Changes In Sympathetic Outflow Research Articles

Neural-Cardiovascular Responses to Orthostasis Following 8-Weeks of Home-Based Lower Leg Heating in Older Women with Hypertension

Background: Hypertension remains a significant health problem for older women (≥60 y). Though effective blood pressure (BP) interventions exist (e.g., exercise, medication), adherence to these options is low. Lower leg heat therapy represents a promising and easily implementable adjuvant treatment that may offer cardioprotective benefits. However, no studies have investigated lower leg heat therapy’s effects on BP and neural-cardiovascular function, let alone in older women with hypertension. Accordingly, we hypothesized that 8-weeks of home-based lower leg heat therapy in older women with hypertension would 1) reduce ambulatory BP and 2) reduce muscle sympathetic nerve activity (MSNA) while augmenting cardiac output and stroke volume during graded head-up tilt (HUT). Methods: Forty older women with hypertension (69 ± 5 y [mean±SD]) were randomized to either heat therapy (INT, 42°C; n = 20) or a thermoneutral control (CON, 35°C; n = 20). Each woman completed 8 wks of at-home sessions (~4/wk; 45 min/session) immersing their legs ~33 cm in a portable spa bath. 24-h ambulatory BP was measured pre- (PRE) and post-intervention (POST). A subset of women (n = 18 for each group) completed supine rest and 5 min of 30° and 60° HUT at each time point, whereby laboratory heart rate, systolic and diastolic BP, MSNA burst frequency and incidence (microneurography), cardiac output (acetylene rebreathing), and stroke volume (cardiac output/heart rate) were measured. Results: Between INT and CON, PRE ambulatory awake systolic BP (140 ± 7 vs. 142 ± 6 mmHg; P = 0.34) and diastolic BP (80 ± 6 vs. 79 ± 6 mmHg; P = 0.51) were not different, nor were PRE supine systolic BP, diastolic BP, or heart rate (all P > 0.05). PRE supine resting MSNA burst frequency (36 ± 13 vs. 33 ± 16 bursts/min), MSNA burst incidence (54 ± 19 vs. 51 ± 22 bursts/100 heartbeats), cardiac output (4.9 ± 0.9 vs. 5.1 ± 1.0 L/min), and stroke volume (72 ± 15 vs. 76 ± 15 mL/beat) were not different between groups (all P > 0.05). From PRE to POST neither ambulatory awake systolic nor diastolic BP differed between groups (all P > 0.05). Despite this, POST laboratory systolic and diastolic BP were greater in INT (both P < 0.05) but not in CON (both P > 0.05) during HUT. POST laboratory heart rate was reduced in INT ( P = 0.025), and trended greater in CON ( P = 0.065) across HUT. Neither MSNA burst frequency nor burst incidence changed during HUT PRE to POST (all P > 0.05). Despite no PRE to POST differences in cardiac output in either group (all P > 0.05), INT had a greater overall POST stroke volume throughout HUT ( P = 0.011), while CON had a reduced stroke volume during 60° HUT ( P = 0.036). Conclusions: Contrary to our hypotheses, 8-weeks of home-based lower leg heat therapy did not improve ambulatory BP or HUT MSNA and cardiac output in older women with hypertension. However, women completing INT appeared to have a greater stroke volume and lower heart rate during HUT. Accordingly, these data suggest that 8-weeks of lower leg heat therapy in older women with hypertension may improve cardiac function during orthostasis without significant changes in sympathetic outflow or ambulatory BP. Supported by the National Institutes of Health (R01AG059314 and F32HL167556). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Changes in skin blood flow, respiration and blood pressure in participants reporting motion sickness during sinusoidal galvanic vestibular stimulation.

What is the central question of the study? We have previously shown that sinusoidal galvanic vestibular stimulation induces greater modulation of skin sympathetic nerve activity, but not muscle sympathetic nerve activity, in participants who report nausea during simulated motion, but the effects on skin blood flow and blood pressure are unknown. What is the main finding and its importance? During vestibular stimulation, nausea was associated with a greater increase in skin blood flow and a progressive reduction in skin sympathetic nerve activity, but no changes in muscle sympathetic nerve activity. This emphasizes the differential changes in sympathetic outflow to different tissues during nausea. We tested the hypothesis that galvanic vestibular stimulation, which produces illusions of side-to-side swaying, causes a greater reduction in skin blood flow in participants who report stimulation-induced nausea. A retrospective analysis was performed on data obtained in 30participants. Bipolar sinusoidal galvanic vestibular stimulation (sGVS) was applied across the mastoid processes (±2mA, 0.08Hz) for 21min. ECG, continuous blood pressure, respiration and skin blood flow were recorded. Muscle sympathetic nerve activity was recorded in 17 participants and skin sympathetic nerve activity in 12. Ten participants reported motion sickness, whereas 20 did not. Both groups showed an initial reduction in skin (finger) blood flow during sGVS, followed by a sustained increase and a subsequent return towards baseline levels throughout the stimulation; the increase was greater in those who experienced nausea. The increase fits with the progressive reduction in skin sympathetic nerve activity observed in the nauseous group. Mean blood pressure was significantly lower in those who experienced nausea and showed a much larger increase at the onset of sGVS, compared with those who did not. Moreover, the respiratory rate was higher at the outset for the subjects who experienced nausea, decreasing progressively during sGVS, whereas respiratory rate remained constant in those who did not experience nausea. Heart rate was more labile in the subjects who experienced nausea, showing a sustained increase towards the end of stimulation. We have shown that several autonomic parameters change during the nausea induced by vestibular stimulation, but a sustained decrease in skin blood flow is not a hallmark of incipient motion sickness.

Intermedin in Paraventricular Nucleus Attenuates Ang II-Induced Sympathoexcitation through the Inhibition of NADPH Oxidase-Dependent ROS Generation in Obese Rats with Hypertension.

Increased reactive oxygen species (ROS) induced by angiotensin II (Ang II) in the paraventricular nucleus (PVN) play a critical role in sympathetic overdrive in hypertension (OH). Intermedin (IMD), a bioactive peptide, has extensive clinically prospects in preventing and treating cardiovascular diseases. The study was designed to test the hypothesis that IMD in the PVN can inhibit the generation of ROS caused by Ang II for attenuating sympathetic nerve activity (SNA) and blood pressure (BP) in rats with obesity-related hypertension (OH). Male Sprague-Dawley rats (160–180 g) were used to induce OH by feeding of a high-fat diet (42% kcal as fat) for 12 weeks. The dynamic changes of sympathetic outflow were evaluated as the alterations of renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) responses to certain chemicals. The results showed that the protein expressions of Ang II type 1 receptor (AT1R), calcitonin receptor-like receptor (CRLR) and receptor activity-modifying protein 2 (RAMP2) and RAMP3 were markedly increased, but IMD was much lower in OH rats when compared to control rats. IMD itself microinjection into PVN not only lowered SNA, NADPH oxidase activity and ROS level, but also decreased Ang II-caused sympathetic overdrive, and increased NADPH oxidase activity, ROS levels and mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) activation in OH rats. However, those effects were mostly blocked by the adrenomedullin (AM) receptor antagonist AM22-52 pretreatment. The enhancement of SNA caused by Ang II can be significantly attenuated by the pretreatment of AT1R antagonist lorsatan, superoxide scavenger Tempol and NADPH oxidase inhibitor apocynin (Apo) in OH rats. ERK activation inhibitor U0126 in the PVN reversed Ang II-induced enhancement of SNA, and Apo and IMD pretreatment in the PVN decreased Ang II-induced ERK activation. Chronic IMD administration in the PVN resulted in significant reductions in basal SNA and BP in OH rats. Moreover, IMD lowered NADPH oxidase activity and ROS level in the PVN; reduced the protein expressions of AT1R and NADPH oxidase subunits NOX2 and NOX4, and ERK activation in the PVN; and decreased Ang II levels-inducing sympathetic overactivation. These results indicated that IMD via AM receptors in the PVN attenuates SNA and hypertension, and decreases Ang II-induced enhancement of SNA through the inhibition of NADPH oxidase activity and ERK activation.

Chemoattraction and Recruitment of Activated Immune Cells, Central Autonomic Control, and Blood Pressure Regulation.

Inflammatory mediators play a critical role in the regulation of sympathetic outflow to cardiovascular organs in hypertension. Emerging evidence highlights the involvement of immune cells in the regulation of blood pressure. However, it is still unclear how these immune cells are activated and recruited to key autonomic brain regions to regulate sympathetic outflow to cardiovascular organs. Chemokines such as C-C motif chemokine ligand 2 (CCL2), and pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β), are upregulated both peripherally and centrally in hypertension. More specifically, they are upregulated in key autonomic brain regions that control sympathetic activity and blood pressure such as the paraventricular nucleus of the hypothalamus and the rostral ventrolateral medulla. Furthermore, this upregulation of inflammatory mediators is associated with the infiltration of immune cells to these brain areas. Thus, expression of pro-inflammatory chemokines and cytokines is a potential mechanism promoting invasion of immune cells into key autonomic brain regions. In pathophysiological conditions, this can result in abnormal activation of brain circuits that control sympathetic nerve activity to cardiovascular organs and ultimately in increases in blood pressure. In this review, we discuss emerging evidence that helps explain how immune cells are chemoattracted to autonomic nuclei and contribute to changes in sympathetic outflow and blood pressure.

Sympathetic preganglionic neurons: properties and inputs.

The sympathetic nervous system comprises one half of the autonomic nervous system and participates in maintaining homeostasis and enabling organisms to respond in an appropriate manner to perturbations in their environment, either internal or external. The sympathetic preganglionic neurons (SPNs) lie within the spinal cord and their axons traverse the ventral horn to exit in ventral roots where they form synapses onto postganglionic neurons. Thus, these neurons are the last point at which the central nervous system can exert an effect to enable changes in sympathetic outflow. This review considers the degree of complexity of sympathetic control occurring at the level of the spinal cord. The morphology and targets of SPNs illustrate the diversity within this group, as do their diverse intrinsic properties which reveal some functional significance of these properties. SPNs show high degrees of coupled activity, mediated through gap junctions, that enables rapid and coordinated responses; these gap junctions contribute to the rhythmic activity so critical to sympathetic outflow. The main inputs onto SPNs are considered; these comprise afferent, descending, and interneuronal influences that themselves enable functionally appropriate changes in SPN activity. The complexity of inputs is further demonstrated by the plethora of receptors that mediate the different responses in SPNs; their origins and effects are plentiful and diverse. Together these different inputs and the intrinsic and coupled activity of SPNs result in the rhythmic nature of sympathetic outflow from the spinal cord, which has a variety of frequencies that can be altered in different conditions.

Behavioral activation treatment increases parasympathetic activity in veterans (1130.23)

Behavioral Activation is an effective treatment for depression and other psychological disorders that works by increasing patients’ preferred daily activities, particularly social engagement. Improving social engagement may improve autonomic function by buffering the impact of stress. We tested if Behavioral Activation improves the autonomic function of deployed Veterans. Veterans (n=5) participated in 12 weekly group sessions where they were encouraged to increase daily behaviors including social engagement. During weeks 1, 4, 8 and 12 autonomic function testing was performed including transcranial Doppler in the middle (MCA) and anterior cerebral artery (ACA) as well as blood pressure during several tests (sit to stand, hyper/ hypocapnia, cold presser and paced auditory serial addition test). All Veterans who started the intervention completed the treatment. Our results show an increase in high‐frequency heart rate variability, an autonomic indicator of parasympathetic activity (Week 1; 660K ± 147K, Week 12; 1390K ± 153K). In addition, mean blood pressure decreased over the same time period, although non‐significantly (Week1; 88.4 ± 3.0, Week 12; 83.2 ± 5.3 mmHg). However, no significant reduction of low‐frequency systolic blood pressure or heart rate variance was found, suggesting no change in sympathetic outflow. Our findings, while preliminary, suggest this behavioral intervention focused on improving social engagement may improve autonomic function. Further 100% of participants who started the treatment were adherent. Our preliminary data suggests that Behavioral Activation may be a promising intervention to improve autonomic dysfunction among Veterans.Grant Funding Source: Supported by: Department of Veteran Affairs and The Office of Public Health

Physiology's Impact: Exploring the Mysteries of Life

The discipline of physiology explores the mysteries of life. How is it possible that the same organism can live in a dangerous environment, where extreme ambient temperatures, gravitational forces, oxygen availability, or other abiotic factors impose serious challenges to the maintenance of

Collateralization of projections from the rostral ventrolateral medulla to the rostral and caudal thoracic spinal cord in felines

Stimulation of vestibular receptors elicits distinct changes in blood flow to the forelimb and hindlimb, showing that the nervous system has the capacity to produce changes in sympathetic outflow which are specific for a particular region of the body. However, it is unclear whether the rostral ventrolateral medulla (RVLM), the primary region of the brainstem that regulates sympathetic outflow to vascular smooth muscle, has the appropriate connectivity with sympathetic preganglionic neurons to generate anatomically patterned responses. To make this determination, the retrograde fluorescent tracer Fast Blue was injected into the T(4) spinal cord segment of cats, which regulates upper body blood flow, whereas Fluoro-Ruby was injected into the T(10) segment to label projections to a region of the spinal cord that regulates lower body blood flow. More neurons were single-labeled by a particular tracer (92 %) than were double labeled by both tracers (8 %), supporting the notion that the RVLM can regulate sympathetic outflow from a limited number of spinal cord segments. Since a large fraction of RVLM neurons that control sympathetic outflow in rodents contain epinephrine, we additionally determined whether the tracer-labeled cells were immunopositive for the enzyme tyrosine hydroxylase (TH), which participates in the synthesis of catecholamines. Double labeling by the two tracers injected into the spinal cord was more common for TH-immunopositive neurons than for the general population of RVLM neurons: 19 % of the TH-positive cells contained both Fast Blue and Fluoro-Ruby, 30 % contained one of the tracers, and 51 % were not labeled by either tracer. Furthermore, many spinally projecting neurons in close proximity to the RVLM catecholaminergic neurons (41 % of the population) were not immunopositive for TH, suggesting that feline RVLM is neurochemically heterogeneous.

The physiological origin of task-evoked systemic artefacts in functional near infrared spectroscopy.

A major methodological challenge of functional near-infrared spectroscopy (fNIRS) is its high sensitivity to haemodynamic fluctuations in the scalp. Superficial fluctuations contribute on the one hand to the physiological noise of fNIRS, impairing the signal-to-noise ratio, and may on the other hand be erroneously attributed to cerebral changes, leading to false positives in fNIRS experiments. Here we explore the localisation, time course and physiological origin of task-evoked superficial signals in fNIRS and present a method to separate them from cortical signals. We used complementary fNIRS, fMRI, MR-angiography and peripheral physiological measurements (blood pressure, heart rate, skin conductance and skin blood flow) to study activation in the frontal lobe during a continuous performance task. The General Linear Model (GLM) was applied to analyse the fNIRS data, which included an additional predictor to account for systemic changes in the skin.We found that skin blood volume strongly depends on the cognitive state and that sources of task-evoked systemic signals in fNIRS are co-localized with veins draining the scalp. Task-evoked superficial artefacts were mainly observed in concentration changes of oxygenated haemoglobin and could be effectively separated from cerebral signals by GLM analysis. Based on temporal correlation of fNIRS and fMRI signals with peripheral physiological measurements we conclude that the physiological origin of the systemic artefact is a task-evoked sympathetic arterial vasoconstriction followed by a decrease in venous volume.Since changes in sympathetic outflow accompany almost any cognitive and emotional process, we expect scalp vessel artefacts to be present in a wide range of fNIRS settings used in neurocognitive research. Therefore a careful separation of fNIRS signals originating from activated brain and from scalp is a necessary precondition for unbiased fNIRS brain activation maps.

Reply from Erica A. Wehrwein, Rita Basu, Ananda Basu, Timothy B. Curry, Robert A. Rizza and Michael J. Joyner

We thank Dr Verberne for furthering the discussion of our recent paper. To address his points, we will focus on three issues: (1) the differential control of sympathetic outflow, (2) the role of a subset of RVLM neurons in hypoglycaemic counterregulation recently described by Drs Verberne and Sartor, and (3) a further comment on these RVLM neurons. (1) In our recent paper (Wehrwein et al. 2010) we do, for the sake of simplicity and generation of a ‘straw man’ argument, refer to the sympathetic nervous system as a unit as we discuss sympathoinhibition as a mechanism for suppression of counterregulation during hyperoxia. Dr Verberne is indeed correct that the modern view of the sympathetic nervous system is that of differential outflow to various tissues. Human microneurography studies from our collaborator Dr Wallin from the 1970s and 1980s made similar points repeatedly. For example, it is well established that there is differential activation of skin sympathetic versus muscle sympathetic nerves (Delius et al. 1972a,b,c; Wallin et al. 1975), especially during common manoeuvres such as orthostasis and exercise (Vissing et al. 1994; Vissing, 1997). A review on the differential control of muscle sympathetic nerve activity by the muscle chemoreflex (Joyner, 1992) summarizes at least some of these ideas from the human studies. These findings are also consistent with the idea of a ‘sympathetic signature’ as put forth by Osborn and Fink in their recent review of this topic as it relates to Angiotensin II hypertension (Osborn & Fink, 2010). Finally, May and colleagues support this notion by showing a disconnect between the cardiac and renal sympathetic outflows in a sheep model of heart failure (May et al. 2010). Thus the concept of differential sympathetic control is clearly important and is relevant to our findings as we study the role of the carotid bodies in the sympathetic and adrenal pathways involved in hypoglycaemic counterregulation. (2) The recent work of Verberne & Sartor (2010) describing a subset of cells in the RVLM is important and it was not cited and discussed in our paper due to timing. Verberne and Sartor demonstrate that a subpopulation of RVLM neurons: (1) serve as baro-insensitive, central glucose sensors, (2) play a role in mediating the counterregulatory response to hypoglycaemia, and (3) drive the adrenomedullary release of adrenaline. As such these cells provide an important mechanistic explanation for our findings and suggest generalized sympathoinhibition does not occur during carotid body inhibition with hyperoxia. Importantly, these RVLM cells do not have cardiac rhythmicity or baroreflex-driven inhibition and are directly targeted to the adrenal gland allowing adrenal stimulation independent of baroreflex driven changes in sympathetic outflow from presympathetic vasomotor neurons in the same brain region. However, it is unclear what the link is between the carotid body chemoreceptors and these specific RVLM cells, or how they might interact to influence the counterregulatory response to hypoglycaemia. Since both type 1 glomus cells in the carotid body and the RVLM subpopulation of neurons described by Verberne and Sartor are glucose sensitive and can mediate counterregulation, we do not yet understand how these cells interact to generate an integrated counterregulatory response. (3) It is well established that the RVLM controls sympathetic vasomotor output and is integral to baroreflex control of MSNA and blood pressure. Activation of adrenaline secretion was known to occur with RVLM disinhinition but until Verberne and Sartor's work described above (Verberne & Sartor, 2010), it was presumed that the neurons controlling sympathetic vasomotor tone and adrenaline secretion were fundamentally similar. By contrast, Verberne and Sartor show that there is a subpopulation of RVLM neurons that are baro-insensitive and whose activity is affected by changes in blood glucose levels. These glucose-sensitive RVLM neurons are targeted specifically to the adrenal medulla and control adrenaline secretion in response to a central hypoglycaemic stimulus (i.e. adrenaline release mediates liver glucose mobilization and an increase in plasma glucose to correct for hypoglycaemia). Their paper is important because it: (1) identifies a subpopulation of RVLM neurons that sense, and mediate changes in, blood glucose and are independent of the classic view of a more uniform role of RVLM neurons, (2) brings to light an important new understanding of integrative physiology and homeostasis, and (3) offers explanation for some of the differential control within the sympathoadrenal system. In conclusion, we are pleased to have this added discussion on mechanisms that might explain some of our findings. We agree with the view that a sympathoadrenal system that functions en masse is not applicable to most physiological states and are pleased that our paper has stimulated discussion on these and related topics.

Synaptic transmission in the inferior mesenteric ganglion of hypertensive and normotensive rats

The inferior mesenteric ganglion (IMG) is a prevertebral sympathetic ganglion that innervates the lower abdominal and pelvic viscera. While extensive studies have been performed on the IMG of several species, there is very little information available concerning the rat IMG. Because of the importance of the mesenteric circulation in the regulation of systemic blood pressure and in the genesis of salt‐sensitive hypertension, we compared the properties and response profiles to pre‐ganglionic input of IMG neurons in normotensive (NT) and hypertensive (HT) animals using intracellular recording in vitro. All rats were uninephrectomized 4 weeks prior to experiments. HT rats received 200mg/kg of deoxycorticosterone s.q. and 1%NaCl/0.2%KCl in drinking water. NT animals (mean arterial pressure < 130mmHg) received tap water. Resting membrane potential, rheobasic current, action potential amplitude, input resistance, and membrane time constant show no significant differences between NT and HT animals. In contrast to the findings in the IMG of other species, nearly all neurons (94% in HT, 91% in NT rats) showed a phasic response to direct current injection. This is the first study of the IMG of the hypertensive rat. While there is a predominance of phasic neurons in this ganglion, changes in sympathetic outflow that occur with hypertension are not due to alterations in the basic properties of the ganglionic neurons. Supported by NIH grant HL70687

Laser capture microdissection of spinally‐projecting RVLM neurons: Analysis of NMDA receptor subunit gene expression.

Spinally‐projecting neurons in the rostral ventrolateral medulla (RVLM) are important in blood pressure regulation. Functional and anatomical studies suggest that N‐methyl‐D‐aspartate receptors (NMDARs) are located in the RVLM and play important roles in cardiovascular reflexes. Since NMDARs are also associated with neuroplasticity, we determined the feasibility of comparing NMDAR subunit gene expression in the RVLM. To test this, Fluorogold (FG) was injected into the intermediolateral cell column of Sprague Dawley rats (n=4) to label spinally‐projecting neurons. After 1–2 wks, FG‐labeled cells were obtained under RNAase free conditions from fresh, frozen sections (8 μm) using laser capture microdissection (Arcturus PixCell II). Total mRNA was isolated, and NMDAR subunits (NR1 and NR2A) and GAPDH were quantified by real time PCR (qRT‐PCR) using Taqman probes. Preliminary findings suggest that we are able to detect NMDAR subunit gene expression in spinally‐projecting RVLM neurons. Alterations in NMDAR number or subunit composition may influence the excitability of RVLM neurons and contribute to changes in sympathetic outflow in physiological and pathophysiological states. Future studies will compare physical activity‐related changes in gene and protein expression levels of NMDAR subunits. (AHA# 09PRE2050230 and HL‐089364)

Plasticity of GABAergic Mechanisms Within the Nucleus of the Solitary Tract in Hypertension

Adaptive changes have long been recognized to occur in the heart and vasculature in response to chronic hypertension. What might be less well-appreciated is the fact that chronically increased blood pressure is also associated with adaptive changes in neurons within the central nervous system (CNS). Changes in the properties of ligand-gated and voltage-gated channels have been described in a variety of neurons in a variety of central nuclei and in a variety of models of hypertension. Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in virtually every region in the adult brain. Microinjections of GABA and GABA receptor subtype-selective agonists and antagonists have been performed within various cardiovascular-related regions of the CNS. In every cardiovascular-related region of the CNS tested, activation of GABA receptors alters cardiovascular function. This is likely attributable to the ubiquitous role of GABA within the CNS. GABAergic inhibition can be mediated by activation of receptors located in presynaptic and postsynaptic loci. Two major subtypes of the GABA receptor exist: the GABAA receptor is a pentameric, chloride ionophore that primarily mediates postsynaptic inhibition,1 whereas the GABAB receptor is a G-protein-coupled receptor that can induce reductions in calcium conductance to mediate presynaptic inhibition and increases in potassium conductance to mediate postsynaptic inhibition.2 GABAergic inhibition of central neurons can result in pressor or depressor responses depending on the central site being examined. Pressor responses are often assumed to be the result of GABAergic inhibition of neurons that reduce sympathetic discharge. Depending on the specific area being studied, GABA injections into the CNS can also alter vagal cardiac function and levels of vasoactive hormones such as vasopressin and angiotensin, in addition to changes in sympathetic outflow.3,4 In addition to microinjection studies, in vivo and in vitro electrophysiological analyses of functionally identified neurons in cardiovascular-related CNS …

Physiological Responses to the Coriolis Illusion: Effects of Head Position and Vision

Changes in sympathetic outflow during Type II spatial disorientation are well documented. In this study we investigated the influences of head position and eye state (open or closed) on sympathetic activation. There were 11 naive subjects (6 men, 5 women) who were tested in a General Aviation Trainer that accelerated at a subthreshold rate for 60 s until a constant angular velocity of 90 degrees x s(-1) was reached. Approximately 40 s later, subjects were instructed to tilt their heads along either the pitch or roll axis, stimulating a Coriolis illusion. Subjects reported the perceived intensity and duration of disorientation. Heart rate, heart rate variability, and electrodermal responses were recorded before, during, and after the period of disorientation. Each subject completed four trials, which were crossed combinations of head position and eye state. There were significant increases in heart rate and the electrodermal response during disorientation, but no significant change in heart rate variability. Head position had no significant effect on any physiological parameters or on the perceived intensity of disorientation; subjects reported a shorter duration of disorientation when the head was tilted into the roll versus the pitch axis. Eye state had no effect on heart rate, heart rate variability, or the intensity of disorientation, but the electrodermal response was somewhat greater, and the duration of disorientation shorter when eyes were open. The results suggest that head position and eye state (open or closed) do not need to be included as factors when investigating sympathetic outflow during a mild Coriolis illusion.

Feast or Famine: The Sympathetic Nervous System Response to Nutrient Intake

: 1. The use of tritiated norepinephrine (NE) to measure the turnover rate of NE in sympathetically innervated organs was pioneered in the laboratory of Julius Axelrod. This technique provides an organ specific assessment of sympathetic activity, integrated over a 24 h period, in free living laboratory animals. As such it has proved useful in estimating changes in sympathetic outflow in different physiologic and patho-physiologic states. 2. Studies employing NE turnover techniques in laboratory rodents have demonstrated conclusively that fasting suppresses and overfeeding stimulates the sympathetic nervous system (SNS). These changes in sympathetic activity also occur in humans. 3. Diet-induced changes in SNS activity are regulated by insulin-mediated glucose uptake and metabolism in central neurons sensitive to insulin and located anatomically in the ventro-medial hypothalamus. The regulation is imposed by descending inhibition of tonically active sympathetic brainstem centers. 4. Diet-induced changes in SNS activity mediate changes in energy production known as dietary thermogenesis. The capacity for dietary thermogenesis serves as a potential buffer against weight gain.5. Insulin stimulated SNS activity contributes to obesity-related hypertension. The insulin resistance of obesity, and consequent hyperinsulinemia, drives sympathetically mediated thermogenesis, restoring energy balance at the expense of SNS over activity. The association of obesity and hypertension, therefore, may be the unintended consequence of mechanisms recruited in the obese to limit further weight gain.

Consequences of removal of vestibular inputs on patterning of blood flow to the limbs during postural alterations in conscious felines

Previous studies showed that removal of vestibular inputs results in lability in blood pressure during postural alterations. In addition, stimulation of vestibular afferents produces reciprocal changes in sympathetic outflow to and perfusion of the forelimb and hindlimb. These findings led to the hypothesis that activation of the vestibular system during postural alterations elicits patterned changes in limb blood flow that serve to maintain orthostatic tolerance. The present study tested this hypothesis by recording flow through the brachial and femoral arteries of conscious felines that were tilted head-up by up to 60°, before and after transection of the VIIIth cranial nerves. Blood pressure was also recorded so that vascular resistance of the forelimb (FVR) and hindlimb (HVR) could be calculated. In vestibular-intact cats, 60° head-up tilts were accompanied by increases in HVR of ~15%, and a ~12% increase in FVR. After VIIIth nerve transections, the posturally-related increases in HVR were significantly diminished, although there was only a small attenuation of the FVR response. These data support the hypothesis that vestibular signals elicit patterned changes in the activity of muscle vasoconstrictor efferents that act to stabilize blood pressure during postural alterations.

Single‐unit responses of serotonergic medullary raphe neurons to cardiovascular challenges in freely moving cats

Single-unit activity of serotonergic neurons in the nuclei raphe obscurus (NRO) and raphe pallidus (NRP) were recorded in conjunction with heart rate in freely moving cats in response to systemic administration of vasoactive drugs and to graded haemorrhage. Bolus administration of phenylephrine hydrochloride and sodium nitroprusside (20 microg/kg, i.v.) produced a marked, transient reflex bradycardia (-42 b.p.m.) and tachycardia (+60 b.p.m.), respectively. The activity of NRO/NRP serotonergic neurons remained unchanged after phenylephrine and nitroprusside administration. The administration of hydralazine (1 mg/kg, i.v.), a long-acting vasodilator, produced sustained tachycardia (+60 b.p.m.), which was not accompanied by changes in neuronal activity, despite prolonged reflex activation of the sympathetic nervous system. The initial withdrawal of up to 15% of total blood volume increased heart rate (+12 b.p.m.), whereas the removal of 22.5% of total blood decreased heart rate (-44 b.p.m.). The activity of NRO/NRP serotonergic neurons remained unaltered throughout graded haemorrhage trials, despite the changes in sympathetic outflow. Thus, serotonergic NRO and NRP neurons appear to be insensitive to alterations in blood pressure and baroreceptor activity, and this lack of responsiveness does not support a specific role for these cells in cardiovascular regulation. Furthermore, these neurons do not appear to be involved in physiological mechanisms underlying alterations in autonomic outflow invoked by hypertension and hypotension. Taken within the context of our previous work, the present data suggest that medullary serotonergic neurons may modulate autonomic outflow, but only in relation to their primary role in motor control.

Development of metabolic systems

In the normal adult rodent and primate, arcuate nucleus (ARH) neurons function as conduits for transmitting metabolic hormonal signals into the hypothalamic circuitry that modulates feeding and energy expenditure. We and others have shown that ARH projections do not fully develop until the 3rd postnatal week in the rodent. This is in stark contrast to the nonhuman primate (NHP) in which ARH projections develop during the 3rd trimester of pregnancy. This species difference suggests that maternal diet and health are likely key factors for the development of ARH projections in the primate, whereas the postnatal environment (i.e., diet) would be more important in the rodent. Furthermore, pertubations in these circuits during critical periods of development may have long-term consequences on feeding behavior and body weight management. Our group has used a rat model of overfeeding and underfeeding specifically during the postnatal period to begin to investigate the metabolic adaptions that may cause developmental abnormalities in the hypothalamic circuitry. While the overfed animals become obese as adults and the underfed maintain a lean phenotype, both models display low basal insulin and IGFII levels as adults. Furthermore, both models have abnormal expression of several key genes in peripheral metabolic tissue that are suggestive of changes in sympathetic outflow. Human studies show that gestational diabetes can also contribute to the development of obesity and diabetes in children; however, the mechanism is unknown. Since the critical periods for the development of hypothalamic circuits are different between rodents and primates our group has begun studies using NHP model to determine if maternal obesity/diabetes causes abnormalities in the development of metabolic systems, including the brain, in the offspring. To do this we have placed female NHPs on either a control diet or a high fat/calorie diet to induce obesity and diabetes. We have characterized the onset of insulin resistance and hyperleptinemia in these animals over the last 2½ years and have collected offspring. Ongoing studies will investigate the metabolic abnormalities in these offspring.

Responses of muscle spindles in feline dorsal neck muscles to electrical stimulation of the cervical sympathetic nerve

Previous studies performed in jaw muscles of rabbits and rats have demonstrated that sympathetic outflow may affect the activity of muscle spindle afferents (MSAs). The resulting impairment of MSA information has been suggested to be involved in the genesis and spread of chronic muscle pain. The present study was designed to investigate sympathetic influences on muscle spindles in feline trapezius and splenius muscles (TrSp), as these muscles are commonly affected by chronic pain in humans. Experiments were carried out in cats anesthetized with alpha-chloralose. The effect of electrical stimulation (10 Hz for 90 s or 3 Hz for 5 min) of the peripheral stump of the cervical sympathetic nerve (CSN) was investigated on the discharge of TrSp MSAs (units classified as Ia-like and II-like) and on their responses to sinusoidal stretching of these muscles. In some of the experiments, the local microcirculation of the muscles was monitored by laser Doppler flowmetry. In total, 46 MSAs were recorded. Stimulation of the CSN at 10 Hz powerfully depressed the mean discharge rate of the majority of the tested MSAs (73%) and also affected the sensitivity of MSAs to sinusoidal changes of muscle length, which were evaluated in terms of amplitude and phase of the sinusoidal fitting of unitary activity. The amplitude was significantly reduced in Ia-like units and variably affected in II-like units, while in general the phase was affected little and not changed significantly in either group. The discharge of a smaller percentage of tested units was also modulated by 3-Hz CSN stimulation. Blockade of the neuromuscular junctions by pancuronium did not induce any changes in MSA responses to CSN stimulation, showing that these responses were not secondary to changes in extrafusal or fusimotor activity. Further data showed that the sympathetically induced modulation of MSA discharge was not secondary to the concomitant reduction of muscle blood flow induced by the stimulation. Hence, changes in sympathetic outflow can modulate the afferent signals from muscle spindles through an action exerted directly on the spindles, independent of changes in blood flow. It is suggested that such an action may be one of the mechanisms mediating the onset of chronic muscle pain in these muscles in humans.

Effects of sympathetic stimulation on the rhythmical jaw movements produced by electrical stimulation of the cortical masticatory areas of rabbits

The somatomotor and sympathetic nervous systems are intimately linked. One example is the influence of peripheral sympathetic fibers on the discharge characteristics of muscle spindles. Since muscle spindles play important roles in various motor behaviors, including rhythmic movements, the working hypothesis of this research was that changes in sympathetic outflow to muscle spindles can change rhythmic movement patterns. We tested this hypothesis in the masticatory system of rabbits. Rhythmic jaw movements and EMG activity induced by long-lasting electrical cortical stimulation were powerfully modulated by electrical stimulation of the peripheral stump of the cervical sympathetic nerve (CSN). This modulation manifested itself as a consistent and marked reduction in the excursion of the mandibular movements (often preceded by a transient modest enhancement), which could be attributed mainly to corresponding changes in masseter muscle activity. These changes outlasted the duration of CSN stimulation. In some of the cortically evoked rhythmic jaw movements (CRJMs) changes in masticatory frequency were also observed. When the jaw-closing muscles were subjected to repetitive ramp-and-hold force pulses, the CRMJs changed characteristics. Masseter EMG activity was strongly enhanced and digastric EMG slightly decreased. This change was considerably depressed during CSN stimulation. These effects of CSN stimulation are similar in sign and time course to the depression exerted by sympathetic activity on the jaw-closing muscle spindle discharge. It is suggested that the change in proprioceptive information induced by an increase in sympathetic outflow (a) has important implications even under normal conditions for the control of motor function in states of high sympathetic activity, and (b) is one of the mechanisms responsible for motor impairment under certain pathological conditions such as chronic musculoskeletal head-neck disorders, associated with stress conditions.