recommendations and government measures during the COVID-19 pandemic have enforced restrictions on daily-living. While these measures are imperative to abate the spreading of COVID-19, the impact of these restrictions on mental health and emotional wellbeing is undefined. Therefore, an international online survey (ECLB-COVID19) was launched on April 6, 2020 in seven languages to elucidate the impact of COVID-19 restrictions on mental health and emotional wellbeing. METHODS: The ECLB-COVID19 electronic survey was designed by a steering group of multidisciplinary scientists, following a structured review of the literature. The survey was uploaded and shared on the Google online-survey-platform and was promoted by thirty-five research organizations from Europe, North-Africa, Western-Asia and the Americas. All participants were asked for their mental wellbeing (SWEMWS) and depressive symptoms (SMFQ) with regard to "during" and "before" home confinement. RESULTS: Analysis was conducted on the first 1047 replies (54% women) from Asia (36%), Africa (40%), Europe (21%) and other (3%). The COVID-19 home confinement had a negative effect on both mental-wellbeing and on mood and feelings. Specifically, a significant decrease (p < .001 and Δ% = 9.4%) in total score of the SWEMWS questionnaire was noted. More individuals (+12.89%) reported a low mental wellbeing "during" compared to "before" home confinement. Furthermore, results from the mood and feelings questionnaire showed a significant increase by 44.9% (p < .001) in SMFQ total score with more people (+10%) showing depressive symptoms "during" compared to "before" home confinement. CONCLUSION: The ECLB-COVID19 survey revealed an increased psychosocial strain triggered by the home confinement. To mitigate this high risk of mental disorders and to foster an Active and Healthy Confinement Lifestyle (AHCL), a crisis-oriented interdisciplinary intervention is urgently needed.

COVID-19 Home Confinement Negatively Impacts Social Participation and Life Satisfaction: A Worldwide Multicenter Study.

Public health recommendations and governmental measures during the new coronavirus disease (COVID-19) pandemic have enforced numerous restrictions on daily living including social distancing, isolation, and home confinement. While these measures are imperative to mitigate spreading of COVID-19, the impact of these restrictions on psychosocial health is undefined. Therefore, an international online survey was launched in April 2020 to elucidate the behavioral and lifestyle consequences of COVID-19 restrictions. This report presents the preliminary results from more than one thousand responders on social participation and life satisfaction. METHODS: Thirty-five research organizations from Europe, North-Africa, Western Asia, and the Americas promoted the survey through their networks to the general society, in 7 languages (English, German, French, Arabic, Spanish, Portuguese, and Slovenian). Questions were presented in a differential format with questions related to responses "before" and "during" confinement conditions. RESULTS: 1047 participations (54% women) from Asia (36%), Africa (40%), Europe (21%), and others (3%) were included in the analysis. Findings revealed psychosocial strain during the enforced COVID-19 home confinement. Large decreases (p < 0.001) in the amount of social activity through family (-58%), friends/neighbors (-44.9%), or entertainment (-46.7%) were triggered by the enforced confinement. These negative effects on social participation were also associated with lower life satisfaction (-30.5%) during the confinement period. Conversely, the social contact score through digital technologies significantly increased (p < 0.001) during the confinement period with more individuals (+24.8%) being socially connected through digital technology. CONCLUSION: These preliminary findings elucidate the risk of psychosocial strain during the early COVID-19 home confinement period in 2020. Therefore, in order to mitigate the negative psychosocial effects of home confinement, implementation of national strategies focused on promoting social inclusion through a technology-based solution is strongly suggested.

Differential Effects of Tai Chi Chuan (Motor-Cognitive Training) and Walking on Brain Networks: A Resting-State fMRI Study in Chinese Women Aged 60.

Background: This cross-sectional study aimed to investigate whether a long-term engagement in different types of physical exercise may influence resting-state brain networks differentially. In particular, we studied if there were differences in resting-state functional connectivity measures when comparing older women who are long-term practitioners of tai chi chuan or walking. Method: We recruited 20 older women who regularly practiced tai chi chuan (TCC group), and 22 older women who walked regularly (walking group). Both the TCC group and the walking group underwent a resting-state functional magnetic resonance imaging (rs-fMRI) scan. The acquired rs-fMRI data of all participants were analyzed using independent component analysis. Age and years of education were added as co-variables. Results: There were significant differences in default network, sensory-motor network, and visual network of rs-fMRI between the TCC group and walking group (p < 0.05). Conclusions: The findings of the current study suggested that long-term practice of different types of physical exercises (TCC vs. walking) influenced brain functional networks and brain functional plasticity of elderly women differentially. Our findings encourage further research to investigate whether those differences in resting-state functional connectivity as a function of the type of physical exercise have implications for the prevention of neurological diseases.

Compliant Titin Isoform Content Is Reduced in Left Ventricles of Sedentary Versus Active Rats.

A sedentary lifestyle is associated with increased cardiovascular risk factors and reduced cardiac compliance when compared to a lifestyle that includes exercise training. Exercise training increases cardiac compliance in humans, but the mechanisms underlying this improvement are unknown. A major determinant of cardiac compliance is the compliance of the giant elastic protein titin. Experimentally reducing titin compliance in animal models reduces exercise tolerance, but it is not known whether sedentary versus chronic exercise conditions cause differences in titin isoform content. We hypothesized that sedentary conditions would be associated with a reduction in the content of the longer, more compliant N2BA isoform relative to the stiffer N2B isoform (yielding a reduced N2BA:N2B ratio) compared to age-matched exercising controls. We obtained left ventricles from 16-week old rats housed for 12 weeks in standard (sedentary) or voluntary running wheel (exercised) housing. The N2BA:N2B ratio was decreased in the hearts of sedentary versus active rats (p = 0.041). Gene expression of a titin mRNA splicing factor, RNA Binding Motif 20 protein (RBM20), correlated negatively with N2BA:N2B ratios (p = 0.006, r = -0.449), but was not different between groups, suggesting that RBM20 may be regulated post-transcriptionally. Total phosphorylation of cardiac titin was not different between the active and sedentary groups. This study is the first to demonstrate that sedentary rats exhibit reduced cardiac titin N2BA:N2B isoform ratios, which implies reduced cardiac compliance. These data suggest that a lack of exercise (running wheel) reduces cardiac compliance and that exercise itself increases cardiac compliance.

Subregional differences in GABAA receptor subunit expression in the rostral ventrolateral medulla of sedentary versus physically active rats.

Neurons in the rostral ventrolateral medulla (RVLM) regulate blood pressure through direct projections to spinal sympathetic preganglionic neurons. Only some RVLM neurons are active under resting conditions due to significant, tonic inhibition by gamma-aminobutyric acid (GABA). Withdrawal of GABAA receptor-mediated inhibition of the RVLM increases sympathetic outflow and blood pressure substantially, providing a mechanism by which the RVLM could contribute chronically to cardiovascular disease (CVD). Here, we tested the hypothesis that sedentary conditions, a major risk factor for CVD, increase GABAA receptors in RVLM, including its rostral extension (RVLMRE ), both of which contain bulbospinal catecholamine (C1) and non-C1 neurons. We examined GABAA receptor subunits GABAAα1 and GABAAα2 in the RVLM/RVLMRE of sedentary or physically active (10-12 weeks of wheel running) rats. Western blot analyses indicated that sedentary rats had lower expression of GABAAα1 and GABAAα2 subunits in RVLM but only GABAAα2 was lower in the RVLMRE of sedentary rats. Sedentary rats had significantly reduced expression of the chloride transporter, KCC2, suggesting less effective GABA-mediated inhibition compared to active rats. Retrograde tracing plus triple-label immunofluorescence identified fewer bulbospinal non-C1 neurons immunoreactive for GABAAα1 but a higher percentage of bulbospinal C1 neurons immunoreactive for GABAAα1 in sedentary animals. Sedentary conditions did not significantly affect the number of bulbospinal C1 or non-C1 neurons immunoreactive for GABAAα2 . These results suggest a complex interplay between GABAA receptor expression by spinally projecting C1 and non-C1 neurons and sedentary versus physically active conditions. They also provide plausible mechanisms for both enhanced sympathoexcitatory and sympathoinhibitory responses following sedentary conditions.

Development of manganese-enhanced magnetic resonance imaging of the rostral ventrolateral medulla of conscious rats: Importance of normalization and comparison with other regions of interest.

Spinally projecting neurons in the rostral ventrolateral medulla (RVLM) are believed to contribute to pathophysiological alterations in sympathetic nerve activity and the development of cardiovascular disease. The ability to identify changes in the activity of RVLM neurons in conscious animals and humans, especially longitudinally, would represent a clinically important advancement in our understanding of the contribution of the RVLM to cardiovascular disease. To this end, we describe the initial development of manganese-enhanced magnetic resonance imaging (MEMRI) for the rat RVLM. Manganese (Mn2+ ) has been used to estimate in vivo neuronal activity in other brain regions because of both its paramagnetic properties and its entry into and accumulation in active neurons. In this initial study, our three goals were as follows: (1) to validate that Mn2+ enhancement occurs in functionally and anatomically localized images of the rat RVLM; (2) to quantify the dose and time course dependence of Mn2+ enhancement in the RVLM after one systemic injection in conscious rats (66 or 33 mg/kg, intraperitoneally); and (3) to compare Mn2+ enhancement in the RVLM with other regions to determine an appropriate method of normalization of T1 -weighted images. In our proof-of-concept and proof-of-principle studies, Mn2+ was identified by MRI in the rat RVLM after direct microinjection or via retrograde transport following spinal cord injections, respectively. Systemic injections in conscious rats produced significant Mn2+ enhancement at 24 h (p < 0.05). Injections of 66 mg/kg produced greater enhancement than 33 mg/kg in the RVLM and paraventricular nucleus of the hypothalamus (p < 0.05 for both), but only when normalized to baseline scans without Mn2+ injection. Consistent with findings from our previous functional and anatomical studies demonstrating subregional neuroplasticity, Mn2+ enhancement was higher in the rostral regions of the RVLM (p < 0.05). Together with important technical considerations, our studies support the development of MEMRI as a potential method to examine RVLM activity over time in conscious animal subjects.

The link between exercise and titin passive stiffness.

NEW FINDINGS: What is the topic of this review? This review focuses on how in vivo and molecular measurements of cardiac passive stiffness can predict exercise tolerance and how exercise training can reduce cardiac passive stiffness. What advances does it highlight? This review highlights advances in understanding the relationship between molecular (titin-based) and in vivo (left ventricular) passive stiffness, how passive stiffness modifies exercise tolerance, and how exercise training may be therapeutic for cardiac diseases with increased passive stiffness. Exercise can help alleviate the negative effects of cardiovascular disease and cardiovascular co-morbidities associated with sedentary behaviour; this may be especially true in diseases that are associated with increased left ventricular passive stiffness. In this review, we discuss the inverse relationship between exercise tolerance and cardiac passive stiffness. Passive stiffness is the physical property of cardiac muscle to produce a resistive force when stretched, which, in vivo, is measured using the left ventricular end diastolic pressure-volume relationship or is estimated using echocardiography. The giant elastic protein titin is the major contributor to passive stiffness at physiological muscle (sarcomere) lengths. Passive stiffness can be modified by altering titin isoform size or by post-translational modifications. In both human and animal models, increased left ventricular passive stiffness is associated with reduced exercise tolerance due to impaired diastolic filling, suggesting that increased passive stiffness predicts reduced exercise tolerance. At the same time, exercise training itself may induce both short- and long-term changes in titin-based passive stiffness, suggesting that exercise may be a treatment for diseases associated with increased passive stiffness. Direct modification of passive stiffness to improve exercise tolerance is a potential therapeutic approach. Titin passive stiffness itself may be a treatment target based on the recent discovery of RNA binding motif 20, which modifies titin isoform size and passive stiffness. Translating these discoveries that link exercise and left ventricular passive stiffness may provide new methods to enhance exercise tolerance and treat patients with cardiovascular disease.