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Exposure to social and environmental stressors may influence behavior as well as autonomic and cardiovascular regulation, potentially leading to depressive disorders and cardiac dysfunction including elevated sympathetic drive, reduced parasympathetic function, and ventricular arrhythmias. The cellular mechanisms that underlie these interactions are not well understood. One mechanism may involve alterations in the expression of Connexin43 (Cx43) and Connexin45 (Cx45), gap junction proteins in the heart that play an important role in ensuring efficient cell-to-cell coupling and the maintenance of cardiac rhythmicity. The present study investigated the hypothesis that long-term social isolation, combined with mild environmental stressors, would produce both depressive behaviors and altered Cx43 and Cx45 expression in the left ventricle of prairie voles - a socially monogamous rodent model. Adult, female prairie voles were exposed to either social isolation (n = 22) or control (paired, n = 23) conditions (4 weeks), alone or in combination with chronic mild stress (CMS) (1 week). Social isolation, versus paired control conditions, produced significantly (p < 0.05) increased depressive behaviors in a 5-min forced swim test, and CMS exacerbated (p < 0.05) these behaviors. Social isolation (alone) reduced (p < 0.05) total Cx43 expression in the left ventricle; whereas CMS (but not isolation) increased (p < 0.05) total Cx45 expression and reduced (p < 0.05) the Cx43/Cx45 ratio, measured via Western blot analysis. The present findings provide insight into potential cellular mechanisms underlying altered cardiac rhythmicity associated with social and environmental stress in the prairie vole.

Hindlimb unloading (HU) is a well-established animal model of cardiovascular deconditioning. Previous data indicate that HU results in cardiac sympathovagal imbalance. It is well established that cardiac sympathovagal imbalance increases the risk for developing cardiac arrhythmias. The cardiac gap junction protein connexin 43 (Cx43) is predominately expressed in the left ventricle (LV) and ensures efficient cell-to-cell electrical coupling. In the current study we wanted to test the hypothesis that HU would result in increased predisposition to cardiac arrhythmias and alter the expression and/or phosphorylation of LV-Cx43. Electrocardiographic data using implantable telemetry were obtained over a 10- to 14-day HU or casted control (CC) condition and in response to a sympathetic stressor using isoproterenol administration and brief restraint. The arrhythmic burden was calculated using a modified scoring system to quantify spontaneous and provoked arrhythmias. In addition, Western blot analysis was used to measure LV-Cx43 expression in lysates probed with antibodies directed against the total and an unphosphorylated form of Cx43 in CC and HU rats. HU resulted in a significantly greater total arrhythmic burden during the sympathetic stressor with significantly more ventricular arrhythmias occurring. In addition, there was increased expression of total LV-Cx43 observed with no difference in the expression of unphosphorylated LV-Cx43. Specifically, the increased expression of LV-Cx43 was consistent with the phosphorylated form. These data taken together indicate that cardiovascular deconditioning produced through HU results in increased predisposition to cardiac arrhythmias and increased expression of phosphorylated LV-Cx43.

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.

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.

The function of the arterial baroreflex has traditionally been assessed by measurement of reflex changes in heart rate (HR) or sympathetic nerve activity resulting from experimenter-induced manipulation of arterial blood pressure (the Oxford method, also termed the pharmacological method). However, logistical and flexibility limitations of this technique have promoted the development of new methods for assessing baroreflex function such as the evaluation of changes in spontaneous arterial pressure and HR. Although this new spontaneous method has been validated in dogs and humans, it has not been rigorously tested in rats. In the present study, the method of correlating spontaneous changes in systolic blood pressure and HR was evaluated in resting, normotensive Sprague-Dawley rats. This technique was found to be neither reliable nor valid under the conditions employed in the present protocol. We also tested a variation of the spontaneous method that evaluates particular sequences of data during which arterial pressure and pulse interval are changing in the same direction for at least three consecutive heartbeats (the sequence method). The sequence method did not provide extra reliability or validity over the spontaneous method. We conclude that due to the restricted range of variability obtained by measuring spontaneous blood pressure fluctuations, the spontaneous and sequence techniques do not provide data that are comparable to the traditional method of assessing HR changes triggered by arterial blood pressure increases and decreases induced by vasoactive drugs. However, it is possible that surgical stress obscured the relationship between blood pressure and HR, and therefore additional studies are needed to determine whether the spontaneous and sequence methods can be applied to rats during different behavioral states.

Hindlimb unloading (HU) is an animal model of microgravity and bed rest. In these studies, we examined the role of ingestive behaviours in regulating body fluid balance during 24 h HU. In the first experiment, all rats were given distilled water to drink while two groups were also given access to a sodium chloride solution (0.9% or 1.8%). Water and saline intakes were measured before, during and after 24 h of HU. Rats reduced water intake during 24 h HU in all conditions. During HU, rats increased their intakes of both saline solutions (0.9% NaCl (n= 11): control 7.8 +/- 3 ml; HU 18.2 +/- 4 ml; recovery 8.9 +/- 2.5 ml; 1.8% NaCl (n= 7): control 1.0 +/- 0.4 ml; HU 3.8 +/- 0.3 ml; recovery 1.2 +/- 0.5 ml). Although water intake decreased there was no reduction in total fluid intake when saline was available. Plasma volumes were reduced during HU compared to rats in a normal posture when only water was available to drink (control (n= 11) versus HU (n= 11): 4.0 +/- 0.2 versus 3.4 +/- 0.2 ml (100 g body weight)(-1)). When 0.9% saline was available in addition to water, plasma volumes after 24 h HU were not different from rats in a normal posture (control (n= 11) versus HU (n= 12): 4.3 +/- 0.4 versus 4.3 +/- 0.1 ml (100 g body weight)(-1)). Plasma aldosterone but not plasma renin activity was significantly elevated after 24 h HU. Central infusions of spironolactone blocked the increased intake of 1.8% saline that was associated with 24 h HU. Thus, HU results in an aldosterone-dependent sodium appetite and the ingestion of sodium may help maintain plasma volume.

Data in humans indicate that individuals with orthostatic hypotension that are refractory to other traditional forms of therapy are responsive to selective serotonin reuptake inhibitor (SSRI) treatment. We tested the hypothesis that SSRI administration would help correct the attenuated baroreflex control of sympathetic nervous system activity in the hindlimb-unloaded (HU) rat model of cardiovascular deconditioning. An initial study was conducted to determine the time course of effects of fluoxetine (Flu) administration on baroreflex control of lumbar sympathetic nerve activity (LSNA) in conscious, chronically instrumented rats. Animals received either vehicle (Veh, sterile water) or 10 mg/kg Flu for 1, 4, or 16 days of treatment. Data indicate that while 1-day and 16-day Flu administration did not affect baroreflex function, baroreflex control of LSNA was enhanced after 4-day (short term) Flu administration. HU rats were then treated with Flu for 4 days and compared with HU rats receiving Veh and to casted control rats maintained in the normal posture that received either Veh or short-term Flu treatment. Similar to pilot data, short-term Flu treatment enhanced baroreflex control of LSNA in both HU rats and control rats. These data taken together indicate that baroreflex control of sympathetic nervous system activity is a possible mechanism responsible for the successful treatment of orthostatic intolerance with Flu.

Bilateral removal of the olfactory lobes in rats produces a number of behavioral, endocrine, and neurochemical alterations in the brain. Little is known, however, regarding the effects of this treatment on cardiovascular function and autonomic reflexes. Male Sprague-Dawley rats underwent bilateral surgical ablation of the olfactory bulbs (n = 10) or were sham operated (n = 8). After 3 wk of recovery, animals were instrumented with femoral catheters and a lumbar sympathetic nerve recording electrode. After 24 h of recovery, cardiovascular responses to arterial baroreflex manipulation, air jet stress, and smoke exposure were recorded. Olfactory bulbectomized rats demonstrated attenuated sympathoexcitatory responses to hypotension, air jet stress, and smoke exposure, as well as elevated basal blood pressure, compared with sham-operated rats. These data indicate that the integrity of the olfactory bulbs in rats is important for the elicitation of normal cardiovascular and autonomic responses to a number of evocative stimuli.

Attenuated baroreflex-mediated increases in renal sympathetic nerve activity (RSNA) in hindlimb unloaded (HU) rats apparently are due to changes within the central nervous system. We hypothesized that GABA(A) receptor-mediated inhibition of the rostral ventrolateral medulla (RVLM) is increased after hindlimb unloading. Responses to bilateral microinjection of the GABA(A) antagonist (-)-bicuculline methiodide (BIC) into the RVLM were examined before and during caudal ventrolateral medulla (CVLM) inhibition in Inactin-anesthetized control and HU rats. Increases in mean arterial pressure (MAP), heart rate (HR), and RSNA in response to BIC in the RVLM were significantly enhanced in HU rats. Responses to bilateral CVLM blockade were not different. When remaining GABA(A) inhibition in the RVLM was blocked by BIC during CVLM inhibition, the additional increases in MAP and RSNA were significantly greater in HU rats. These data indicate that GABA(A) receptor-mediated inhibition of RVLM neurons is augmented after hindlimb unloading. Effects of input from the CVLM were unaltered. Thus, after cardiovascular deconditioning in rodents, the attenuated increase in sympathetic nerve activity in response to hypotension is associated with greater GABA(A) receptor-mediated inhibition of RVLM neurons originating at least in part from sources other than the CVLM.

Depressed patients with and without a history of cardiovascular pathology display signs, such as elevated heart rate, decreased heart rate variability, and increased physiological reactivity to environmental stressors, which may indicate a predisposition to cardiovascular disease. The specific physiological mechanisms associating depression with such altered cardiovascular parameters are presently unclear. The current study investigated cardiovascular regulation in the chronic mild stress rodent model of depression and examined the specific autonomic nervous system mechanisms underlying the responses. Sprague-Dawley rats exposed to a series of mild, unpredictable stressors over 4 wk displayed anhedonia (an essential feature of human depression), along with elevated resting heart rate, decreased heart rate variability, and exaggerated pressor and heart rate responses to air jet stress. Results obtained from experiments studying autonomic blockade suggest that cardiovascular alterations in the chronic mild stress model are mediated by elevated sympathetic tone to the heart. The present findings have implications for the study of pathophysiological links between affective disorders and cardiovascular disease.

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.

The effect of cardiovascular deconditioning on central nervous system processing of baroreceptor afferent activity was evaluated following 14 days of hindlimb unloading (HU). Inactin-anesthetized rats were instrumented with catheters, renal sympathetic nerve electrodes, and aortic depressor nerve electrodes for measurement of mean arterial pressure, heart rate, renal sympathetic nerve activity (RSNA), and aortic depressor nerve activity (ADNA). Baroreceptor and baroreflex functions were assessed during infusion of phenylephrine and sodium nitroprusside. Central processing of baroreceptor afferent input was evaluated by linear regression relating RSNA to ADNA. The maximum baroreflex-elicited increase in RSNA was significantly reduced in HU rats (122 +/- 3.8 vs. 144 +/- 4.9% of baseline RSNA), whereas ADNA was not altered. The slope (-0.18 +/- 0.04 vs. -0.40 +/- 0.04) and y-intercept (121 +/- 3.2 vs. 146 +/- 4.3) of the linear regression relating increases in efferent RSNA to decreases in afferent ADNA during hypotension were significantly reduced in HU rats. There were no differences during increases in arterial pressure. Results demonstrate that the attenuation in baroreflex-mediated increases in RSNA following HU is due to changes in central processing of baroreceptor afferent information rather than aortic baroreceptor function.

Glutamate is the proposed neurotransmitter of baroreceptor afferents at the level of the nucleus of the solitary tract (NTS). Blockade of ionotropic glutamate receptors with kynurenic acid blocks the arterial baroreflex but, paradoxically, does not abolish the response to exogenous glutamate. This study tested the hypothesis that exogenous glutamate in the NTS activates both ionotropic and metabotropic glutamate receptors (mGluRs). In urethan-anesthetized rats, unilateral microinjections of glutamate into the NTS decreased mean arterial pressure, heart rate, and lumbar sympathetic nerve activity. The cardiovascular response to injection of glutamate was not altered by NTS blockade of mGluRs with alpha-methyl-4-carboxyphenylglycine (MCPG). Blockade of ionotropic glutamate receptors with kynurenic acid attenuated the response to glutamate injection. After combined NTS injection of MCPG and kynurenic acid, the response to glutamate was blocked. These data suggest that exogenous glutamate microinjected into the NTS acts at both ionotropic glutamate receptors and mGluRs. In addition, blockade of both classes of glutamate receptors is required to block the cardiovascular response to microinjection of glutamate in the NTS.

The effect of cardiovascular deconditioning on baroreflex control of the sympathetic nervous system was evaluated after 14 days of hindlimb unloading (HU) or the control condition. Rats were chronically instrumented with catheters and sympathetic nerve recording electrodes for measurement of mean arterial pressure (MAP) and heart rate (HR) and recording of lumbar (LSNA) or renal (RSNA) sympathetic nerve activity. Experiments were conducted 24 h after surgery, with the animals in a normal posture. Baroreflex function was assessed using a logistic function that related HR and LSNA or RSNA to MAP during infusion of phenylephrine and nitroprusside. Baroreflex influence on HR was not affected by HU. Maximum baroreflex-elicited LSNA was significantly reduced in HU rats (204 +/- 11.9 vs. 342 +/- 30.6% baseline LSNA), as was maximum reflex gain (-4.0 +/- 0.6 vs. -7.8 +/- 1.3 %LSNA/mmHg). Maximum baroreflex-elicited RSNA (259 +/- 10.8 vs. 453 +/- 28.0% baseline RSNA), minimum baroreflex-elicited RSNA (-2 +/- 2.8 vs. 13 +/- 4.5% baseline RSNA), and maximum gain (-5.8 +/- 0.5 vs. -13.6 +/- 3.1 %RSNA/mmHg) were significantly decreased in HU rats. Results demonstrate that baroreflex modulation of sympathetic nervous system activity is attenuated after cardiovascular deconditioning in rodents. Data suggest that alterations in the arterial baroreflex may contribute to orthostatic intolerance after a period of bedrest or spaceflight in humans.