Sympathetic Activity Research Articles

Enhancing motor performance through brief skin cooling: exploring the role of enhanced sympathetic tone and muscle spindle sensitivity

Enhancing motor performance through brief skin cooling: exploring the role of enhanced sympathetic tone and muscle spindle sensitivity

Organ-specific Sympathetic Innervation Defines Visceral Functions.

The autonomic nervous system orchestrates the brain and body functions through the sympathetic and parasympathetic pathways. However, our understanding of the autonomic system, especially the sympathetic system, at the cellular and molecular levels is severely limited. Here, we show unique topological representations of individual visceral organs in the major abdominal sympathetic ganglion complex. Using multi-modal transcriptomic analyses, we identified distinct sympathetic populations that are both molecularly and spatially separable in the celiac-superior mesenteric ganglia (CG-SMG). Notably, individual CG-SMG populations exhibit selective and mutually exclusive axonal projections to visceral organs, targeting either the gastrointestinal (GI) tract or secretory areas including the pancreas and bile tract. This combinatorial innervation pattern suggests functional segregation between different CG-SMG populations. Indeed, our neural perturbation experiments demonstrated that one class of neurons selectively regulates GI food transit. Another class of neurons controls digestion and glucagon secretion independent of gut motility. These results reveal the molecularly diverse sympathetic system and suggest modular regulations of visceral organ functions through distinct sympathetic populations.

Autonomic nervous system activity correlates with peak experiences induced by DMT and predicts increases in well-being.

Non-ordinary states of consciousness induced by psychedelics can be accompanied by so-called "peak experiences," characterized at the emotional level by their intensity and positive valence. These experiences are strong predictors of positive outcomes following psychedelic-assisted therapy, and it is therefore important to better understand their biology. Despite growing evidence that the autonomic nervous system (ANS) plays an important role in mediating emotional experiences, its involvement in the psychedelic experience is poorly understood. The aim of this study was to investigate to what extent changes in the relative influence of the sympathetic (SNS) and parasympathetic nervous systems (PNS) over cardiac activity may reflect the subjective experience induced by the short-acting psychedelic N,N-Dimethyltryptamine (DMT). We derived measures of SNS and PNS activity from the electrocardiograms of 17 participants (11 males, mean age = 33.8 years, SD = 8.3) while they received either DMT or placebo. Results show that the joint influence of SNS and PNS ("sympathovagal coactivation") over cardiac activity was positively related to participants' ratings of "Spiritual Experience" and "Insightfulness" during the DMT experience, while also being related to improved well-being scores 2 weeks after the session. In addition, we found that the state of balance between the two ANS branches ("sympathovagal balance") before DMT injection predicted scores of "Insightfulness" during the DMT experience, as well as subsequent sympathovagal coactivation. These findings demonstrate the involvement of the ANS in psychedelic-induced peak experiences and may pave the way to the development of biofeedback-based tools to enhance psychedelic therapy.

Sympathetic innervation of interscapular brown adipose tissue is not a predominant mediator of OT-elicited reductions of body weight gain and adiposity in male diet-induced obese rats.

Recent studies indicate that central administration of oxytocin (OT) reduces body weight (BW) in high fat diet-induced obese (DIO) rodents by reducing energy intake and increasing energy expenditure (EE). Previous studies in our lab have shown that administration of OT into the fourth ventricle (4V; hindbrain) elicits weight loss and stimulates interscapular brown adipose tissue temperature (TIBAT) in DIO rats. We hypothesized that OT-elicited stimulation of sympathetic nervous system (SNS) activation of IBAT contributes to its ability to activate BAT and reduce BW in DIO rats. To test this, we determined the effect of disrupting SNS activation of IBAT on OT-elicited stimulation of TIBAT and reduction of BW in DIO rats. We first confirmed that bilateral surgical SNS denervation to IBAT was successful based on having achieved ≥ 60% reduction in IBAT norepinephrine (NE) content from DIO rats. NE content was selectively reduced in IBAT by 94.7 ± 2.7, 96.8 ± 1.8 and 85.9 ± 6.1% (P<0.05) at 1, 6 and 7-weeks post-denervation, respectively, and was unchanged in liver or inguinal white adipose tissue. We then measured the impact of bilateral surgical SNS denervation to IBAT on the ability of acute 4V OT (1, 5 μg) to stimulate TIBAT in DIO rats. We found that the high dose of 4V OT (5 μg) stimulated TIBAT similarly between sham and denervated rats (P=NS) and that the effects of 4V OT to stimulate TIBAT did not require beta-3 adrenergic receptor signaling. We subsequently measured the effect of bilateral surgical denervation of IBAT on the effect of chronic 4V OT (16 nmol/day) or vehicle infusion to reduce BW, adiposity and energy intake in DIO rats. Chronic 4V OT reduced BW gain by -7.2 ± 9.6 g and -14.1 ± 8.8 g in sham and denervated rats (P<0.05 vs vehicle treatment), respectively, and this effect was similar between groups (P=NS). These effects were associated with reductions in adiposity and energy intake (P<0.05). Collectively, these findings support the hypothesis that sympathetic innervation of IBAT is not required for central OT to increase BAT thermogenesis and reduce BW gain and adiposity in male DIO rats.

HDAC5 controls a hypothalamic STAT5b-TH axis, the sympathetic activation of ATP-consuming futile cycles and adult-onset obesity in male mice

With age, metabolic perturbations accumulate to elevate our obesity burden. While age-onset obesity is mostly driven by a sedentary lifestyle and high calorie intake, genetic and epigenetic factors also play a role. Among these, members of the large histone deacetylase (HDAC) family are of particular importance as key metabolic determinants for healthy ageing, or metabolic dysfunction. Here, we aimed to interrogate the role of class 2 family member HDAC5 in controlling systemic metabolism and age-related obesity under non-obesogenic conditions. Starting at 6 months of age, we observed adult-onset obesity in chow-fed male global HDAC5-KO mice, that was accompanied by marked reductions in adrenergic-stimulated ATP-consuming futile cycles, including BAT activity and UCP1 levels, WAT-lipolysis, skeletal muscle, WAT and liver futile creatine and calcium cycles, and ultimately energy expenditure. Female mice did not differ between genotypes. The lower peripheral sympathetic nervous system (SNS) activity in mature male KO mice was linked to higher dopaminergic neuronal activity within the dorsomedial arcuate nucleus (dmARC) and elevated hypothalamic dopamine levels. Mechanistically, we reveal that hypothalamic HDAC5 acts as co-repressor of STAT5b over the control of Tyrosine hydroxylase (TH) gene transactivation, which ultimately orchestrates the activity of dmARH dopaminergic neurons and energy metabolism in male mice under non-obesogenic conditions.

Elevated correlations in cardiac–neural dynamics: An impact of mantra meditation on stress alleviation

Mantra meditation is a widely practiced technique with a demonstrated ability to promote relaxation and alleviate stress. This study aims to evaluate the impact of regular mantra meditation practice on electroencephalogram (EEG) patterns and heart rate variability (HRV) in young adults grappling with increased stress levels. Furthermore, the study explored possible correlations between these two physiological markers. Thirty-eight participants practiced mantra meditation for eight weeks, and their EEG and HRV were recorded before and after. The pre-post analysis evaluated brain activity and autonomic nervous system regulation alterations by examining EEG and HRV in the time, frequency, and nonlinear domains. Data analysis revealed significant correlations between EEG patterns and HRV indices following mantra meditation, suggesting a potential interconnection between neural and cardiovascular regulation. A notable increase in Root Mean Square of Successive Differences (RMSSD) and Standard Deviation of NN intervals (SDNN) within HRV, along with a decrease in Heart Rate (HR) and Stress Index (SI) and an increase in EEG alpha and theta power, accompanied by a reduction in their ratio, was observed. Three pivotal correlations consistently increased during eight weeks: Alpha/Theta Ratio (ATR) with Low-Frequency/High-Frequency Ratio (LHR), ATR with SD2/SD1 Ratio (SDR), and Relaxation Index (RI) with Stress Index (SI). After eight weeks, these correlations attained statistical significance, optimizing the balance between calmness and vigilance, boosting parasympathetic activity, and reducing chaos between the parasympathetic and sympathetic systems. The study elucidates the scientific mechanisms of mantra meditation, enriching research on its stress-reducing effects and emphasizing mental and physical well-being.

Cardiovascular dysautonomia and cognitive impairment in Parkinson's disease (Review).

Cognitive impairment is a prevalent non-motor symptom of Parkinson's disease (PD), which can result in significant disability and distress for patients and caregivers. There is a marked variation in the timing, characteristics and rate at which cognitive decline occurs in patients with PD. This decline can vary from normal cognition to mild cognitive impairment and dementia. Cognitive impairment is associated with several pathophysiological mechanisms, including the accumulation of β-amyloid and tau in the brain, oxidative stress and neuroinflammation. Cardiovascular autonomic dysfunctions are commonly observed in patients with PD. These dysfunctions play a role in the progression of cognitive impairment, the incidents of falls and even in mortality. The majority of symptoms of dysautonomia arise from changes in the peripheral autonomic nervous system, including both the sympathetic and parasympathetic nervous systems. Cardiovascular changes, including orthostatic hypotension, supine hypertension and abnormal nocturnal blood pressure (BP), can occur in both the early and advanced stages of PD. These changes tend to increase as the disease advances. The present review aimed to describe the cognitive changes in the setting of cardiovascular dysautonomia and to discuss strategies through which these changes can be modified and managed. It is a multifactorial process usually involving decreased blood flow to the brain, resulting in the development of cerebral ischemic lesions, an increased presence of abnormal white matter signals in the brain, and a potential influence on the process of neurodegeneration in PD. Another possible explanation is this association being independent observations of PD progression. Patients with clinical symptoms of dysautonomia should undergo 24-h ambulatory BP monitoring, as they are frequently subtle and underdiagnosed.

Low-intensity focused ultrasound combined with microbubbles for non-invasive downregulation of rabbit carotid body activity in the treatment of hypertension.

Targeting the carotid body (CB) is a new approach in treating hypertension. This study investigates the efficacy and safety of ultrasound combined with microbubbles in targeting CB to treat hypertension. Twenty-seven hypertensive rabbits were randomly assigned to three groups: microbubbles only (sham group, n = 11), ultrasound plus microbubbles (LIFU group, n = 11), and bilateral carotid sinus nerve denervation (CSND group, n = 5). Four weeks post-intervention, blood pressure, hypoxic ventilatory response (HVR), blood pressure variability (BPV), heart rate variability (HRV), biochemical indicators, neurohormones, and histopathology were assessed in all groups. The results indicated significant reductions in systolic and diastolic blood pressure in the LIFU and CSND groups post-intervention, along with decreases in BPV, HRV, and catecholamines. HVR results showed a 35.10% reduction in CB activity in the LIFU group compared to the sham group, which was significantly lower than the reduction in the CSND group compared to the sham group (73.85%). Histopathology and transmission electron microscopy confirmed CB damage and cell apoptosis, with immunofluorescence showing a reduction in type I and II cells. In conclusion, LIFU combined with microbubbles can reduce blood pressure by lowering CB and sympathetic nerve activity.

Rita Levi-Montalcini: From Persecution to the Nobel Prize and an Honorary Degree From a Canadian University.

Rita Levi-Montalcini (RLM) is recognized as a prestigious and renowned researcher of her time. She was the fourth woman to earn the Nobel Prize in Physiology and Medicine in 1986 for the discovery of nerve growth factor (NGF). We review her biography and scientific discovery, and provide an example of why her discovery is still important. She had a special relationship with McGill University, Canada, which we describe. We searched for articles and books about her for biographical and scientific material and met with Dr. Claudio Cuello, Former Chair of McGill's Faculty of Medicine. RLM was born in 1909 in Turin, Italy, where she had studied medicine. She started her career in research. Because of the anti-Jewish racial laws in Italy in 1938, she went underground and continued her projects in her bedroom. After the war, she visited St. Louis, USA, and conducted research there. Her experiments confirmed that tumors release a factor that causes nerve growth and cancer proliferation. Initially, scientists responded to this discovery with skepticism, but after its purification in 1959 and determination of its protein structure in 1971, NGF became widely accepted.Currently, crosstalk between cancers and nerves is poorly understood. The example of prostate cancer shows that surgical or chemical denervation of sympathetic nerves prevents the initiation of prostate tumors, whereas inhibition of parasympathetic nerve signaling reduces the spread of prostate cancer. McGill University awarded RLMa doctoral degree in 2011. It was the first time in itshistory that the University awarded an honorary doctorate outside of Canada, and the second one outside of Quebec.Through her discovery of NGF, RLM exemplified the power of passion and determination despite the obstacles she faced. Her relentless dedication has led to remarkable achievements.

Rat Sympathetic Neuron Calcium Channels Are Insensitive to Gabapentin.

The gabapentenoids such as gabapentin (GP) and pregabalin are approved for the treatment of chronic pain, but their utility is limited by persistent side effects. These adverse effects result from GPs affecting many types of neurons and muscle cells, not just the pain-sensing neurons that are the intended targets. We have recently discovered a type of peripheral neuron, rat sympathetic neurons from the superior cervical ganglion (SCG), that is uniquely insensitive to GP effects. Currents were measured using whole-cell patch-clamp electrophysiology from cells in primary culture from either the SCG or the Nodose Ganglion (NDG) as a positive control for the effects of GP. We find that the calcium current density was dramatically reduced by GP pretreatment in NDG neurons, but that neurons from the SCG were resistant. Further, when GP was cytoplasmically injected into these neurons, the resistance of SCG neurons to GP treatment persisted. These data demonstrate that rat sympathetic neurons appear to be uniquely resistant to GP treatment. These results may help us to better understand the mechanism of action of, and resistance to, GP in altering calcium channel current density, which may help to develop future treatments with fewer side effects.

Long-term effects of siponimod on cardiovascular and autonomic nervous system in secondary progressive multiple sclerosis.

Siponimod, a second-generation, selective sphingosine 1-phosphate receptor (S1PR) 1 and 5 modulator, represents an important therapeutic choice for active secondary progressive multiple sclerosis (SPMS). Besides the beneficial immunomodulatory effects, siponimod impacts cardiovascular function through S1PR1 modulation. Short-term vagomimetic effects on cardiac activity have proved to be mitigated by dose titration. However, long-term consequences are less known. This study aimed to investigate the long-term impact of siponimod on cardiac autonomic modulation in people with SPMS (pwSPMS). Heart rate variability (HRV) and vascular hemodynamic parameters were evaluated using Multiple Trigonometric Regressive Spectral analysis in 47 pwSPMS before siponimod therapy and after one, three, six and 12months of treatment. Autonomic activation tests (tilt test for the sympathetic and deep breathing test for the parasympathetic cardiac modulation) were performed at each examination. pwSPMS preserved regular cardiovascular modulation responses during the autonomic tests reflected in the variation of several HRV parameters, such as RMSSD, pNN50, total power of HRV, high-frequency and low-frequency bands of the spectral domain or hemodynamic vascular parameters (Cwk, Zao, TPR, MAP) and baroreflex sensitivity (BRS). In the long-term follow-up, RMSSD, pNN50, total power, BRS and CwK presented a significant decrease, underlining a reduction of the parasympathetic and a shift towards sympathetic predominance in cardiac autonomic modulation that tends to stabilise after 1year of treatment. Due to dose titration, the short-term effects of siponimod on cardiac autonomic modulation are mitigated. The long-term impact on cardiac autonomic modulation is similar to fingolimod. The autonomic activation tests showed normal cardiovascular responses during 1-year follow-up in pwSPMS, confirming the safety profile of siponimod. Further research on autonomic function could reveal whether the observed sympathetic activation is a compensatory response to S1P signaling intervention or a feature of the disease, while also shedding light on the role of S1PR modulation in MS.

Natural killer cells in neuroblastoma: immunological insights and therapeutic perspectives.

Natural killer (NK) cells have multifaceted roles within the complex tumor milieu. They are pivotal components of innate immunity and shape the dynamic landscape of tumor-immune cell interactions, and thus can be leveraged for use in therapeutic interventions. NK-based immunotherapies have had remarkable success in hematological malignancies, but these therapies are met with many challenges in solid tumors, including neuroblastoma (NB), a childhood tumor arising from the sympathetic nervous system. With a focus on NB, this review outlines the mechanisms employed by NK cells to recognize and eliminate malignant cells, delving into the dynamic relationship between ligand-receptor interactions, cytokines, and other molecules that facilitate the cross talk between NK and NB cells. We discuss the immunomodulatory functions of NK cells and the mechanisms that contribute to loss of this immunosurveillance in NB, with a focus on how this dynamic has been utilized in recent immunotherapy advancements for NB.

Cytokines reprogram airway sensory neurons in asthma.

Nociceptor neurons play a crucial role in maintaining the body's homeostasis by detecting and responding to potential dangers in the environment. However, this function can be detrimental during allergic reactions, since vagal nociceptors can contribute to immune cell infiltration, bronchial hypersensitivity, and mucus imbalance, in addition to causing pain and coughing. Despite this, the specific mechanisms by which nociceptors acquire pro-inflammatory characteristics during allergic reactions are not yet fully understood. In this study, we aimed to investigate the molecular profile of airway nociceptor neurons during allergic airway inflammation and identify the signals driving such reprogramming. Using retrograde tracing and lineage reporting, we identified a unique class of inflammatory vagal nociceptor neurons that exclusively innervate the airways. In the ovalbumin mouse model of airway inflammation, these neurons undergo significant reprogramming characterized by the upregulation of the NPY receptor Npy1r. A screening of cytokines and neurotrophins revealed that IL-1β, IL-13 and BDNF drive part of this reprogramming. IL-13 triggered Npy1r overexpression in nociceptors via the JAK/STAT6 pathway. In parallel, sympathetic neurons and macrophages release NPY in the bronchoalveolar fluid of asthmatic mice, which limits the excitability of nociceptor neurons. Single-cell RNA sequencing of lung immune cells has revealed that a cell-specific knockout of Npy1r in nociceptor neurons in asthmatic mice leads to an increase in airway inflammation mediated by T cells. Opposite findings were observed in asthmatic mice in which nociceptor neurons were chemically ablated. In summary, allergic airway inflammation reprograms airway nociceptor neurons to acquire a pro-inflammatory phenotype, while a compensatory mechanism involving NPY1R limits nociceptor neurons' activity.

Expansion of a neural crest gene signature following ectopic MYCN expression in sympathoadrenal lineage cells in vivo.

Neural crest cells (NCC) are multipotent migratory stem cells that originate from the neural tube during early vertebrate embryogenesis. NCCs give rise to a variety of cell types within the developing organism, including neurons and glia of the sympathetic nervous system. It has been suggested that failure in correct NCC differentiation leads to several diseases, including neuroblastoma (NB). During normal NCC development, MYCN is transiently expressed to promote NCC migration, and its downregulation precedes neuronal differentiation. Overexpression of MYCN has been linked to high-risk and aggressive NB progression. For this reason, understanding the effect overexpression of this oncogene has on the development of NCC-derived sympathoadrenal progenitors (SAP), which later give rise to sympathetic nerves, will help elucidate the developmental mechanisms that may prime the onset of NB. Here, we found that overexpressing human EGFP-MYCN within SAP lineage cells in zebrafish led to the transient formation of an abnormal SAP population, which displayed expanded and elevated expression of NCC markers while paradoxically also co-expressing SAP and neuronal differentiation markers. The aberrant NCC signature was corroborated with in vivo time-lapse confocal imaging in zebrafish larvae, which revealed transient expansion of sox10 reporter expression in MYCN overexpressing SAPs during the early stages of SAP development. In these aberrant MYCN overexpressing SAP cells, we also found evidence of dampened BMP signaling activity, indicating that BMP signaling disruption occurs following elevated MYCN expression. Furthermore, we discovered that pharmacological inhibition of BMP signaling was sufficient to create an aberrant NCC gene signature in SAP cells, phenocopying MYCN overexpression. Together, our results suggest that MYCN overexpression in SAPs disrupts their differentiation by eliciting abnormal NCC gene expression programs, and dampening BMP signaling response, having developmental implications for the priming of NB in vivo.

Intestinal gluconeogenesis controls the neonatal development of hypothalamic feeding circuits

ObjectiveIntestinal gluconeogenesis (IGN) regulates adult energy homeostasis in part by controlling the same hypothalamic targets as leptin. In neonates, leptin exhibits a neonatal surge controlling axonal outgrowth between the different hypothalamic nuclei involved in feeding circuits and autonomic innervation of peripheral tissues involved in energy and glucose homeostasis. Interestingly, IGN is induced during this specific time-window. We hypothesized that the neonatal pic of IGN also regulates the development of hypothalamic feeding circuits and sympathetic innervation of adipose tissues. MethodsWe genetically induced neonatal IGN by overexpressing G6pc1 the catalytic subunit of glucose-6-phosphatase (the mandatory enzyme of IGN) at birth or at twelve days after birth. The neonatal development of hypothalamic feeding circuits was studied by measuring Agouti-related protein (AgRP) and Pro-opiomelanocortin (POMC) fiber density in hypothalamic nuclei of 20-day-old pups. The effect of the neonatal induction of intestinal G6pc1 on sympathetic innervation of the adipose tissues was studied via tyrosine hydroxylase (TH) quantification. The metabolic consequences of the neonatal induction of intestinal G6pc1 were studied in adult mice challenged with a high-fat/high-sucrose (HFHS) diet for 2 months. ResultsInduction of intestinal G6pc1 at birth caused a neonatal reorganization of AgRP and POMC fiber density in the paraventricular nucleus of the hypothalamus, increased brown adipose tissue tyrosine hydroxylase levels, and protected against high-fat feeding-induced metabolic disorders. In contrast, inducing intestinal G6pc1 12 days after birth did not impact AgRP/POMC fiber densities, adipose tissue innervation or adult metabolism. ConclusionThese findings reveal that IGN at birth but not later during postnatal life controls the development of hypothalamic feeding circuits and sympathetic innervation of adipose tissues, promoting a better management of metabolism in adulthood.

Low-Level Tragus Stimulation Attenuates Blood Pressure in Young Individuals With Hypertension: Results From a Small-Scale Single-Blind Controlled Randomized Clinical Trial.

Hypertension is a significant risk factor for cardiovascular and chronic kidney diseases. Its management in young people remains limited. Device-based therapies, such as low-level tragus stimulation (LL-TS), a noninvasive method that reduces sympathetic activity, have recently been explored for resistant hypertension. This trial involved patients with Grade 1 hypertension with no other medical history. LL-TS (20 Hz, 1 mA, 1 h/day) was applied for 3 months on the tragus (Intervention group [IG]) or earlobe (Control group [CG]). Blood pressure and outcomes were assessed at the first, second, and third months. Among 40 patients, 21 were in IG and 19 in CG. Baseline systolic blood pressure was similar between IG (142.62±8.18 mm Hg) and CG (143.00±8.61 mm Hg), P=0.89. Post-LL-TS, systolic blood pressure showed significant reductions in IG compared with CG at the first (IG: 134.47±5.95 mm Hg, CG: 141.28±6.78 mm Hg, P=0.002), second (IG: 132.50±7.51 mm Hg, CG: 140.62±7.15 mm Hg, P=0.001), and third months (IG: 128.81±7.13 mm Hg, CG: 136.51±7.96 mm Hg, P=0.003). diastolic blood pressure also differed significantly: first month (IG: 85.34±5.81 mm Hg, CG: 89.74±6.32 mm Hg, P=0.03), second month (IG: 82.12±5.22 mm Hg, CG: 88.57±7.11 mm Hg, P=0.002), and third month (IG: 80.71±5.96 mm Hg, CG: 87.55±5.26 mm Hg, P=0.001). Heart rate was unchanged (P>0.05). Only 0.01% of IG subjects reported site irritation, with no serious adverse events. LL-TS led to significant blood pressure reductions in young patients with essential hypertension. Further larger trials are needed to confirm the safety and efficacy of LL-TS. URL: https://www.chictr.org.cn/; Unique identifier: ChiCTR2000038448.

Cold Pressor Test Induces Significant Changes in Internal Jugular Vein Flow Dynamics in Healthy Young Adults.

BACKGROUND The cold pressor test (CPT), which has long been used to test autonomic functions by causing sympathetic excitation, increases systolic and diastolic blood pressure and heart rate and causes coronary vasodilation within physiological limits in healthy individuals. This study aimed to evaluate internal jugular vein (IJV) flow parameters using the CPT with systolic and diastolic blood pressure and heart rate in 40 healthy volunteers aged 18-40 years. MATERIAL AND METHODS The volunteers' IJV diameter, blood flow peak velocity, and volumetric flow values were recorded. Then, their right hands were immersed in a bucket of cold water maintained at 1°C up to the wrist level. At the end of the first minute (CPT-1), systolic and diastolic blood pressure, heart rhythm, IJV diameter, peak velocity, and volumetric flow measurements were performed again. RESULTS Systolic and diastolic blood pressure values were significantly higher at CPT-1 compared to baseline values (P<0.001, P<0.001). Heart rate and peak velocity values also showed a significant increase at CPT-1 compared to baseline values (P<0.001, P=0.001). While diameter values showed a significant decrease compared to baseline, volumetric flow rate values showed a significant increase at CPT-1 (P=0.003, P<0.001). CONCLUSIONS Sympathetic nervous system activation triggered by CPT increases IJV volumetric flow and flow velocity in healthy young individuals, and sympathetic nervous system activation causes a venoconstrictive effect in the IJV.

A Closed-Loop Nanosystem Based on Piezoelectric Sensor and Pd-Nanoshell Photothermal Ablation for Renal Denervation to Treat Hypertension.

Renal sympathetic nerves play a crucial role in the pathogenesis of hypertension, and renal denervation (RDN) is a new solution for patients with refractory hypertension. However, current RDN techniques show inconsistent results in clinical application probably owing to incomplete endovascular ablation of the sympathetic nerves and a lack of measures to localize and assess efficacy. In this study, a closed-loop RDN system consisting of a sensing unit with a piezoelectric thin-film sensor (PTFS) and a treatment unit with a hollow Pd nanoparticle shell (PdNPS) with a diameter of 202.0nm for photothermal neural ablation is constructed. The PTFS can monitor and collect arterial pulsation and blood pressure (BP) and direct PdNPS to maximize RDN. PdNPS maintains a local temperature of 58-62°C under near-infrared-II irradiation (1,064nm) to achieve effective RDN within a range of 90-120s treatment window. Photothermal ablation significantly inhibits the activities of renal sympathetic nerves post-procedure and after one month and reduces the elevation of BP by > 50%. The novel closed-loop system enables safe and efficient targeting, dynamic monitoring, and ablation of the renal sympathetic nerves. This closed-loop system provides a new strategy for RDN technology and even for treating sympathetic nerve-related chronic diseases.

Epigallocatechin gallate enhances sympathetic heart rate variability and decreases blood pressure in obese subjects: a randomized control trial

This study aimed to investigate effects of epigallocatechin gallate (EGCG) on blood pressure (BP) and autonomic nervous system, indicated by 5-min heart rate variability (HRV) measurement in obese subjects, and determine correlations of BP with metabolic factors. In a double-blind, randomized controlled trial, obese subjects (n = 30) were randomly allocated to receive 150 mg EGCG (n = 15) or placebo (n = 15) twice a day without dietary restrictions. After 8-week EGCG treatment, systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) significantly decreased, while the low-frequency (LF) to high-frequency power (HF) ratio (LF/HF ratio) significantly increased (P < 0.05 all), indicating a shift toward sympathetic dominance, either directly or indirectly after BP lowering. SBP had positive correlations with obesity parameters, leptin, insulin, and insulin resistance but had a negative correlation with insulin sensitivity. DBP was positively correlated with age and HF in normalized unit, but negatively correlated with height and LF in ms2. High-density lipoprotein cholesterol (HDL-C) was negatively correlated with SBP, DBP, and MAP reflecting its protective effect against elevated BP. In conclusion, the 8-week EGCG treatment decreased BP and increased the LF/HF ratio, reflecting increased sympathetic activity, either a direct EGCG effect or an indirect compensatory response following BP reduction.

Abstract A041: Deciphering the bidirectional influences of sympathetic neurons and cancer associated fibroblasts and the resulting contributions to PDAC progression

Abstract The pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME) is innervated by a variety of peripheral nerves that are emerging as facilitators of tumor initiation, progression and metastasis. However, the influences of sympathetic nerves on the TME and how these bi-directional interactions can exacerbate PDAC progression remains unclear. Sympathetic nerves innervate both human and murine PDAC tumors and are frequently surrounded by abundant and heterogeneous cancer-associated fibroblasts (CAFs), which are known to play various crucial roles in PDAC progression. In our studies, we aim to elucidate the bidirectional CAF and sympathetic-neuron crosstalk that may promote tumor growth using a variety of in vitro coculture systems to model sympathetic-CAF interactions, as well as in vivo modeling of nerves in murine PDAC tumors. Our nerve-CAF cocultures reveal that CAFs closely and frequently interact with sympathetic nerves, and also enhance sympathetic nerve outgrowth. We further sequenced these cocultured conditions to evaluate intrinsic transcriptional changes that may be contributing to the enhanced nerve outgrowth. We identified several genes that may contribute to upregulated CAF adhesion, ECM deposition and neuroactive ligand-receptor interactions, which may also be supportive of the axon outgrowth and tumor cell growth. We are also currently characterizing human and murine PDAC samples that contain and lack sympathetic innervation to evaluate spatial phenotypic shifts within the TME. Collectively, our results suggest that this crosstalk between sympathetic neurons and CAFs may both enhance tumor innervation and tumor-promoting phenotypes in the TME, such as axonogenesis and fibrosis in PDAC. Citation Format: Ariana Sattler, Parham Diba, Tetiana Korzun, Marigold Kuykendall, Kevin MacPherson-Hawthorne, Mara Sherman, Teresa Zimmers, Sebnem E Eksi. Deciphering the bidirectional influences of sympathetic neurons and cancer associated fibroblasts and the resulting contributions to PDAC progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A041.