Increase In Autonomic Activity Research Articles

Abstract 027: Early Life Sodium Restriction Programs Long-term Changes In Energy Flux And Autonomic Activity

As sodium (Na) retention by the kidney is not fully efficient until the final weeks of a normal gestation, prematurely born infants are at high risk of Na depletion. We hypothesize that early-life sodium depletion contributes to delayed somatic growth and increased cardiometabolic risks associated with premature birth, via programmed increases in autonomic activity. To model early-life Na depletion, mice were weaned at 3 weeks of age onto custom variations of a soy-free diet (Teklad 2920x) containing either low (0.04% n=6m+8f) or high (0.30% n=8m+8f) Na. At 6 weeks of age, all mice were returned to standard (0.15% Na) diet. Energy flux was studied using NMR and a multiplexed phenotyping system (Promethion) at 6, 7, 8, 10, and 18 weeks of age, and data were analyzed by General Linear Modeling to account for covariates such as fat-free mass (FFM) and fat mass. Low Na supply caused delayed gains in FFM (diet x age interaction p<0.01) but no change in fat mass (p>0.77) in both sexes. In male mice supplied low Na in early life, food intake was reduced for weeks to months after return to normal diet even after correction for FFM and fat masses (diet p<0.01, diet x age p=0.93), primarily due to smaller meal sizes. Water intake was increased (diet p<0.01, diet x age p=0.03), primarily due to more drinking events. Total daily energy expenditure was also increased even after correction for FFM mass, fat mass, and food intake (diet p<0.01, diet x age p>0.99), though no changes in locomotion were observed (p>0.60). Throughout, female mice exhibited qualitatively similar yet quantitatively smaller effects. A parallel study indicated that after low Na supply, basal metabolic rate was increased at 8 weeks of age (n=8m each, +16%, p=0.01), and this increase was abolished with autonomic blockade via hexamethonium (30 mg/kg, ip; p=0.02). Finally, preliminary data (n=4 vs 5) indicate Ucp1 mRNA may be increased in inguinal fat at 6 (2.8-fold p=0.08) and 18 weeks of age (2.2-fold p=0.12) in the low Na group. Together these findings support the concept that Na depletion in early life is sufficient to program persistent cardiometabolic and autonomic dysfunctions long after Na repletion.

Ontogeny and control of the heart rate power spectrum in the last third of gestation in fetal sheep

Power spectral analysis of fetal heart rate variability has been proposed to provide a non-invasive estimate of autonomic balance. However, there are few systematic data before birth. We therefore examined developmental changes in the frequency power spectrum at very low (0-0.04 Hz), low (0.04-0.15 Hz) and high frequencies (0.15-0.4 Hz), as well as the ratio of low- to high-frequency power (LF/HF), in chronically catheterized, healthy fetal sheep at 0.6 (n = 8), 0.7 (n = 7) and 0.8 gestational age (ga; n = 11). In a second study, 0.8 ga fetuses received either atropine (4.8 mg bolus, then 4.8 mg h(-1) for 30 min, n = 6) or 6-hydroxydopamine (20 mg ml(-1) at 2.5 ml h(-1) for 3 h; n = 9). Data were analysed by sleep state, defined by low-voltage-high-frequency (LV) or high-voltage-low-frequency (HV) EEG. Total spectral power increased with gestational age (P < 0.05), while LF/HF decreased from 0.6 to 0.7 ga. At 0.8 ga, heart rate and LF/HF were significantly higher during HV than LV sleep (P < 0.05). Consistent with this, although total spectral power was not significantly greater during HV sleep, there was a significant interaction between sleep state and frequency band (P = 0.02). Both atropine (P = 0.05) and 6-hydroxydopamine (P < 0.05) were associated with an overall reduction in spectral power but no significant effect on the LF/HF ratio. This study does not support substantial, consistent differences between the frequencies of sympathetic and parasympathetic activity in late-gestation fetal sheep.

Psychophysiological reactivity to environmental tobacco smoke on smokers and non-smokers

Environmental tobacco smoke (ETS) is an air pollutant with a relevant impact on public health. In addition, ETS is a significant stimulus that may elicit different responses depending on previous experience and current status regarding smoking. Exposure to cigarette cues has been shown to be a reliable method for inducing subjective and physiological responses. However, the role of ETS as a stimulus has not received, to date, enough attention in the research literature. This study aimed to analyse both the autonomic and subjective responses of smokers and non-smokers to exposure to ETS. To that end, 41 non-smokers and 57 smokers were exposed to ETS, in a controlled laboratory setting. We measured the subjective perception of smoke, unpleasantness, heart rate and skin conductance to compare the reactions of smokers and non-smokers to ETS. Additionally, subjective tobacco craving after exposure was assessed for current smokers. We found different psychophysiological responses to ETS exposure for smokers and non-smokers. Smokers showed a generalised increase in autonomic activity, significantly greater than that of non-smokers. In addition, heart rate increase during exposure to ETS was positively correlated with subjective craving. Our data suggested that ETS was an important stimulus and acted as a relevant cue for smokers; it induced both psychophysiological reactions and subjective craving. Hence, this kind of stimulus within the cue-reactivity research paradigm may be useful for studying the effect of ETS on smokers' reactions, craving, quitting attempts, or relapse probabilities.

Should Neonates Sleep Alone?

Maternal-neonate separation (MNS) in mammals is a model for studying the effects of stress on the development and function of physiological systems. In contrast, for humans, MNS is a Western norm and standard medical practice. However, the physiological impact of this is unknown. The physiological stress-response is orchestrated by the autonomic nervous system and heart rate variability (HRV) is a means of quantifying autonomic nervous system activity. Heart rate variability is influenced by level of arousal, which can be accurately quantified during sleep. Sleep is also essential for optimal early brain development. To investigate the impact of MNS in humans, we measured HRV in 16 2-day-old full-term neonates sleeping in skin-to-skin contact with their mothers and sleeping alone, for 1 hour in each place, before discharge from hospital. Infant behavior was observed continuously and manually recorded according to a validated scale. Cardiac interbeat intervals and continuous electrocardiogram were recorded using two independent devices. Heart rate variability (taken only from sleep states to control for level of arousal) was analyzed in the frequency domain using a wavelet method. Results show a 176% increase in autonomic activity and an 86% decrease in quiet sleep duration during MNS compared with skin-to-skin contact. Maternal-neonate separation is associated with a dramatic increase in HRV power, possibly indicative of central anxious autonomic arousal. Maternal-neonate separation also had a profoundly negative impact on quiet sleep duration. Maternal separation may be a stressor the human neonate is not well-evolved to cope with and may not be benign.

Regulation and function of Ca2+–calmodulin‐dependent protein kinase II of fast‐twitch rat skeletal muscle

The activation and function of Ca(2+)-calmodulin-dependent kinase II (CaMKII) in contracting rat skeletal muscle was examined. The increase in autonomous activity and phosphorylation at Thr(287) of CaMKII of gastrocnemius muscle in response to contractions in situ was rapid and transient, peaking at 1-3 min, but reversed after 30 min of contractions. There was a positive correlation between CaMKII phosphorylation at Thr(287) and autonomous CaMKII activity. In contrast to the rapid and transient increase in autonomous CaMKII activity, the phosphorylation of the putative CaMKII substrate trisk95/triadin was rapid and sustained during contractions. There were no changes in CaMKII activity and phosphorylation or trisk95 phosphorylation in the resting contralateral muscles during stimulation. When fast-twitch muscles were contracted ex vivo, CaMKII inhibition resulted in a greater magnitude of fatigue as well as blunted CaMKII and trisk95 phosphorylation, identifying trisk95 as a physiological CaMKII substrate. In summary, skeletal muscle CaMKII activation was rapid and sustained during exercise/contraction and is mediated by factors within the contracting muscle, probably through allosteric activation via Ca(2+)-CaM. CaMKII may signal through trisk95 to modulate Ca(2+) release in fast-twitch rat skeletal muscle during exercise/contraction.

Exercise and CaMK activation both increase the binding of MEF2A to theGlut4promoter in skeletal muscle in vivo

In vitro binding assays have indicated that the exercise-induced increase in muscle GLUT4 is preceded by increased binding of myocyte enhancer factor 2A (MEF2A) to its cis-element on the Glut4 promoter. Because in vivo binding conditions are often not adequately recreated in vitro, we measured the amount of MEF2A that was bound to the Glut4 promoter in rat triceps after an acute swimming exercise in vivo, using chromatin immunoprecipitation (ChIP) assays. Bound MEF2A was undetectable in nonexercised controls or at 24 h postexercise but was significantly elevated approximately 6 h postexercise. Interestingly, the increase in bound MEF2A was preceded by an increase in autonomous activity of calcium/calmodulin-dependent protein kinase (CaMK) II in the same muscle. To determine if CaMK signaling mediates MEF2A/DNA associations in vivo, we performed ChIP assays on C(2)C(12) myotubes expressing constitutively active (CA) or dominant negative (DN) CaMK IV proteins. We found that approximately 75% more MEF2A was bound to the Glut4 promoter in CA compared with DN CaMK IV-expressing cells. GLUT4 protein increased approximately 70% 24 h after exercise but was unchanged by overexpression of CA CaMK IV in myotubes. These results confirm that exercise increases the binding of MEF2A to the Glut4 promoter in vivo and provides evidence that CaMK signaling is involved in this interaction.

Autonomous activity of CaMKII is only transiently increased following the induction of long‐term potentiation in the rat hippocampus

A major role has been postulated for a maintained increase in the autonomous activity of CaMKII in the expression of long-term potentiation (LTP). However, attempts to inhibit the expression of LTP with CaMKII inhibitors have yielded inconsistent results. Here we compare the changes in CaMKII autonomous activity and phosphorylation at Thr286 of alphaCaMKII in rat hippocampal slices using chemical or tetanic stimulation to produce either LTP or short-term potentiation (STP). Tetanus-induced LTP in area CA1 requires CaMKII activation and Thr286 phosphorylation of alphaCaMKII, but we did not observe an increase in autonomous activity. Next we induced LTP by 10 min exposure to 25 mM tetraethyl-ammonium (TEA) or 5 min exposure to 41 mM potassium (K) after pretreatment with calyculin A. Exposure to K alone produced STP. These protocols allowed us to monitor temporal changes in autonomous activity during and after exposure to the potentiating chemical stimulus. In chemically induced LTP, autonomous activity was maximally increased within 30 s whereas this increase was significantly delayed in STP. However, in both LTP and STP the two-fold increase in autonomous activity measured immediately after stimulation was short-lived, returning to baseline within 2-5 min after re-exposure to normal ACSF. In LTP, but not in STP, the phosphorylation of alphaCaMKII at Thr286 persisted for at least 60 min after stimulation. These results confirm that LTP is associated with a maintained increase in autophosphorylation at Thr286 but indicate that a persistent increase in the autonomous activity of CaMKII is not required for the expression of LTP.

Temporal Activation of Ca2+-Calmodulin-sensitive Protein Kinase Type II Is Obligate for Adipogenesis

Differentiation of 3T3-L1 embryonic fibroblasts to adipocytes in response to induction by dexamethasone and isobutylmethylxanthine is blocked by inhibitors of Ca2+-calmodulin-sensitive protein kinase type II, but not by inhibitors of protein kinase A or protein kinase C. CaM kinase II displays a biphasic increase in autonomous activity, rising after an initial transient peak from 1 to 15 h, declining at 24 h, followed by a sustained rise from 24 to 48 h, which is 2. 5-fold greater than basal values at induction of adipogenesis. Adipogenesis was blocked effectively by CaM kinase II inhibitors, either KN-62 or KN-93, if the inhibitors are introduced at 6 h and maintained until 12 h of induction of adipogenesis. Equally effective, however, is inhibition of CaM kinase II activity at 24-48 h after induction, during the later phase of autonomous CaM kinase activity. Inhibition of cultures with KN-62 or KN-93 either for 0 to 6 h or for 12 to 24 h failed to influence adipogenesis. Two temporally-distinct phases of CaM kinase II activation, either 6 to 12 h or 24 to 48 h, if inhibited with either KN-62 or KN-93, blocked the conversion to adipocytes. Thus, a biphasic activation of CaM kinase II is obligate for the progression of the embryonic fibroblasts to adipocytes. Inhibition of either phase of CaM kinase activity blocks adipogenesis and expression of several intermediate early gene products.

An autonomous kinase generated during long-term facilitation in Aplysia is related to the Ca(2+)-independent protein kinase C Apl II.

Prolonged treatment with serotonin leads to long-term facilitation of sensory-to-motor neuron synapses in Aplysia. We have shown previously that there is a protein synthesis-dependent increase in an autonomous kinase activity that phosphorylates a protein kinase C substrate during an intermediate phase of this facilitation. Here, I report that the increase in autonomous activity was independent of RNA synthesis, suggesting it may play a role in the maintenance phase of synaptic facilitation. Immunoprecipitation experiments using an antibody specific to the Ca(2+)-independent protein kinase C, Apl II, demonstrated that the autonomous kinase activity increased by serotonin emanated from Apl II. Chelerythrine, an inhibitor targeted to the substrate binding site of protein kinase C, also blocked the autonomous kinase activity increased by serotonin. Using immunoblotting experiments and calphostin-C, an inhibitor targeted to the regulatory domain of protein kinase C, the autonomous activity is shown not to be a catalytic fragment of Apl II. Furthermore, a higher concentration of calphostin-C was required to inhibit autonomous kinase activity than regulated kinase activity, suggesting that calphostin-C's binding site in the regulatory domain of Apl II is modified in the autonomous kinase. These data suggest that an autonomous kinase derived from Apl II may play a role in synaptic facilitation in Aplysia.

MUSIC ENHANCES THE EFFECT OF POSITIVE EMOTIONAL STATES ON SALIVARYIgA

This study examines the effects of music and positive emotional states on autonomic and immune functions in normal, healthy individuals. Autonomic activity was assessed using power spectral density analysis of heart rate variability, and salivary IgA was used as a marker of immunity. The effects of rock, new age and designer music were examined alone, and in conjunction with a self-induced positive emotional state. The results indicate that only the designer music and the self-induced state of appreciation produced a significant increase in autonomic activity and salivary IgA (S-IgA). In addition, the combination of the designer music and the self-induced appreciation produced a much greater immunoenhancement than either of these two conditions alone. We conclude that music can be designed to enhance the beneficial effects of positive emotional states on immunity, and that this effect may be mediated by the autonomic nervous system. These data raise the tantalizing possibility that music and emotional self-management may have significant health benefits in a variety of clinical situations in which there is immunosuppression and autonomic imbalance.

The psychophysiology of crying

Two conflicting views have emerged as to why people cry when they are sad. One suggests that crying serves homeostasis by facilitating recovery; the other suggests that crying produces an aversive high-arousal state that motivates behavior aimed at ending the tears. To test hypotheses drawn from these views, we showed a short film known to elicit sadness to 150 women. During this film, 33 subjects spontaneously cried and 117 did not. Subjects who cried exhibited more expressive behavior and reported feeling more sadness and pain than did subjects who did not cry. Crying also was associated with increases in somatic and autonomic nervous system activity. The increases in autonomic activity could not be accounted for solely by the increases in somatic activity. Crying is thus associated with an aversive state, including negative emotion and a complex mixture of sympathetic, parasympathetic, and somatic activation, and we speculate about the functional implications of these findings.

Autonomic Correlates of Stuttering and Speech Assessed in a Range of Experimental Tasks

Electrodermal activity, peripheral blood flow, and heart rate were recorded from 19 stutterers and 19 normal speakers during performance of jaw movements, a strenuous breath-holding task, reading, and spontaneous speech. The tasks were selected to produce a range of autonomic activation and thus help scale autonomic activation for speech relative to other motor behaviors. Speaking was associated with relatively large increases in autonomic activity in both stutterers and normal speakers. There were no differences between the two groups of speakers, suggesting that the stutterers did not have abnormally high levels of autonomic activation in speech. Within the group of stutterers, the more extreme increases in arousal (specifically increases in measures reflecting sympathetic arousal) were correlated with the occurrence and increased severity of disfluent speech. Significant correlations were found for the intervals prior to, during, and after speech. Although significantly correlated with disfluency, measures of autonomic arousal accounted for small percentages of the variances of fluency and severity. The results are consistent with the hypothesis that sympathetic arousal accompanies the breakdowns in speech motor processes characteristic of stuttering. Mechanisms linking autonomic nervous system functions and somatic sensorimotor processes involved in speech production are discussed.

Autonomic responses to stress in Vietnam combat veterans with posttraumatic stress disorder

This study tested the hypothesis that combat veterans with posttraumatic stress disorder (PTSD) experience sympathetic nervous system activation in response to war-related laboratory stimuli. Circulating plasma catecholamines, vital signs, and affect ratings were measured in 10 Vietnam combat veterans with PTSD and 11 control subjects, during and after viewing combat and noncombat stress films. PTSD subjects responded more strongly than controls to the combat film, with greater increases in plasma epinephrine, pulse, blood pressure, and subjective distress. The increases in autonomic activity of PTSD subjects was more pronounced and long lasting in response to the combat film than to the noncombat film, but type of film had no systematic effect on control subjects' responses. These findings are consistent with biological models that posit sympathoadrenal activation in response to memory-evoking cues of traumatic events in PTSD.

Stimulation of ciliary beat frequency by autonomic agonists: in vivo.

beta 2-Adrenergic bronchodilator and muscarinic cholinergic bronchoconstrictor agonists both stimulate ciliary activity in vitro. To test the hypothesis that increases in autonomic activity would result in increases in ciliary beat frequency (CBF) in vivo, a correlation analysis heterodyne laser light-scattering system was developed and validated to measure the stimulating effects of sympathomimetic and parasympathomimetic agonists on tracheal CBF in intact, anesthetized beagles. The mean baseline CBF from 42 studies of 274 measurements in 9 (5 male and 4 female) adult beagles was 6.6 +/- 1.1 Hz. The stimulating effects of a beta 2-adrenergic agonist, fenoterol, and a muscarinic cholinergic agonist, methacholine, on CBF were studied on four and eight beagles, respectively. The studies were randomized and blinded. Aerosolized 10(-5) M fenoterol stimulated the CBF from the base line of 6.8 +/- 2.5 to 32.0 +/- 17.9 Hz in four dogs. Aerosolized methacholine stimulated the CBF from the base line of 5.8 +/- 0.7 to 9.4 +/- 3.0 Hz for 10(-8) M, and to 12.6 +/- 3.1 Hz for 10(-6) M in eight dogs. These are the first data obtained in intact animals that demonstrate CBF in the lower respiratory tract is regulated by autonomic agonists.

Physiological accompaniments of neutral and phobic imagery.

SYNOPSISEach of 16 phobic patients was treated by six sessions of flooding and six sessions of desensitization in a balanced crossover design. Clinical and physiological measurements were made before treatment and after the sixth and 12th sessions of treatment. Physiological measures were made of increase in heart rate and in spontaneous fluctuations and maximum change in level of skin conductance during neutral and phobic imagery. Patients estimated subjective anxiety during the imagery. Heart rate, skin conductance, and subjective anxiety ratings all differentiated significantly between phobic and neutral imagery. Increase in autonomic activity during imagery was roughly proportional to the intensity of the imagery in a phobic hierarchy. Autonomic changes during imagery imagined in silence did not produce autonomic changes considerably different from those during imagery stimulated by a running commentary from the therapist. Clinical ratings correlated significantly with measures of skin conductance, so that autonomic measures can be useful indicators of change after treatment. However, heart rate, skin conductance, and subjective anxiety during brief periods of imagery did not usually correlate significantly with one another. This supports the view of emotion as a System of responses linked imperfectly across several Systems.