Peripheral Sympathetic Activity Research Articles

Gestational diabetes causes hyperactivity of the sympathetic nervous system and hypertension in adult mice offspring

ABSTRACT Background Gestational diabetes can lead to increased blood pressure in offspring, accompanied by impaired renal sodium excretion function and vasoconstriction and diastole dysfunction. However, there are few studies on whether it is accompanied by increased sympathetic nerve activity. Methods Pregnant C57BL/6 mice were intraperitoneally injected with streptozotocin (35 mg/kg) or citrate buffer at day 0 of gestation. The mice of control mother offspring (CMO) and diabetic mother offspring (DMO) at 16 weeks of age were infused with vehicle (artificial cerebrospinal fluid, aCSF, 0.4 μL/h) or tempol (1 mmol/L, 0.4 μL/h) into the bilateral paraventricular nucleus (PVN) of mice for 4 weeks, respectively. Results Compared with CMO group, SBP and peripheral sympathetic nerve activity (increased heart rate, LF/HF and plasma norepinephrine and decreased SDNN and RMSSD) were increased in DMO group, which was accompanied by increased angiotensin II type-1 receptor (AT1R) expression and function in PVN. The increase in AT1R expression levels was attributed to a decrease in the methylation level of the AT1R promoter region, resulting in an increase in AT1R mRNA levels in PVN of DMO. Moreover, compared with CMO group, the levels of oxidative stress were increased and DNMT1 expression was decreased in PVN of DMO. Bilateral PVN infusion of tempol attenuated oxidative stress increased the level of DNMT1 expression and the binding of DNMT1 to the AT1R promoter region, which reduced mRNA and protein expression level of AT1R, heart rate and SBP in DMO, but not in CMO. Conclusions The present study provides evidence for overactive sympathetic nervous systems in the pathogenesis of gestational diabetes-induced hypertension in offspring. Central antioxidant intervention in the PVN may be an important treatment strategy for fetal-programmed hypertension.

Interoceptive Signals Bias Decision Making in Rhesus Macaques.

The brain adjusts body physiology to the behavioral agenda of the organism through autonomic efferents; concomitantly interoceptive afferents carry signals that inform the brain about the physiological state of the body, closing a homeostatic regulatory loop. Persuasive theories proposed that interoceptive afferents contribute to higher cognitive functions, including emotion. Empirical evidence that these signals are sufficient to bias complex behavior has been limited by the difficulty of isolating interoceptive afferents from the rest of the homeostatic loop. Here we selectively manipulated the autonomic state of the body using drugs with limited penetrance of the brain in macaques performing decision-making tasks. Sympathetic-dominated peripheral states significantly altered decision making, suggesting that changes in interoceptive afferent signals are sufficient to bias behavior.

Inhibition of CB1R in the Hypothalamic Paraventricular Nucleus Ameliorates Hypertension Through Wnt/β-Catenin/RAS Pathway.

The hypothalamic paraventricular nucleus (PVN), as an important integrating center, plays a prominent role in the pathogenesis of hypertension, in maintaining the stability of cardiovascular activity through peripheral sympathetic nervous activity and secretion of various humoral factors. Acknowledging that the mechanistic targets of the endocannabinoid type 1 receptor (CB1R) are the key signaling systems involved in the regulation of hypertension, we sought to clarify whether inhibition of CB1R within the PVN ameliorates hypertension through Wnt/β-catenin/RAS pathway. Spontaneously hypertensive rats (SHRs) and Wistar Kyoto rats were randomly assigned to different groups and treated with bilateral PVN injections of AM251 (CB1R antagonist, 10µg/h) or vehicle (artificial cerebrospinal fluid, aCSF) for four weeks. Bilateral PVN injections of AM251 significantly decreased the heart rate, the body weight and the mean arterial pressure in SHRs. AM251 lowered the expression of CB1R, Wnt3, active-β-catenin, p-IKKβ, RAS components, pro-inflammatory cytokines and elevated the expression level of Glycogen synthase kinase3β and Superoxide Dismutase in the PVN of hypertensive rats. Our findings suggest that inhibition of CB1R in the PVN ameliorates hypertension through Wnt/β-catenin/RAS pathway and broaden our current understanding of the pathological mechanism and clinical treatment of hypertension.

Exercise-induced central and peripheral sympathetic activity in a community-based group of epilepsy patients differ from healthy controls

Ictal and interictal activity within the autonomic nervous system is characterized by a sympathetic overshoot in people with epilepsy. This autonomic dysfunction is assumed to be driven by alterations in the central autonomic network. In this study, exercise-induced changes of the interrelation of central and peripheral autonomic activity in patients with epilepsy was assessed. 21 patients with epilepsy (16 seizure-free), and 21 healthy matched controls performed an exhaustive bicycle ergometer test. Immediately before and after the exercise test, resting state electroencephalography measurements (Brain Products GmbH, 128-channel actiCHamp) of 5 min were carried out to investigate functional connectivity assessed by phase locking value in source space for whole brain, central autonomic network and visual network. Additionally, 1-lead ECG (Brain products GmbH) was performed to analyze parasympathetic (root mean square of successive differences (RMSSD) of the heart rate variability) and sympathetic activity (electrodermal activity (meanEDA)). MeanEDA increased (p < 0.001) and RMSSD decreased (p < 0.001) from pre to post-exercise in both groups. Correlation coefficients of meanEDA and central autonomic network functional connectivity differed significantly between the groups (p = 0.004) after exercise. Both patients with epilepsy and normal control subjects revealed the expected physiological peripheral autonomic responses to acute exhaustive exercise, but alterations of the correlation between central autonomic and peripheral sympathetic activity may indicate a different sympathetic reactivity after exercise in patients with epilepsy. The clinical relevance of this finding and its modulators (seizures, anti-seizure medication, etc.) still needs to be elucidated.

Secretin-dependent signals in the ventromedial hypothalamus regulate energy metabolism and bone homeostasis in mice

Secretin, though originally discovered as a gut-derived hormone, is recently found to be abundantly expressed in the ventromedial hypothalamus, from which the central neural system controls satiety, energy metabolism, and bone homeostasis. However, the functional significance of secretin in the ventromedial hypothalamus remains unclear. Here we show that the loss of ventromedial hypothalamus-derived secretin leads to osteopenia in male and female mice, which is primarily induced by diminished cAMP response element-binding protein phosphorylation and upregulation in peripheral sympathetic activity. Moreover, the ventromedial hypothalamus-secretin inhibition also contributes to hyperphagia, dysregulated lipogenesis, and impaired thermogenesis, resulting in obesity in male and female mice. Conversely, overexpression of secretin in the ventromedial hypothalamus promotes bone mass accrual in mice of both sexes. Collectively, our findings identify an unappreciated secretin signaling in the central neural system for the regulation of energy and bone metabolism, which may serve as a new target for the clinical management of obesity and osteoporosis.

Acetic Acid: An Underestimated Metabolite in Ethanol-Induced Changes in Regulating Cardiovascular Function.

Acetic acid is a bioactive short-chain fatty acid produced in large quantities from ethanol metabolism. In this review, we describe how acetic acid/acetate generates oxidative stress, alters the function of pre-sympathetic neurons, and can potentially influence cardiovascular function in both humans and rodents after ethanol consumption. Our recent findings from in vivo and in vitro studies support the notion that administration of acetic acid/acetate generates oxidative stress and increases sympathetic outflow, leading to alterations in arterial blood pressure. Real-time investigation of how ethanol and acetic acid/acetate modulate neural control of cardiovascular function can be conducted by microinjecting compounds into autonomic control centers of the brain and measuring changes in peripheral sympathetic nerve activity and blood pressure in response to these compounds.

Noninvasive characterization of peripheral sympathetic activation across sensory stimuli using a peripheral arterial stiffness index.

Introduction: The peripheral arterial stiffness index has been proposed and validated as a noninvasive measure quantifying stimulus intensity based on amplitude changes induced by sympathetic innervation of vascular tone. However, its temporal response characteristics remain unclear, thus hindering continuous and accurate monitoring of the dynamic process of sympathetic activation. This paper presents a study aimed at modeling the transient response of the index across sensory stimuli to characterize the corresponding peripheral sympathetic activation. Methods: The index was measured using a continuous arterial pressure monitor and a pulse oximeter during experiments with local pain and local cooling stimuli designed to elicit different patterns of sympathetic activation. The corresponding response of the index was modeled to clarify its transient response characteristics across stimuli. Results: The constructed transfer function accurately depicted the transient response of the index to local pain and local cooling stimuli (Fit percentage: 78.4% ± 11.00% and 79.92% ± 8.79%). Differences in dead time (1.17 ± 0.67 and 0.99 ± 0.56 s, p = 0.082), peak time (2.89 ± 0.81 and 2.64 ± 0.68 s, p = 0.006), and rise time (1.81 ± 0.50 and 1.65 ± 0.48 s, p = 0.020) revealed different response patterns of the index across stimuli. The index also accurately characterized similar vasomotor velocities at different normalized peak amplitudes (0.19 ± 0.16 and 0.16 ± 0.19 a.u., p = 0.007). Discussion: Our findings flesh out the characterization of peripheral arterial stiffness index responses to different sensory stimuli and demonstrate its validity in characterizing peripheral sympathetic activation. This study valorizes a noninvasive method to characterize peripheral sympathetic activation, with the potential to use this index to continuously and accurately track sympathetic activators.

AUTONOMIC ACTIVITY AND THE AGING BRAIN

Abstract Aging affects both autonomic activity and the brain regions that help modulate autonomic activity. In this symposium, we present new findings on how the relationships between autonomic activity and the brain change in aging. In addition, we demonstrate that modulating autonomic activity can affect the aging brain and emotional and cognitive functions controlled by the brain. Kathy Liu will present research from over 600 participants showing that, unlike younger adults who show the expected positive relationship between heart rate variability (HRV) and brain and behavioral indicators of emotion regulation, older adults showed a negative relationship between HRV and emotion regulation. Julian Thayer will present findings on how blood pressure and total peripheral resistance relate to brain structure. Richard Song will present functional MRI data revealing that the older brain shows less blood oxygen level dependent (BOLD) response to physiological fluctuations than younger brains. Jungwon Min will present findings that random assignment to daily biofeedback to either increase or decrease heart rate oscillations had a large effect on plasma amyloid-β. Mara Mather will present a new theoretical model positing that older brains attempt to compensate for hyperactive peripheral sympathetic activity, and that this ventromedial prefrontal compensatory activity leads to the biases in attention and memory known as the age-related positivity effect. Together, the empirical findings and theoretical perspectives presented in this symposium indicate that the autonomic system exerts important influences over the aging brain and that this provides a significant opportunity for intervening to improve brain health.

Low-intensity focused ultrasound modulation of the paraventricular nucleus to prevent myocardial infarction–induced ventricular arrhythmia

BackgroundOur previous study showed that light-emitting diode modulation of the hypothalamic paraventricular nucleus (PVN), which is the control center of the sympathetic nervous system, might attenuate neuroinflammation in the PVN and prevent ventricular arrhythmias (VAs) after myocardial infarction (MI). Low-intensity focused ultrasound (LIFU) has deeper penetration than does light-emitting diode, while its effect on the PVN has not been reported. ObjectiveThis study aimed to explore the effect of LIFU modulation of the PVN on the inducibility of post-MI VAs. MethodsFifty-four Sprague-Dawley rats were randomly divided into acute control (n = 12, 22.22%), acute MI (AMI, n = 12, 22.22%), AMI + LIFU (n = 12, 22.22%), chronic control (n = 6, 11.11%), chronic MI (CMI, n = 6, 11.11%), and CMI + LIFU (n = 6, 11.11%) groups. MI was induced by left anterior artery ligation, and electrocardiographic recording for 0.5 hours after MI and programmed electrophysiological stimulation were used to test the vulnerability of VAs. Peripheral sympathetic neural activity was assessed by measuring left stellate ganglion neural activity. Finally, hearts and brains were extracted for Western blotting and histopathological analysis, respectively. ResultsCompared with the AMI group, AMI-induced VAs (P < .05) and left stellate ganglion neural activity (P < .05) were significantly attenuated in the AMI + LIFU group. In addition, LIFU resulted in a significant reduction of microglial activation in the PVN and expression of inflammatory cytokines in the peri-ischemic myocardium. In the CMI + LIFU group, there was no obvious tissue damage in the brain. ConclusionLIFU modulation of the PVN may prevent the incidence of post-MI VAs by attenuating MI-induced sympathetic neural activation and inflammatory response.

Mutual Information between EDA and EEG in Multiple Cognitive Tasks and Sleep Deprivation Conditions.

Sleep deprivation, a widespread phenomenon that affects one-third of normal American adults, induces adverse changes in physical and cognitive performance, which in turn increases the occurrence of accidents. Sleep deprivation is known to increase resting blood pressure and decrease muscle sympathetic nerve activity. Monitoring changes in the interplay between the central and autonomic sympathetic nervous system can be a potential indicator of human's readiness to perform tasks that involve a certain level of cognitive load (e.g., driving). The electroencephalogram (EEG) is the standard to assess the brain's activity. The electrodermal activity (EDA) is a reflection of the general state of arousal regulated by the activation of the sympathetic nervous system through sweat gland stimulation. In this work, we calculated the mutual information between EDA and EEG recordings in order to consider linear and non-linear interactions and provide an insight of the relationship between brain activity and peripheral autonomic sympathetic activity. We analyzed EEG and EDA data from ten participants performing four cognitive tasks every two hours during 24 h (12 trials). We decomposed EEG data into delta, theta, alpha, beta, and gamma spectral components, and EDA into tonic and phasic components. The results demonstrate high values of mutual information between the EDA and delta component of EEG, mainly in working memory tasks. Additionally, we found an increase in the theta component of EEG in the presence of fatigue caused by sleep deprivation, the alpha component in tasks demanding inhibition and attention, and the delta component in working memory tasks. In terms of the location of brain activity, most of the tasks report high mutual information in frontal regions in the initial trials, with a trend to decrease and become uniform for all the nine analyzed EEG channels as a consequence of the sleep deprivation effect. Our results evidence the interplay between central and sympathetic nervous activity and can be used to mitigate the consequences of sleep deprivation.

Immediate effect of caffeine on sympathetic nerve activity: why coffee is safe? A single-centre crossover study

PurposesHabitual coffee drinking is ubiquitous and generally considered to be safe despite its transient hypertensive effect. Our purpose was to determine the role of the sympathetic nervous system in the hypertensive response.MethodsIn a single-centre crossover study, medical caregivers were studied after consumption of standard coffee (espresso), water and decaffeinated coffee (decaff) given in random order at least 1 month apart. Plasma caffeine levels, mean arterial pressure, heart rate, total peripheral resistance and muscle sympathetic activity were recorded. Baroreflex activity was assessed using burst incidence and RR interval changes to spontaneous blood pressure fluctuations.ResultsA total of 16 subjects (mean [± standard error] age 34.4 ± 2 years; 44% female) were recruited to the study. Three agents were studied in ten subjects, and two agents were studied in six subjects. Over a 120-min period following the consumption of standard coffee, mean (± SE) plasma caffeine levels increased from 2.4 ± 0.8 to 21.0 ± 4 µmol/L and arterial pressure increased to 103 ± 1 mmHg compared to water (101 ± 1 mmHg; p = 0.066) and decaff (100 ± 1 mmHg; p = 0.016). Peripheral resistance in the same period following coffee increased to 120 ± 4% of the baseline level compared to water (107 ± 4; p = 0.01) and decaff (109 ± 4; p = 0.02). Heart rate was lower after both coffee and decaff consumption: 62 ± 1 bpm compared to water (64 bpm; p = 0.01 and p = 0.02, respectively). Cardio-vagal baroreflex activity remained stable after coffee, but sympathetic activity decreased, with burst frequency of 96 ± 3% versus water (106 ± 3%; p = 0.04) and decaff (112 ± 3%; p = 0.001) despite a fall in baroreflex activity from – 2.2 ± 0.1 to – 1.8 ± 0.1 bursts/100 beats/mmHg, compared to water (p = 0.009) and decaff (p = 0.004).ConclusionThe hypertensive response to coffee is secondary to peripheral vasoconstriction but this is not mediated by increased sympathetic nerve activity. These results may explain why habitual coffee drinking is safe.

Anthocyanin attenuates high salt-induced hypertension via inhibiting the hyperactivity of the sympathetic nervous system

ABSTRACT Background Anthocyanin plays a protective role in cardiovascular disease through antioxidant effect. Whether anthocyanin can reduce salt-induced hypertension and the related mechanisms remain unclear. Methods Chronic infusion of vehicle (artificial cerebrospinal fluid, aCSF, 0.4 μL/h) or anthocyanin (10 mg/kg, 0.4 μL/h) into bilateral paraventricular nucleus (PVN) of Sprague-Dawley rats was performed. Then, the rats were fed a high salt diet (8% NaCl, HS) or normal salt diet (0.9%, NaCl, NS) for 4 weeks. Results High salt diet induced an increase in blood pressure and peripheral sympathetic nerve activity (increased LF/HF and decreased SDNN and RMSSD), which was accompanied by increased reactive oxygen species (ROS) production and angiotensin II type-1 receptor (AT1R) expression and function in the PVN. Moreover, the NOD-like receptor protein 3 (NLRP3) and related inflammatory proteins (caspase-1) expression, the pro-inflammatory cytokine levels including IL-1β and TNF-α were higher in PVN of rats with a high salt diet. Bilateral PVN infusion of anthocyanin attenuated NLRP3-dependent inflammation (NLRP3, caspase-1, IL-1β and TNF-α) and ROS production, reduced AT1R expression and function in PVN and lowered peripheral sympathetic nerve activity and blood pressure in rats with salt-induced hypertension. Conclusions Excessive salt intake activates NLRP3-dependent inflammation and oxidative stress and increased AT1R expression and function in the PVN. Bilateral PVN infusion of anthocyanin lowers peripheral sympathetic nerve activity and blood pressure in rats with salt-induced hypertension by improvement of expression and function of AT1R in the PVN through inhibiting NLRP3 related inflammatory and oxidative stress.

A HYPERADRENERGIC STATE IN HYPERTENSION IS ASSOCIATED WITH MOOD DISTURBANCE AND IMPAIRED STRESS-MODULATED VASOMOTOR RESPONSES

Objective: Increasing evidence suggests a high prevalence of affective disorders in hypertension, however, the physiological associations remain unclear. Noradrenergic activation in the central and peripheral nervous systems is a putative mechanism that may explain the link between both conditions. Here, we investigate whether these stress-sensitive co-morbidities may be dependent on basal noradrenergic activity and whether vascular responses to centrally acting stimuli vary according to noradrenergic activity. Design and method: We examined the relation of affective disorders and stress-mediated vascular responses to plasma concentrations of normetanephrine (NMN), a measure of noradrenergic activity, in subjects with primary hypertension. Subjects on antidepressant medication, alpha- and beta-blockers were excluded. The Patient Health Questionnaire (PHQ-9), the 16-item Quick Inventory of Depressive Symptomatology-Self Report (QIDSSR-16), and Generalised Anxiety Disorder-7 (GAD-7) questionnaires were used for the evaluation of symptoms of depression and anxiety. Forearm blood flow (strain gauge plethysmography) was used to assess vascular responses to mental stress (Stroop colour-word test) and slow breathing (by biofeedback), interventions that respectively increase or decrease noradrenergic activity in the pre-frontal cortex and locus coeruleus. Results: 100 subjects (53% male) with (mean ± SD) age 43.4 ± 10.9 years were recruited. 88% of subjects were treated with anti-hypertensive medications and 4% had type 2 diabetes. 31% and 34% of the study population scored moderate to severe depression for PHQ-9 and QIDSSR-16 respectively indicating significant mood disturbance. Scores representing low mood and high anxiety were 2-3-fold higher for hypertensive subjects in the highest compared to lowest NMN tertiles (PHQ-9: 9.2 ± 5.8 vs 3.8 ± 2.7, P &lt; 0.001; QIDSSR-16: 12.3 ± 4.9 vs 4.5 ± 3.5, P = 0.003; GAD-7: 9.0 ± 5.5 vs 4.6 ± 3.8, P = 0.003). Forearm vasodilator responses to mental stress and vasoconstrictor responses to slow breathing were attenuated in those with high compared to low NMN (28.3 ± 21% vs. 47.1 ± 30% increases for mental stress and 3.7 ± 21% vs. 18.6 ± 15% decreases for slow breathing for highest vs. lowest tertiles of NMN, both P &lt; 0.01). Conclusions: A hyperadrenergic state in hypertension is associated with mood disturbance and impaired stress-modulated vasomotor responses. This association may be mediated by chronic stress impinging on pathways regulating central arousal and peripheral sympathetic nerve activity.

Dynamic fluctuations in ascending heart-to-brain communication under mental stress.

Dynamical information exchange between central and autonomic nervous systems, as referred to functional brain-heart interplay, occurs during emotional and physical arousal. It is well documented that physical and mental stress lead to sympathetic activation. Nevertheless, the role of autonomic inputs in nervous system-wise communication under mental stress is yet unknown. In this study, we estimated the causal and bidirectional neural modulations between electroencephalogram (EEG) oscillations and peripheral sympathetic and parasympathetic activities using a recently proposed computational framework for a functional brain-heart interplay assessment, namely the sympathovagal synthetic data generation model. Mental stress was elicited in 37 healthy volunteers by increasing their cognitive demands throughout three tasks associated with increased stress levels. Stress elicitation induced an increased variability in sympathovagal markers, as well as increased variability in the directional brain-heart interplay. The observed heart-to-brain interplay was primarily from sympathetic activity targeting a wide range of EEG oscillations, whereas variability in the efferent direction seemed mainly related to EEG oscillations in the γ band. These findings extend current knowledge on stress physiology, which mainly referred to top-down neural dynamics. Our results suggest that mental stress may not cause an increase in sympathetic activity exclusively as it initiates a dynamic fluctuation within brain-body networks including bidirectional interactions at a brain-heart level. We conclude that directional brain-heart interplay measurements may provide suitable biomarkers for a quantitative stress assessment and bodily feedback may modulate the perceived stress caused by increased cognitive demand.

Short-Term Outcome of Unilateral Inspiration-Coupled Hypoglossal Nerve Stimulation in Patients with Obstructive Sleep Apnea

Hypoglossal nerve stimulation (HGNS) is a therapeutic option for patients with obstructive sleep apnea (OSA) and intolerance of positive airway pressure (PAP) therapy. Most reported data are based on multicentre pivotal trials with selected baseline core clinical features. Our aim was to investigate polysomnography (PSG)-based outcomes of HGNS-therapy in a patient cohort with higher average AHI and BMI than previously reported. Data of 29 consecutive patients (nine female; mean age: 55.52 ± 8.6 years, mean BMI 30.13 ± 3.93 kg/m2) were retrospectively evaluated. Numerical values of PSG- based metrics were compared before and after intervention using Wilcoxon's rank-sum test. AHI (38.57/h ± 12.71, 24.43/h ± 13.3, p < 0.001), hypopnea index (24.05/h ± 9.4, 15.27/h ± 8.23, p < 0.001), apnea index (14.5/h ± 12.05, 9.17/h ± 10.86, p < 0.01), snoring index (262.68/h ± 170.35, 143.48/h ± 162.79, p < 0.001), cortical arousal index (20.8/h ± 10.34 vs. 14.9/h ± 8.36, p < 0.01) and cumulative duration of apnea and hypopnea during sleep (79.79 min ± 40.32 vs. 48.62 min ± 30.56, p < 0.001) were significantly lower after HGNS. HGNS provides an effective therapy option for selected patients not tolerating PAP-therapy with higher average AHI and BMI than usually reported. HGNS-therapy appears to suppress central nervous system arousal circuits while not eliciting peripheral autonomous sympathetic activation. Such metrics as the snoring index and the cumulative duration of respiratory events during sleep may be considered in future HGNS studies.

Sympathetic neural reactivity to the Trier social stress test.

Sympathetic responsiveness to laboratory mental stress is highly variable, making interpretations of its role in stress reactivity challenging. The present study assessed muscle sympathetic nerve activity (MSNA, microneurography) responsiveness to the Trier social stress test (TSST), which employs an anticipatory stress phase, followed by a public speaking and mental arithmetic task. We hypothesized that sympathetic reactivity to the anticipatory phase would offer a more uniform response between individuals due to elimination of confounds (i.e. respiratory changes, muscle movement, etc.) observed during more common stress tasks. Participants included 26healthy adults (11men, 15 women, age: 25±6years, body mass index: 24±3kg/m2 ). Continuous heart rate (electrocardiogram) and beat-to-beat blood pressure (finger plethysmography) were recorded from all participants, while MSNA recordings were obtained in 20 participants. MSNA burst frequency was significantly reduced during anticipatory stress. During the speech, although burst frequency was unchanged, total MSNA was significantly increased. Changes in diastolic arterial pressure were predictive of changes in MSNA during anticipatory (β=-0.680, P=0.001), but not the speech (P=0.318) or mental maths (P=0.051) phases. Lastly, sympathetic reactivity to anticipatory stress was predictive of subsequent reactivity to both speech (β=0.740, P=0.0002) and maths (β=0.663, P=0.001). In conclusion, anticipatory social stress may offer a more versatile means of assessing sympathetic reactivity to mental stress in the absence of confounds and appears to predict reactivity to subsequent mental stress paradigms. KEY POINTS: Cardiovascular reactivity to laboratory mental stress is predictive of future health outcomes. However, reactivity of the sympathetic nervous system to mental stress is highly variable. The current study assessed peripheral muscle sympathetic nerve activity in response to the Trier social stress test, a psychosocial stressor that includes anticipatory stress, public speaking and mental arithmetic. Our findings demonstrate that sympathetic neural activity is consistently reduced during anticipatory stress. Conversely, the classically observed inter-individual variability of sympathetic responsiveness was observed during speech and maths tasks. Additionally, sympathetic reactivity to the anticipatory period accurately predicted how an individual would respond to both speech and maths tasks, outlining the utility of anticipatory stress in future research surrounding stress reactivity. Utilization of the Trier social stress test in autonomic physiology may offer an alternative assessment of sympathetic responsiveness to stress with more consistent inter-individual responsiveness and may be a useful tool for further investigation of stress reactivity.

Effect of TLR4/MyD88/NF-kB axis in paraventricular nucleus on ventricular arrhythmias induced by sympathetic hyperexcitation in post-myocardial infarction rats.

Sympathetic activation after myocardial infarction (MI) leads to ventricular arrhythmias (VAs), which can result in sudden cardiac death (SCD). The toll‐like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/nuclear factor‐kappa B (NF‐kB) axis within the hypothalamic paraventricular nucleus (PVN), a cardiac‐neural sympathetic nerve centre, plays an important role in causing VAs. An MI rat model and a PVN‐TLR4 knockdown model were constructed. The levels of protein were detected by Western blotting and immunofluorescence, and localizations were visualized by multiple immunofluorescence staining. Central and peripheral sympathetic activation was visualized by immunohistochemistry for c‐fos protein, renal sympathetic nerve activity (RSNA) measurement, heart rate variability (HRV) analysis and norepinephrine (NE) level detection in serum and myocardial tissue measured by ELISA. The arrhythmia scores were measured by programmed electrical stimulation (PES), and cardiac function was detected by the pressure–volume loop (P‐V loop). The levels of TLR4 and MyD88 and the nuclear translocation of NF‐kB within the PVN were increased after MI, while sympathetic activation and arrhythmia scores were increased and cardiac function was decreased. However, inhibition of TLR4 significantly reversed these conditions. PVN‐mediated sympathetic activation via the TLR4/MyD88/NF‐kB axis ultimately leads to the development of VAs after MI.

An immune-sympathetic neuron communication axis guides adipose tissue browning in cancer-associated cachexia

Cancer-associated cachexia (CAC) is a hypermetabolic syndrome characterized by unintended weight loss due to the atrophy of adipose tissue and skeletal muscle. A phenotypic switch from white to beige adipocytes, a phenomenon called browning, accelerates CAC by increasing the dissipation of energy as heat. Addressing the mechanisms of white adipose tissue (WAT) browning in CAC, we now show that cachexigenic tumors activate type 2 immunity in cachectic WAT, generating a neuroprotective environment that increases peripheral sympathetic activity. Increased sympathetic activation, in turn, results in increased neuronal catecholamine synthesis and secretion, β-adrenergic activation of adipocytes, and induction of WAT browning. Two genetic mouse models validated this progression of events. 1) Interleukin-4 receptor deficiency impeded the alternative activation of macrophages, reduced sympathetic activity, and restrained WAT browning, and 2) reduced catecholamine synthesis in peripheral dopamine β-hydroxylase (DBH)-deficient mice prevented cancer-induced WAT browning and adipose atrophy. Targeting the intraadipose macrophage-sympathetic neuron cross-talk represents a promising therapeutic approach to ameliorate cachexia in cancer patients.

Autonomic control of cerebral blood flow: fundamental comparisons between peripheral and cerebrovascular circulations in humans.

Understanding the contribution of the autonomic nervous system to cerebral blood flow (CBF) control is challenging, and interpretations are unclear. The identification of calcium channels and adrenoreceptors within cerebral vessels has led to common misconceptions that the function of these receptors and actions mirror those of the peripheral vasculature. This review outlines the fundamental differences and complex actions of cerebral autonomic activation compared with the peripheral circulation. Anatomical differences, including the closed nature of the cerebrovasculature, and differential adrenoreceptor subtypes, density, distribution and sensitivity, provide evidence that measures on peripheral sympathetic nerve activity cannot be extrapolated to the cerebrovasculature. Cerebral sympathetic nerve activity seems to act opposingly to the peripheral circulation, mediated at least in part by changes in intracranial pressure and cerebral blood volume. Additionally, heterogeneity in cerebral adrenoreceptor distribution highlights region-specific autonomic regulation of CBF. Compensatory chemo- and autoregulatory responses throughout the cerebral circulation, and interactions with parasympathetic nerve activity are unique features to the cerebral circulation. This crosstalk between sympathetic and parasympathetic reflexes acts to ensure adequate perfusion of CBF to rising and falling perfusion pressures, optimizing delivery of oxygen and nutrients to the brain, while attempting to maintain blood volume and intracranial pressure. Herein, we highlight the distinct similarities and differences between autonomic control of cerebral and peripheral blood flow, and the regional specificity of sympathetic and parasympathetic regulation within the cerebrovasculature. Future research directions are outlined with the goal to further our understanding of autonomic control of CBF in humans.

Fetal Undernutrition Programming, Sympathetic Nerve Activity, and Arterial Hypertension Development.

A wealth of evidence showed that low birth weight is associated with environmental disruption during gestation, triggering embryotic or fetal adaptations and increasing the susceptibility of progeny to non-communicable diseases, including metabolic and cardiovascular diseases, obesity, and arterial hypertension. In addition, dietary disturbance during pregnancy in animal models has highlighted mechanisms that involve the genesis of arterial hypertension, particularly severe maternal low-protein intake (LP). Functional studies demonstrated that maternal low-protein intake leads to the renal decrease of sodium excretion and the dysfunction of the renin-angiotensin-aldosterone system signaling of LP offspring. The antinatriuretic effect is accentuated by a reduced number of nephron units and glomerulosclerosis, which are critical in establishing arterial hypertension phenotype. Also, in this way, studies have shown that the overactivity of the central and peripheral sympathetic nervous system occurs due to reduced sensory (afferent) renal nerve activity. As a result of this reciprocal and abnormal renorenal reflex, there is an enhanced tubule sodium proximal sodium reabsorption, which, at least in part, contributes directly to arterial hypertension development in some of the programmed models. A recent study has observed that significant changes in adrenal medulla secretion could be involved in the pathophysiological process of increasing blood pressure. Thus, this review aims to compile studies that link the central and peripheral sympathetic system activity mechanisms on water and salt handle and blood pressure control in the maternal protein-restricted offspring. Besides, these pathophysiological mechanisms mainly may involve the modulation of neurokinins and catecholamines pathways.