Abstract

METHODS

Statistical Analysis

In experiment 1, current-response functions were calculated for each individual rat at different time points (baseline, immediate post-HU or -CC condition, and 7 days post-HU or -CC recovery). Data points from individual rats were plotted using Sigma Plot (Jandel Scientific, Chicago, IL), and the following three-parameter sigmoidal function was fit to the data:

(1)

Mean current-response functions were calculated by averaging the response rate for each rat at each level of current intensity and by plotting the mean data using Sigma Plot. A three-parameter sigmoidal function was similarly fit to these data shown above where y = the number of lever presses per minute, x = the standardized current level; x₀ = the ECU₅₀; a = the maximum parameter and b = the minimum parameter.

From each individual fit curve, three parameters were calculated: 1) threshold or current intensity which supported 50% of the maximum response rate (x₀ defined as the effective current “50”; ECu₅₀), 2) maximum rate of responding and corresponding current intensity (a), and 3) minimum rate of responding and corresponding current intensity (b). Mean ECu₅₀ and maximum response values were statistically compared in HU and CC groups using mixed-design ANOVA and Student's t-tests, and a Bonferroni correction for relevant multiple comparisons. Anhedonia was operationally defined as an increase in ECu₅₀, representing a rightward shift in the current-response relationship relative to the baseline values for this function.

In experiment 2, cardiovascular data, HRV and spectral analyses were compared using Student's t-tests and a Bonferroni correction for relevant multiple comparisons. Cardiac autonomic blockade data were analyzed using repeated-measures ANOVA.

In both sets of experiments, changes in body weight were compared using two-way ANOVA with repeated measures design, as were absolute water and sucrose intake in experiment 2. Absolute change in body weight, soleus and plantaris muscle wet weights and muscle weight to body weight ratios were compared using independent t-tests. For all statistical analyses in both sets of experiments, a probability value <0.05 was considered to be statistically significant.

RESULTS

Experiment 1

HU.

Body weights before, immediately after, and following 7 days of recovery from the HU or CC condition are shown in Table 1. Body weight was significantly lower in HU animals 14 days following HU and after 7 days of recovery from HU (P < 0.05). Both soleus and plantaris wet muscle weights and soleus and plantaris muscle-to-body weight ratios measured following 7 days of recovery from HU were not significantly different between groups.

Table 1.

Body weight and muscle weights in casted control and hindlimb unloaded groups in experiment 1

	n	BW, g			Soleus Wt 7-day Recovery, mg	Plantaris Wt 7-day Recovery, mg	Soleus/BW × 103, mg/g	Plantaris/BW × 103, mg/g
		Baseline	Post-HU/CC	7-day Recovery
Casted control	6	333±7.4	358±14.4	378±13.6	131±0.01	412±0.03	0.35±0.02	1.09±0.07
Hindlimb unloaded	6	322±2.2	316±6.9*	329±8.4*	110±0.01	363±0.02	0.34±0.02	1.10±0.03

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Values are means ± SE; n, no. of rats. HU, hindlimb unloading; BW, body weight.

^*P < 0.05 vs. casted control group.

Behavioral responses to electrical stimulation following HU.

A sigmoidal current-response relationship between current intensity and response rate was observed for rewarding electrical brain stimulation. As current intensity increased, response rates increased and reached an asymptote.

HU resulted in reduced responding for electrical stimulation across a range of current intensities, relative to baseline responding and to the responses of CC rats (Figs. 1 and ​and2).2). A parallel rightward shift was observed in the current-response function in the HU group, compared with baseline (Fig. 2B) and CC group responses (Fig. 2A).

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Fig. 1.

Mean current-response parameters (± SE) to intracranial self-stimulation (ICSS) for effective current 50 (ECu₅₀) (A), maximum (B), and minimum (C) stimulation parameters at baseline, immediately following 14 days of hindlimb unloading (post), and after 7 days of recovery in casted control (CC; open bars) and hindlimb unloaded (HU; filled bars) rats. ANOVA revealed a significant main effect for the maximum parameter in HU rats; however, there was no significant interaction. ECu₅₀ was significantly greater immediately following hindlimb unloading thus indicating a rightward shift, or reduced sensitivity to the ICSS reward stimulus. *P < 0.05 vs. CC post time point.

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Fig. 2.

A: mean current-response curves to ICSS showing all HU and CC animals at baseline (solid line) and immediately following 14 days of HU (dotted line) or CC (dashed line) condition. B: only HU animals at baseline (solid line) immediately following 14 days of HU (dotted line) and following 7 days of recovery from HU (dashed line). Data indicate that HU produces a rightward shift in the current-response relationship to ICSS and that this effect fully recovers following 7 days after HU is terminated.

Mean curve parameters, including the maximum, ECu₅₀, and minimum for both groups at baseline, immediately following, and after recovery from the HU or CC condition, are shown in Fig. 1. There were no significant differences with respect to minimal parameters at any time point. The baseline ECu₅₀ values were not different between HU and CC rats. However, immediately following 14 days of HU, the HU rats displayed a significantly higher mean ECu₅₀ than its respective baseline value (P < 0.05) and the CC group (P < 0.05). In the CC group, the mean ECu₅₀ value did not differ significantly from its respective baseline value after 14 days of the CC condition. A mixed-design ANOVA yielded a significant main effect of group (P < 0.05) but no significant interaction for the maximum response rate in HU and CC rats.

Behavioral responses to electrical stimulation following recovery from HU.

Electrical responses to ICSS were able to be maintained through a 7-day recovery period in all CC and HU rats. Additional analysis was performed on these animals to determine the extent of ICSS recovery after the HU or CC condition. Data indicate that a 7-day recovery from the HU procedure resulted in a leftward shift of the current-response curve, that is a return to the baseline function in HU rats (Fig. 2B), whereas the CC rats demonstrated no further change in the response to ICSS (Fig. 1). While the ECu₅₀ value post-HU was significantly greater than this subgroup's respective baseline value (P < 0.05), the ECu₅₀ value following 7 days of recovery from HU was not significantly different from baseline. In addition, this value was also not significantly different from the CC group, indicating that full restoration of responding for electrical stimulation had occurred over the 7-day recovery period.

Experiment 2

HU.

The effects of HU on body weight and hindlimb muscle weight are shown in Table 2. Similar to results in experiment 1, body weight was significantly higher in CC rats compared with HU rats immediately following 14 days of the protocol. Both soleus and plantaris wet muscle weights and soleus and plantaris muscle-to-body weight ratios measured after 14 days of the HU or CC condition were significantly lower in HU rats (P < 0.05).

Table 2.

Body weight and muscle weights in casted control and hindlimb unloaded groups in experiment 2

	n	BW (g)		Soleus Wt Post-HU, mg	Plantaris Wt Post-HU, mg	Soleus/BW × 103, mg/g	Plantaris/BW × 103, mg/g
		Baseline	Post-HU/CC
Casted control	12	297±2.1	306±3.1	130±0.00	343±0.01	0.43±0.01	1.12±0.03
Hindlimb unloaded	12	292±2.1	271±3.3*	70.9±0.01*	271±0.01*	0.26±0.02*	1.00±0.04*

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Values are means ± SE; n, no. of rats.

^*P < 0.05 vs. casted control group.

Sucrose preference.

Although two-way ANOVA for repeated measures revealed no significant differences in absolute water intake (CC, day 1: 3.2 ± 0.5 ml; CC, day 11: 2.9 ± 0.3 ml vs. HU, day 1: 3.0 ± 0.2 ml; HU, day 11: 4.4 ± 0.5 ml), there was a significant group, day, and group × day interaction in absolute sucrose intake. Post hoc analysis revealed no significant difference in absolute baseline sucrose consumption between groups (CC, day 1: 8.4 ± 0.8 ml vs. HU, day 1: 7.8 ± 1.2) and a significant reduction in absolute sucrose intake on day 11 of the protocol (CC, day 11: 13.3 ± 1.4 ml vs. HU, day 11: 6.9 ± 0.9 ml). Data illustrating normalized sucrose preference at baseline and on day 11 of the protocol in HU and CC rats is shown in Fig. 3. Although there was no significant difference at baseline between CC and HU rats (Fig. 3A), HU rats exhibited a significant reduction in the relative amount of sucrose as a percentage of total fluid consumed on day 11 of the HU procedure (P < 0.05; Fig. 3B). Although the absolute intake of sucrose increased in control animals over the course of the protocol, there was no difference in CC rats at baseline and on day 11 of the CC procedure with regard to percent preference for sucrose.

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Fig. 3.

Sucrose preference tests at baseline (A) and during the HU or CC condition (B). Although there were no significant differences in the percent total fluid preference for water (open bars) vs. 2% sucrose (solid bars) at baseline between groups, HU animals had a significantly reduced preference for 2% sucrose on day 11 of the HU procedure, indicating anhedonia. *P < 0.05 vs. CC group.

Plasma corticosterone.

Data comparing plasma corticosterone levels between CC and HU rats are shown in Table 3. There was no significant difference in plasma corticosterone levels between CC and HU rats measured at death on the 14th day of the HU or CC procedure (Table 3).

Table 3.

Baseline cardiovascular parameters and plasma corticosterone concentration in casted control and hindlimb unloaded groups in experiment 2

	N	MAP, (mmHg)	HR, beats/min	SDNN, ms	SD ΔNN, ms	Plasma Corticosterone, μg/dl
Casted control	11	121±3.9	383±9.6	10.4±1.4	3.43±0.4	11.1±1.4
Hindlimb unloaded	11	128±3.0	462±9.1*	6.96±0.7*	2.48±0.2*	11.0±2.6

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Values are means ± SE; MAP, mean arterial pressure; HR, heart rate; SDNN, standard deviation of normal-to-normal (NN) intervals; SD ΔNN, standard deviation of change in NN intervals. n, no. of rats.

^*P < 0.05 vs. casted control group.

Resting baseline hemodynamic parameters.

Baseline cardiovascular parameters following 14 days of the HU or CC condition are shown in Table 3. HU elicited no significant change in resting mean arterial pressure, although there was a significant elevation in resting heart rate compared with CC rats (P < 0.05). Two indices of HRV were calculated in the HU and CC rats. Both the SDNN Index and the SD of ΔNN was significantly reduced following HU, relative to the CC group (P < 0.05; Table 3).

Spectral analysis of arterial blood pressure.

Results from a spectral analysis of arterial blood pressure in both groups of rats following 14 days of the HU or CC condition are shown in Table 4. The spectral analysis revealed that HU rats had a significant reduction in total power and absolute LF power and normalized LF power (P < 0.05). Although absolute HF power was reduced in HU rats, compared with CC rats (P < 0.05), there was no significant difference in normalized HU power.

Table 4.

Spectral analysis of blood pressure at baseline following 14 days of casted control and hindlimb unloading in experiment 2

	n	Total Power, ms2	LF, ms2	HF, ms2	LF, nu	HF, nu
Casted control	11	28.9±4.38	3.48±0.87	3.55±0.78	42.02±5.57	45.97±4.79
Hindlimb unloaded	11	10.8±1.86*	0.58±0.09*	1.59±0.25*	19.34±2.54*	48.76±3.38

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Values are means ± SE; n, no. of rats. LF, low frequency; HF, high frequency; nu, normalized units.

^*P < 0.05 vs. casted control group.

Cardiac autonomic blockade.

Data indicating the effects of cardiac autonomic blockade following HU are shown in Table 5 and Fig. 4, A and B. Baseline heart rate was significantly higher in HU vs. CC rats (P < 0.05; Tables 2 and ​and5;5; Fig. 4A). Administration of propranolol alone in ½ of the HU (n = 6) and CC (n = 6) rats to block cardiac β-adrenergic receptors (cardiac sympathetic tone) resulted in a greater decrease in heart rate in HU rats compared with CC rats (P < 0.05; Table 5, Fig. 4B). The steady-state heart rate recorded following administration of propranolol was not different between groups (Table 5, Fig. 4A). The response to administration of methylatropine alone to block cardiac muscarinic receptors (cardiac parasympathetic tone) in the remainder of HU (n = 5) and CC (n = 5) rats resulted in a significantly greater increase in heart rate from baseline in CC rats and no significant change in heart rate from baseline in HU rats (P < 0.05; Table 5, Fig. 4B). The steady-state heart rate recorded following cardiac parasympathetic blockade was not different between the groups.

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Fig. 4.

Cardiac autonomic blockade indicating the absolute heart rate (HR) response (A) and change (Δ) in HR (B) to intravenous administration of cardiac autonomic blockers (propranolol and atropine) as well as total autonomic blockade (prop + atr) indicating intrinsic HR. Baseline HR was significantly elevated in HU rats (solid bars) compared with CC rats (open bars). There was a greater decrease in HR to sympathetic blockade (propranolol) and very little increase in HR to parasympathetic (atropine) blockade in HU animals compared with CC animals. bpm, Beats/min. *P < 0.05 vs. CC group.

Table 5.

Heart rate response to selective cardiac autonomic blockade

	n	BL HR, beats/min	Atropine HR, beats/min	Atropine Change From BL, Δbeats/min	Atropine + Propranolol HR, beats/min	Propranolol Change From Atropine, Δbeats/min	Total Blockade Change From BL, Δbeats/min
CC	5	395±12.6	454±12.9†	59±14.9	346±12.1†	−108 ±11.8‡	−49±19.6
HU	5	478±12.0*	482±7.4	4.3±8.9*	358±5.9†	−124±9.7	−120±15.8*

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		BL HR, beats/min	Propranolol HR, beats/min	Propranolol Change From BL, Δbeats/min	Propranolol + Atropine HR, beats/min	Atropine Change From Propranol, Δbeats/min	Total Blockade Change From BL, Δbeats/min
CC	6	373±12.5	315±18.4†	−58±8.4	339±16.5	24±7.7	−33±8.4
HU	6	449±11.2*	335±8.2†	−113±4.9*	346±10.5†	11±7.0	−102±8.5*

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Values are means ± SE; n, no. of rats. BL, baseline; CC, casted control; HU, hindlimb unloaded.

^*P < 0.05 vs. CC group;

^†P < 0.05 vs. respective baseline;

^‡P < 0.05 vs. Propranolol Change from BL in respective CC group.

In all rats in both groups, following administration of the first autonomic blocker the second drug was administered to achieve complete cardiac autonomic blockade, thus enabling the measurement of intrinsic heart rate. In both groups of rats, absolute intrinsic heart rate was not different between groups but was significantly lower than baseline heart rate when data from the subgroups of rats were combined (P < 0.05; Fig. 4A). However, the decrease in heart rate from baseline was significantly greater in HU rats compared with CC rats (P < 0.05; Table 5, Fig. 4B).

In CC rats, the change in heart rate in response to propranolol in the presence of atropine was significantly greater than the response to propranolol alone (P < 0.05; Table 5). Although the response to atropine in the presence of propranolol was smaller in CC animals this effect did not reach statistical significance. The heart rate response was not altered by the order of drug administration in either HU group.

DISCUSSION

In the present study, we examined the hypothesis that the HU rat model of cardiovascular deconditioning would be accompanied by both anhedonia and cardiovascular autonomic imbalance. We performed two separate experiments to more fully test this hypothesis. Data indicate that HU results in anhedonia when measured either during or immediately after termination of HU. This was evidenced by both reduced behavioral responding for ICSS and reduced sucrose preference. Thus, with two different experimental methods, converging evidence indicates that HU produces anhedonia. In addition, the experimentally-induced cardiovascular deconditioning is also associated with altered cardiac sympathovagal balance, reduced HRV, and altered spectral analysis of blood pressure.

Anhedonia, defined as the reduced responsiveness to pleasurable stimuli, is estimated to be present in ~95% of all depressed patients (34), and this symptom is a core feature of Major Depressive Disorder according to Diagnostic and Statistical Manual of Mental Disorder, 4th Edition, Text Revision criteria (1). Data from the present study indicate that cardiovascular deconditioning produced through hindlimb unloading induces anhedonia. Two separate specific hedonic measures were obtained which led to this conclusion. In experiment 1 a greater ECu₅₀ was present in HU rats immediately following 14 days of HU compared with their own baseline and the CC group. This value indicates a rightward shift in the current-response function, such that responding is reduced at the same level of current that previously supported the responses and a greater current intensity is required to produce the same level of previously recorded responding (Fig. 1). Parallel shifts in current- or frequency-response functions in electrical brain stimulation paradigms have been suggested as evidence for a change in the reinforcing efficacy of the electrical stimulation (40). Furthermore, the ECu₅₀ in HU rats returned to baseline levels following a 7-day recovery in the normal posture. This recovery value was not significantly different from the HU animals’ original baseline value or that of CC animals (Fig. 2).

Although the maximum response rate to electrical stimulation was not significantly altered in response to HU, animals that recovered from HU did have a tendency toward an increased maximal response. This may indicate that HU rats had improved motor performance following recovery. This response is not surprising considering that HU rats are required to increase forelimb use during the HU procedure and thus they may have improved motor capacity as a result. In addition, any attenuation in ICSS reward could not be attributable to reduced motor performance in this group; in fact, just the opposite could be argued. These conclusions regarding use of these curve parameters as a measure of ICSS reward properties are well supported by previous research employing identical methods in a number of models and task-dependent manipulations (17, 40, 47).

Further evidence for anhedonia in HU rats is supported by the observation that sucrose preference was reduced on day 11 of the 14 day HU protocol. Sucrose preference was not significantly different between CC and HU groups at baseline. The use of sucrose preference as a specific measure of anhedonia has been used extensively in a wide range of depressive animal models and is indicative of the reduced responsiveness to pleasurable stimuli (anhedonia) often observed in human depression (1, 34). The reduced preference for sucrose during the later stages of HU was specific to the procedure and not due to attenuated ingestive behaviors since HU rats did not consume less water than CC animals when preference was measured on day 11 of the protocol. In addition, a second test of sucrose preference in CC animals revealed no significant reductions; thus the attenuation in preference in HU rats is not attributable to a reduced preference as a function of repeated exposure to sucrose.

Psychological depression is characterized by depressed mood, anhedonia, fatigue and physical inactivity (1). Although adverse psychological changes following bed rest or microgravity in humans have been previously documented (25, 27, 33, 66), whether cardiovascular deconditioning leads to psychological depression is not commonly reported. In the present study, we used the HU animal model to more systematically evaluate the hypothesis that cardiovascular deconditioning is associated with depression and cardiovascular autonomic dysfunction.

Data from the present studies indicate that HU results in a profound change in sympathovagal balance. This conclusion is supported from multiple observations. Results from experiment 2 indicate that although there is no change in resting mean arterial pressure, HU rats exhibit a resting tachycardia and reduced HRV (Table 3). Data from cardiac autonomic blockade indicate that these effects are due to both an increased cardiac sympathetic tone and near absence of cardiac vagal tone in the HU rats (Table 5, Fig. 4). This is evidenced by the observation that cardiac sympathetic blockade by administration of propranolol resulted in a greater decrease in heart rate in HU vs. CC rats. In addition, pharmacological blockade of parasympathetic tone to the heart by administration of methylatropine did not significantly increase heart rate above baseline in HU rats, while heart rate increased by 59 ± 14.9 beats/min in CC rats. We did observe that the heart rate response to propranolol was significantly greater following atropine administration in the CC group (Table 5). This is likely due to accentuated antagonism from presynaptic cholinergic inhibition of norepinephrine release from cardiac sympathetic terminals (35). It is interesting to note that this effect was only observed in CC animals, which emphasizes the lack of vagal tone to the heart in HU animals.

These findings taken together indicate that sympathovagal balance is altered in response to HU such that there is both a significant increase in sympathetic tone and profound reduction in parasympathetic tone to the heart. This finding is in agreement with Mueller et al. (48) in which HU rats were reported to have a blunted increase in heart rate in response to parasympathetic blockade by atropine, and enhanced reductions in heart rate and mean arterial pressure in response to ganglionic blockade via hexamethonium. In addition, reduced parasympathetic and increased sympathetic cardiac tone has been reported in astronauts following exposure to microgravity (39).

Additional findings from the present study indicate that autonomic tone to the vasculature is altered by HU. Power spectral analysis of arterial blood pressure revealed that HU resulted in a significantly reduced total power, absolute HF power, and both absolute and normalized LF power (P < 0.05; Table 4). Only normalized HF power was not significantly different between CC and HU rats. There are several possible interpretations of this finding. Because blood pressure and sympathetic nervous system activity have been found to be tightly coupled at 0.4 Hz (within the LF band designated in the present study; Refs. 5, 8), in general, changes in power from 0.2 to 0.8 Hz have been used to indicate changes in vasomotor sympathetic drive, although not without exception (57). Thus, one interpretation of the spectral analysis data from the present study is that HU resulted in reduced sympathetic vascular tone. This interpretation, however, would be in disagreement with the current finding that HU results in augmented cardiac sympathetic tone, as well as previous data indicating that HU rats have a greater resting sympathetic tone to the vasculature (48). In addition, the use of changes in power from 0.2 to 0.8 Hz as an index of chronic sympathetic tone to the vasculature has been called into question by data indicating that a higher level of directly measured splanchnic sympathetic nerve activity was not associated with higher blood pressure power at 0.2–0.8 Hz (65). The most plausible interpretation for the current data is that reduced total power and greatly reduced LF power is reflective of reduced baroreflex control of sympathetic nervous system activity to the vasculature. This explanation is consistent with previous studies indicating that baroreflex control of sympathetic nerve activity is attenuated following HU in rats (12, 41, 44, 45) and that sympathetic responses to orthostatic stress are attenuated in humans (31, 62). Furthermore, this finding is consistent with the observation that LF power (0.27–0.74 Hz, similar to the LF band used in the present study) is reduced, while HF power is preserved following sinoaortic baroreceptor denervation in rats (8, 28, 29). The authors noted that the presence of the well-described LF peak at ~0.4 Hz was abolished following sinoaortic baroreceptor denervation. It is interesting to note that in the present study this peak was clearly observed in 9 of 11 CC rats, while this peak was detectable only in 4 of 11 HU rats and at a much reduced amplitude of power than in CC rats. This effect has been substantiated in humans in that the sensitivity of the gain of the baroreflex is positively correlated with LF power (10, 64). Thus the reduction in LF power in HU rats observed in the present study may be related to the attenuation in baroreflex control of sympathetic nervous system activity that has been previously well described in the HU rat model (12, 41, 44, 45).

Although absolute power in the HF band was reduced following HU (P < 0.05; Table 5), there was no difference in normalized HF power in HU vs. CC rats. Although HF blood pressure power may be indicative of cardiac vagal drive, this index is controversial and is most consistently associated with mechanical effects related to respiration (57). Thus this finding may indicate that HU rats have altered respiration, although we did not measure the respiratory rate in HU rats. In addition, normalized HF power was not altered, which is an index normalized to total power minus very LF power (0.0–0.195 Hz). We did not believe that the very LF power could be legitimately evaluated in this study due to the relatively short (<1 h) recording period. However, because HU resulted in a greatly reduced very LF power (data not shown), this effect could have served to result in no change in normalized HF power.

Data from the present study indicate that HU results in elevated cardiac sympathetic nervous system activity. It is unknown if there is a generalized increase in sympathetic outflow, which may be indicative of increased stress associated with this model. In the present study, we found no significant differences in plasma corticosterone levels following 14-days of HU or CC condition. This finding is in agreement with previous data indicating that 14 days of HU does not induce hypertrophy of the adrenal glands (12). These values are similar to those measured using similar collection techniques in control animals during the evening hours when corticosterone levels are at their peak (23, 36, 38). These data indicate that any elevation in sympathetic tone is most likely due to specific physiological adjustments associated with cardiovascular deconditioning (i.e., compensation for reduced blood and plasma volume or autonomic dysregulation) rather than a generalized, nonspecific stress response to the HU paradigm.

Psychological depression has a bidirectional association with cardiovascular disease indicating that the presence of one of these conditions increases an individual's likelihood of developing the other disorder (18). Previously, our laboratory demonstrated the presence of both anhedonia and autonomic imbalance in the chronic mild stress rodent model of depression (20), as well as altered sympathoexcitatory responses to behavioral and pharmacological stimuli in the olfactory bulbectomy depression model (42). Although the association between depression-related signs and autonomic imbalance has been repeatedly demonstrated, the precise physiological mechanisms that underlie this relationship have yet to be understood. It is possible that the link between depression and cardiovascular dysfunction may be mediated in part by autonomic imbalance and dysregulation of autonomic reflexes that serve to regulate cardiovascular function. Reduced HRV, increase sympathetic tone, and reduced baroreflex sensitivity have been observed in depressed patients (2, 58, 70, 71) with an increase in HRV found with successful treatment for depression (2).

Previous studies in humans following bed rest and microgravity have indicated that cardiovascular deconditioning is associated with depression (25, 33, 66) and disordered autonomic tone (3, 39), although no studies to our knowledge have systematically explored the interrelationship between these factors. The present study describes the presence of both depressive-like signs and sympathovagal imbalance in an animal model of cardiovascular deconditioning. It is possible that HU leads to sympathovagal imbalance, similar to the imbalance that is observed in depressed patients and in experimental rat models of depression (18, 70). This sympathovagal imbalance may in turn affect the behavioral and cardiovascular changes in these rats. Although the mechanisms responsible for this effect are unknown, underlying changes within the central nervous system are likely. Likely candidates include changes in serotonin and/or catecholamines (i.e., norepinephrine and/or dopamine) neurotransmitter systems. Anhedonia was reversed and cardiovascular dysfunction was partially reversed following treatment with fluoxetine in the chronic mild stress rat model of depression (16). In addition, short-term fluoxetine treatment reversed attenuated baroreflex control of sympathetic nervous system activity following 14-days of HU in rats (44).

HU produces a significant reduction in plasma volume (67), similar to what is observed in humans following prolonged bed rest or exposure to microgravity (9). Elevations in volume regulating hormones, which are thought to help compensate for this contracted circulating volume, have been measured both during and after HU. Although changes in plasma renin activity have not been found to be altered either during or after HU (50, 67), elevations in plasma aldosterone have been observed within 24 h (67), and after 7 days (52) of HU. Interestingly an increase in aldosterone, in the absence of any changes in plasma renin activity, was measured in two separate studies of clinically depressed patients (11, 51). In addition, aldosterone has been implicated in both the anhedonic state in sodium-deprived rats (47) as well as attenuated baroreflex control of sympathetic nerve activity in heart failure rats (13). Thus, although aldosterone may be a critical link between changes in affect and sympathovagal balance following cardiovascular deconditioning, future studies are needed to address this hypothesis.

GRANTS

This work was supported by National Heart, Lung, and Blood Institute Grants HL-14388 and HL-57472; National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-066086 (to A. K. Johnson); and National Institute of Mental Health Grant MH-65839 (to A. J. Grippo).

Acknowledgments

Notes

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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