Julia A. Moffitt

Regulation of sympathetic nervous system function after cardiovascular deconditioning

Abstract: Humans subjected to prolonged periods of bed rest or microgravity undergo deconditioning of the cardiovascular system, characterized by resting tachycardia, reduced exercise capability, and a predisposition for orthostatic intolerance. These changes in cardiovascular function are likely due to a combination of factors, including changes in control of body fluid balance or cardiac alterations resulting in inadequate maintenance of stroke volume, altered arterial or venous vascular function, reduced activation of cardiovascular hormones, and diminished autonomic reflex function. There is evidence indicating a role for each of these mechanisms. Diminished reflex activation of the sympathetic nervous system and subsequent vasoconstriction appear to play an important role. Studies utilizing the hindlimb‐unloaded (HU) rat, an animal model of deconditioning, evaluated the potential role of altered arterial baroreflex control of the sympathetic nervous system. These studies indicate that HU results in blunted baroreflex‐mediated activation of both renal and lumbar sympathetic nerve activity in response to a hypotensive stimulus. HU rats are less able to maintain arterial pressure during hemorrhage, suggesting that diminished ability to increase sympathetic activity has functional consequences for the animal. Reflex control of vasopressin secretion appears to be enhanced following HU. Blunted baroreflex‐mediated sympathoexcitation appears to involve altered central nervous system function. Baroreceptor afferent activity in response to changes in arterial pressure is unaltered in HU rats. However, increases in efferent sympathetic nerve activity for a given decrease in afferent input are blunted after HU. This altered central nervous system processing of baroreceptor inputs appears to involve an effect at the rostral ventrolateral medulla (RVLM). Specifically, it appears that tonic GABAA‐mediated inhibition of the RVLM is enhanced after HU. Augmented inhibition apparently arises from sources other than the caudal ventrolateral medulla. If similar alterations in control of the sympathetic nervous system occur in humans in response to cardiovascular deconditioning, it is likely that they play an important role in the observed tendency for orthostatic intolerance. Combined with potential changes in vascular function, cardiac function, and hypovolemia, the predisposition for orthostatic intolerance following cardiovascular deconditioning would be markedly enhanced by blunted ability to reflexly activate the sympathetic nervous system.

Evaluation of baroreceptor reflex function in the chronic mild stress rodent model of depression.

Objective: There is a bidirectional relationship between mood disorders (e.g., depression) and altered cardiovascular regulation (e.g., heart disease); however, the precise causal and/or common mechanisms underlying this association are unclear. In previous studies, we have noted indications of altered sympathetic drive to the heart in rats that exhibit anhedonia, an operational sign of depression induced by subjecting the animals to a series of mild and unpredictable stressors (chronic mild stress (CMS) rodent model of depression). The purpose of the present study was to more fully characterize baroreceptor reflex function in rats with experimentally induced depression. Methods: Male, Sprague-Dawley rats were exposed to either 4 weeks of mild, unpredictable stressors (CMS group) or standard housing conditions (control group). Depression-like behavior, resting hemodynamic and cardiac parameters, and baroreceptor reflex function were investigated in all animals after the CMS period. Results: CMS produced anhedonia, evidenced by reduced sucrose intake and sucrose preference, as well as elevated resting heart rate (HR), slightly elevated blood pressure, and reduced HR variability. These animals also exhibited significantly attenuated sympathoexcitatory responses to hypotension, and an elevation of basal sympathetic nerve activity. Conclusions: These findings suggest that CMS is associated with altered sympathoexcitatory responses after baroreceptor unloading and provide further insights into potential common mechanisms underlying the association of depression and altered cardiovascular control. ANOVA = analysis of variance; CMS = chronic mild stress; DSM-IV-TR = Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision; HR = heart rate; LSNA = lumbar sympathetic nerve activity; MAP = mean arterial pressure; SEM = standard error of the mean; SDNN = standard deviation of normal-to-normal intervals.

The Integration of Depressive Behaviors and Cardiac Dysfunction During an Operational Measure of Depression: Investigating the Role of Negative Social Experiences in an Animal Model

Objective There is a bidirectional association between depression and cardiovascular disease. The neurobiological mechanisms underlying this association may involve an inability to cope with disrupted social bonds. This study investigated in an animal model the integration of depressive behaviors and cardiac dysfunction after a disrupted social bond and during an operational measure of depression, relative to the protective effects of intact social bonds. Methods Depressive behaviors in the forced swim test and continuous electrocardiographic parameters were measured in 14 adult, female socially monogamous prairie voles (rodents), after 4 weeks of social pairing or isolation. Results After social isolation, animals exhibited (all values are mean ± standard error of the mean; isolated versus paired, respectively) increased heart rate (416 ± 14 versus 370 ± 14 bpm, p < .05) and reduced heart rate variability (3.3 ± 0.2 versus 3.9 ± 0.2 ln(ms2)). During the forced swim test, isolated animals exhibited greater helpless behavior (immobility = 106 ± 11 versus 63 ± 11 seconds, p < .05), increased heart rate (530 ± 22 versus 447 ± 15 bpm, p < .05), reduced heart rate variability (1.8 ± 0.4 versus 2.7 ± 0.2 ln(ms2), p < .05), and increased arrhythmias (arrhythmic burden score = 181 ± 46 versus 28 ± 12, p < .05). Conclusions The display of depressive behaviors during an operational measure of depression is coupled with increased heart rate, reduced heart rate variability, and increased arrhythmias, indicative of dysfunctional behavioral and physiological stress coping abilities as a function of social isolation. In contrast, social pairing with a sibling is behaviorally protective and cardioprotective. The present results can provide insight into a possible social mechanism underlying the association between depression and cardiovascular disease in humans. Abbreviations ANOVA = analysis of variance DSI = Data Sciences International ECG = electrocardiographic FST = forced swim test HR = heart rate RSA = respiratory sinus arrhythmia SDNN = standard deviation of normal-to-normal intervals SEM = standard error of the mean

Reduced hedonic behavior and altered cardiovascular function induced by mild sodium depletion in rats

Interactions among sodium homeostasis, fatigue, mood, and cardiovascular regulation have been described previously. The present study investigates the effects of sodium deficiency on an index of mood (hypohedonia; Experiment 1), cardiovascular function (Experiment 2), and plasma electrolytes (Experiment 3) in rats. Following 48 hr of sodium depletion with a diuretic (furosemide) and a sodium deficient diet, rats displayed hypohedonia evidenced by reduced responding for rewarding electrical brain stimulation into the hypothalamus. Also, sodium depletion produced increased heart rate and reduced heart rate variability. Plasma sodium levels were lower in sodium-depleted rats versus control rats, whereas potassium levels were unchanged. Thus, mild sodium depletion produces hypohedonia and cardiovascular alterations, which has implications for understanding behavioral and cardiovascular consequences of sodium deficiency.

Hindlimb Unloading Elicits Anhedonia and Sympathovagal Imbalance

The hindlimb-unloaded (HU) rat model elicits cardiovascular deconditioning and simulates the physiological adaptations to microgravity or prolonged bed rest in humans. Although psychological deficits have been documented following bed rest and spaceflight in humans, few studies have explored the psychological effects of cardiovascular deconditioning in animal models. Given the bidirectional link established between cardiac autonomic imbalance and psychological depression in both humans and in animal models, we hypothesized that hindlimb unloading would elicit an alteration in sympathovagal tone and behavioral indexes of psychological depression. Male, Sprague-Dawley rats confined to 14 days of HU displayed anhedonia (a core feature of human depression) compared with casted control (CC) animals evidenced by reduced sucrose preference (CC: 81 +/- 2.9% baseline vs. HU: 58 +/- 4.5% baseline) and reduced (rightward shift) operant responding for rewarding electrical brain stimulation (CC: 4.4 +/- 0.3 muA vs. 7.3 +/- 1.0 muA). Cardiac autonomic blockade revealed elevated sympathetic [CC: -54 +/- 14.1 change in (Delta) beats/min vs. HU: -118 +/- 7.6 Delta beats/min] and reduced parasympathetic (CC: 45 +/- 11.8 Delta beats/min vs. HU: 8 +/- 7.3 Delta beats/min) cardiac tone in HU rats. Heart rate variability was reduced (CC: 10 +/- 1.4 ms vs. HU: 7 +/- 0.7 ms), and spectral analysis of blood pressure indicated loss of total, low-, and high-frequency power, consistent with attenuated baroreflex function. These data indicate that cardiovascular deconditioning results in sympathovagal imbalance and behavioral signs consistent with psychological depression. These findings further elucidate the pathophysiological link between cardiovascular diseases and affective disorders.