Spontaneous Running Research Articles

Exercise pressor reflex in decerebrate and anesthetized rats.

I investigated whether muscular contraction evokes cardiorespiratory increases (exercise pressor reflex) in alpha-chloralose- and chloral hydrate-anesthetized and precollicular, midcollicular, and postcollicular decerebrated rats. Mean arterial pressure (MAP), heart rate (HR), and minute ventilation (Ve) were recorded before and during 1-min sciatic nerve stimulation, which induced static contraction of the triceps surae muscles, and during 1-min stretch of the calcaneal tendon, which selectively stimulated mechanosensitive receptors in the muscles. Anesthetized rats showed various patterns of MAP response to both stimuli, i.e., biphasic, depressor, pressor, and no response. Sciatic nerve stimulation to muscle in precollicular decerebrated rats always evoked spontaneous running, so the exercise pressor reflex was not determined from these preparations. None of the postcollicular decerebrated rats showed a MAP response or spontaneous running. Midcollicular decerebrated rats consistently showed biphasic blood pressure response to both stimulations. The increases in MAP, HR, and Ve were related to the tension developed. The static contractions in midcollicular decerebrated rats (381 +/- 65 g developed tension) significantly increased MAP, HR, and Ve from 103 +/- 12 to 119 +/- 24 mmHg, from 386 +/- 30 to 406 +/- 83 beats/min, and from 122 +/- 7 to 133 +/- 25 ml/min, respectively. After paralysis, sciatic nerve stimulation had no effect on MAP, HR, or Ve. These results indicate that the midcollicular decerebrated rat can be a model for the study of the exercise pressor reflex.

The significance of circadian phase for performance on a reward-based learning task in hamsters

In humans and animal models, circadian modulation of learning has been demonstrated on numerous tests. However, it is unclear which aspects of the cognitive process are rhythmically regulated. In these experiments, we used a conditioned place preference task in hamsters to ask whether memory acquisition (hypothesis 1) or memory recall and performance (hypothesis 2) were subject to circadian modulation. In golden hamsters, access to a running wheel has been used as a reward to condition a place preference, but when given unrestricted access to a wheel, animals perform most of their spontaneous running within a few hours each day or circadian cycle. This suggested that either the perceived reward value of the wheel changes through the day or that the response to this reward is temporally restricted. Contrary to the hypotheses, we found that learning was not tied to the time of training nor to the time of testing, but rather animals showed a preference for a reward-paired context only at the circadian time that training had taken place. Timing is not an explicit discriminative cue in these experiments. Hence, the learning mechanism must be predisposed to register circadian time as an attribute during context learning.

Effects of daily spontaneous running on the electrophysiological properties of hindlimb motoneurones in rats.

No evidence currently exists that motoneurone adaptations in electrophysiological properties can result from changes in the chronic level of neuromuscular activity. We examined, in anaesthetized (ketamine/xylazine) rats, the properties of motoneurones with axons in the tibial nerve, from rats performing daily spontaneous running exercise for 12 weeks in exercise wheels ('runners') and from rats confined to plastic cages ('controls'). Motoneurones innervating the hindlimb via the tibial nerve were impaled with sharp glass microelectrodes, and the properties of resting membrane potential, spike threshold, rheobase, input resistance, and the amplitude and time-course of the afterhyperpolarization (AHP) were measured. AHP half-decay time was used to separate motoneurones into 'fast' (AHP half-decay time < 20 ms) and 'slow' (AHP half-decay time >/= 20 ms), the proportions of which were not significantly different between controls (58 % fast) and runners (65 % fast). Two-way ANOVA and ANCOVA revealed differences between motoneurones of runners and controls which were confined to the 'slow' motoneurones. Specifically, runners had slow motoneurones with more negative resting membrane potentials and spike thresholds, larger rheobasic spike amplitudes, and larger amplitude AHPs compared to slow motoneurones of controls. These adaptations were not evident in comparing fast motoneurones from runners and controls. This is the first demonstration that physiological modifications in neuromuscular activity can influence basic motoneurone biophysical properties. The results suggest that adaptations occur in the density, localization, and/or modulation of ionic membrane channels that control these properties. These changes might help offset the depolarization of spike threshold that occurs during rhythmic firing.

Immunomodulatory action of chronic exercise on macrophage and lymphocyte cytokine production in mice.

This study was designed to evaluate the effects of 8-week voluntary running exercise on cytokine production of macrophages and lymphocytes. Seven-week-old-male BALB/c inbred mice were divided into two groups: a group given voluntary exercise (exercise group, n=32), and the other, a non-exercise group (control group, n=32). Exercise consisted of spontaneous running in wheels for 3 days per week over 8 weeks. The levels of nitric oxide (NO2-) and interleukin (IL)-1 beta production by lipopolysaccharide (LPS)-stimulated peritoneal macrophages from the exercise group was significantly higher than that in the control group (P < 0.05-P < 0.01). In the exercise group, stimulation indices by concanavalin A (Con A) was significantly higher than they were in the control group (P < 0.05-P < 0.001). When compared with the control group, the exercise group showed a significant (P < 0.05) increase in the splenic lymphocyte production of IL-2 stimulated by Con A (449.5 +/- 28.2 and 853.7 +/- 116.0 pg 4 x 10(5) cells(-1) 48 h(-1) for the control group and the exercise group, respectively). IL-4 production of splenocytes stimulated by Con A in the exercise group (37.6 +/- 5.1 pg 4 x 10(5) cells(-1) 48 h(-1)) was higher than that in the control group (30.9 +/- 3.9 pg 4 x 10(5) cells(-1) 48 h(-1)); however, the difference was not statistically significant. These results suggest that 8-week voluntary running exercise effectively enhanced macrophage and lymphocyte functions in mice.

Daily Exercise Reduces Measures of Heart Rate and Blood Pressure Variability in Hypertensive Rats

This study was designed to test the hypothesis that daily spontaneous running (DSR) reduces measures of heart rate and blood pressure variability in spontaneously hypertensive rats (SHR). After 8 weeks of DSR or sedentary control, rats were chronically instrumented with arterial catheters. Daily exercise reduced most measures of heart rate (HR) and blood pressure variability. Specifically DSR decreased heart rate, Low Frequency Power (LF: 0.19–0.61 Hz), and Low Frequency/High Frequency (HF: 1.2–2.5 Hz) ratio of HR. Furthermore, Total Power (TP), LF power, and LF/HF ratio of systolic blood pressure were reduced by daily spontaneous running. Finally, TP, LF and HF powers and LF/HF ratios of diastolic blood pressure were reduced by daily spontaneous running. These data demonstrate that daily exercise reduces sympathetic activity and possibly increases cardiac reserve in hypertensive animals.

Cytokine expression in the mouse brain in response to immune activation by Corynebacterium parvum.

Cytokine expression in the brain has been suggested to mediate various sickness behaviors. Here we report that intraperitoneal injection of a Corynebacterium parvum antigen in C57BL/6 mice was followed by prolonged upregulation of cytokines in the cerebral cortex and subcortical structures in a time course that coincided with reduced spontaneous running activity.

Behavioral feedback regulation of circadian rhythm phase angle in light-dark entrained mice.

Induced and spontaneous wheel running can alter the phase and period (tau) of circadian rhythms in rodents. The relationship between spontaneous running and the phase angle (psi) of entrainment to 24-h light-dark (LD) cycles was evaluated in C57BL/6j mice. With a wheel freely available, psi was significantly correlated with the absolute (r = 0.32) and relative (r = 0.44) amount of activity during the first 2 h of the activity period. When wheels were locked during the first half of the night in LD and then unlocked in constant dark (DD), mice exhibited a delayed psi and lengthened tau compared with mice that had wheels locked during the second half of the night. In DD, tau correlated negatively with total daily activity. To evaluate if wheel running modulates the phase-resetting actions of LD, phase shifts to light pulses were measured at two time points in DD, when daily activity levels differed by 40%. Phase delays to light were 56% greater when activity levels were lower. However, in a counterbalanced follow-up experiment, phase advances and delays to light pulses were not affected by the availability of wheels, although an effect of time in DD was replicated. Spontaneous activity can regulate psi and tau without altering the response of the pacemaker to light.

Changes in ambient temperature at the onset of thermoregulatory responses in exercise-trained rats.

Spontaneous running in a wheel has emerged as a useful method of exercise in rodents. We investigated how exercise training with a running wheel affects ambient temperatures (T(a)) at the onset of thermoregulatory responses in rats. Female rats were allowed to run freely in the wheel for 6 months. Sedentary control rats did not exercise during the same period. After the exercise training period, they were loosely restrained and T(a) values at the onset of tail skin vasodilation and cold-induced thermogenesis were determined by raising or lowering T(a). Resting levels of core temperature and heat production of the exercise-trained rats were significantly higher than those of the controls. T(a) values at the onset of tail skin vasodilation and cold-induced thermogenesis of the exercise-trained rats were higher than those of the controls. The results suggest that, in rats, exercise training with a running wheel elevates ambient temperatures for heat loss and heat production, which may then contribute to maintaining the core temperature at a high level.

Immunomodulation by 8-week voluntary exercise in mice.

This study was designed to evaluate the effects of voluntary exercise on macrophage and lymphocyte functions in mice. Male A/He inbred mice aged 19 weeks were divided into two groups: a group given voluntary exercise and a control group (n = 10 in each group). Exercise consisted of spontaneous running in wheels for 8 weeks (3 days week-1). Glucose consumption of peritoneal macrophages in the exercise group during incubation up to 72 h was significantly higher than that in the control group (70 and 13%, respectively). Also, activities of acid phosphatase (APH) (10.75 +/- 0.37 IU), beta-glucuronidase (GLU) (1.55 +/- 0.07 IU) and lactate dehydrogenase (LDH) (43.3 +/- 0.7 IU) in the peritoneal macrophages in the exercise group was significantly increased (P < 0.01). Compared with the control group, the exercise group had a significant increase of about twofold in macrophage production of nitric oxide (NO2-) stimulated by lipopolysaccharide (LPS) (11.1 +/- 0.1 vs. 5.9 +/- 0.1 microM mL-1 in exercise and control groups, respectively; P < 0.01). Stimulation indices both by concanavalin A (Con A) and phytohaemagglutinin were also significantly higher in the exercise group (P < 0.01). A significant increase in the splenocyte production of interleukin-2 (IL-2) stimulated by Con A was noticed in the exercise group (354.1 +/- 28.8 vs. 218.9 +/- 23.5 pg mL-1 in exercise and control groups, respectively; P < 0.01). These findings suggest that voluntary exercise enhances not only macrophage function but also lymphocyte responsiveness in mice. In the studies of voluntary exercise, evaluation of NO2- production, as an indicator of macrophage function, is recommended.

Myosin heavy chain composition of skeletal muscles in young rats growing under hypobaric hypoxia conditions.

This study investigated the effects of voluntary wheel running on the myosin heavy chain (MHC) composition of the soleus (Sol) and plantaris muscles (Pla) in rats developing under hypobaric choronic hypoxia (CH) conditions during 4 wk in comparison with those of control rats maintained under local barometric pressure conditions (C) or rats pair-fed an equivalent quantity of food to that consumed by CH animals (PF). Compared with C animals, sedentary rats subjected to CH conditions showed a significant decrease in type I MHC in Sol (-12%, P < 0.01). Although strongly decreased under hypoxia, spontaneous running activity increased the expression of type I MHC (P < 0.01) so that no difference in the MHC profile of Sol was shown between CH active and C active rats. The MHC distribution in Sol of PF rats was not significantly different from that found in C animals. CH resulted in a significant decrease in type I (P < 0.01) and type IIA (P < 0.005) MHC, concomitant with an increase in type IIB MHC in Pla (P < 0.001), compared with C and PF animals. In contrast to results in Sol muscle, this slow-to-fast shift in the MHC profile was unaffected by spontaneous running activity. These results suggest that running exercise suppresses the hypoxia-induced slow-to-fast transition in the MHC expression in Sol muscles only. The hypoxia-induced decrease in food intake has no major influence on MHC expression in developing rats.

Spontaneous wheel running attenuates cardiovascular responses to stress in rats

Spontaneous wheel running attenuates cardiovascular responses to stress in rats

DAILY EXERCISE ATTENUATED THE SYMPATHETIC COMPONENT OF THE SPONTANEOUS ARTERIAL BAROREFLEX CONTROL OF HEART RATE IN HYPERTENSIVE RATS

The influence of daily spontaneous running on the sympathetic and parasympathetic components of the spontaneous arterial baroreflex control of heart rate was examined in 22 female spontaneously hypertensive rats [12 sedentary and 10 daily spontaneous running]. Following 8 weeks of sedentary control or daily spontaneous running, animals were chronically instrumented with an arterial catheter. Daily spontaneous running resulted in an increased heart weight/body weight ratio (5.2±0.27 vs 4.3±0.01 g/kg) and a resting bradycardia (321±8 bpm vs 360±6). The spontaneous changes in arterial pressure and the reflex responses of heart rate were examined under three experimental conditions: 1) pre-blockade, 2) following β1-adrenergic receptor blockade, and 3) following muscarinic-cholinergic receptor blockade. Daily spontaneous running attenuated the spontaneous gain of the arterial baroreflex control of heart rate (56%). After muscarinic-cholinergic receptor blockade, the spontaneous gain remained reduced in daily spontaneous running rats (57%). In contrast, after β1-adrenergic receptor blockade the spontaneous gain was not different between sedentary control and daily spontaneous running animals. Results demonstrate that daily spontaneous running decreased the sympathetic component resulting in an apparently greater influence of the parasympathetic component on the spontaneous arterial baroreflex control of heart rate.

DAILY EXERCISE ATTENUATES THE DEVELOPMENT OF ARTERIAL BLOOD PRESSURE RELATED CARDIOVASCULAR RISK FACTORS IN HYPERTENSIVE RATS

This study was designed to test the hypothesis that daily spontaneous running (DSR) attenuates the development of blood pressure-related cardiovascular disease risk factors (BP-related CVD risk factors) in spontaneously hypertensive rats (SHR). After 8 weeks of DSR or sedentary control, rats were chronically instrumented with arterial catheters. Daily exercise attenuated the development of all measures of BP-related CVD risk factors. Specifically DSR attenuated the increase in systolic blood pressure (Δ-22 mmHg), systolic blood pressure variability (Δ-2.5 mmHg), and systolic blood pressure load (Δ-27%). Similarly, DSR attenuated the increase in diastolic blood pressure (Δ-15 mmHg), diastolic blood pressure variability (Δ-1.19 mmHg), and diastolic blood pressure load (Δ-17%). Finally, DSR attenuated the development of tachycardia (Δ-63 bpm). These data demonstrate that daily exercise attenuates the development of hypertension and tachycardia in animals predisposed to hypertension.

Deprived of habitual running, rats downregulate BDNF and TrkB messages in the brain

To study possible effects of physical training on the expression of neurotrophic factors and their receptors in the brain, we used a rat strain (spontaneously hypertensive rat, SHR), known to spontaneously run up to 20 km/night. We show that such long-distance running affects the brain-derived neurotrophic factor (BDNF) and TrkB system in hippocampus, and in particular that abrupt deprivation of habitual running leads to long-lasting decreases of BDNF/TrkB expression in hippocampus. Quantitative in situ hybridization demonstrates that running increases the expression of mRNA coding for BDNF and its high affinity receptor TrkB in hippocampus in a running length dependent manner. In addition, we show that an abrupt interruption of prolonged spontaneous exercise decrease expression of mRNA encoding BDNF and TrkB in certain hippocampal areas and that this decrease lasts at least 10 days. This down-regulation was most prominent in medial cornu ammonis 3 (CA3M). Several other trophic factors and receptors were investigated, including NGF, NT3, GDNF, trkC and p75. For these other probes investigated, no robust changes in mRNA expression were noted. Areas examined included sensorimotor cortex and hippocampus. For RET, p75, NT3, TrkB and BDNF we also examined the spinal cord without detecting any robust changes. We conclude that spontaneous running as well as its abrupt termination, leads to area-specific and trophic factor-specific changes in hippocampus.

Decreased expression of the mRNA for somatostatin in the periventricular nucleus of depression-model rats

Expression of the mRNA for somatostatin (SRIF) in the periventricular nucleus (PeN), the level of SRIF in the stalk-median eminence (SME) and the concentration of growth hormone (GH) in the plasma were examined in depression-model rats in an attempt to confirm the hypothesis that SRIF neurons in the hypothalamus are hypofunctional in this model. We exposed male Wistar rats to intermittent walking stress for two weeks and then we measured their spontaneous running activity for 12 days. We divided the rats into a depression-model group and a partial-recovery group according to the spontaneous running activity of each rat after the termination of exposure to stress. Expression of SRIF mRNA in the PeN of the hypothalamus was monitored by in situ hybridization and relative levels were determined with an image analysis system. The relative level of expression of SRIF mRNA in the PeN was lower in rats in the depression-model group than in the control group and the partial-recovery group. The level of SRIF in the SME was lower and the plasma concentration of GH was higher in the depression-model group than in the other groups. Our findings suggest that reduced expression of mRNA for SRIF in the PeN might be associated with the pathophysiology of rats with this particular model of depression.

Brain energy stores in C57BL/6 mice after C. parvum injection.

Activation of the immune system has been associated with the development of fatigue of unknown cause. We were interested in brain energy stores (e.g., phosphocreatine (PCr) and creatine kinase) after immune activation to investigate whether this system was altered. In this model, fatigue (defined as > 50% reduction in spontaneous running) was induced in C57BL/6 mice after a single injection of Corynebacterium parvum antigen. Maximal fatigue (about 86% reduction on day 10 post injection) was associated with reduced (about 29%) brain PCr/gamma-ATP and increased creatine kinase levels (approximately 31%), suggesting an active process of brain ATP depletion and replenishment. These findings need to be further delineated to establish the relationship between immune activation, reduced brain energy pools and fatigue.

Thermoregulatory responses to acute heat loads in rats following spontaneous running.

Earlier studies showed that spontaneous exercise training in rodents shifted their core temperature and thermoeffector thresholds to high levels. The present study investigated heat loss and heat production responses to acute heat loads of exercise-trained rats. The exercise-trained rats were allowed to run in a running wheel freely for 6 months, while the sedentary controls were denied access to the wheel during the same period. Then, they were loosely restrained and put in a direct calorimeter. After thermal equilibrium had been attained, they were warmed for 30 min with an intraperitoneal electric heater (internal heating). At least 2 h later, the rats were externally warmed for 90 min by raising the ambient temperature from 24 to 38C (external warming). Hypothalamic temperature (Thy), evaporative and nonevaporative heat loss (R+C+K) and heat production were measured. Internal and external heating significantly increased Thy. During internal heating, the magnitude of the increase in Thy was significantly smaller and the amount of increase in (R+C+K) was significantly greater in the exercise-trained rats than in the controls. The slope showing the relationship between Thy and (R+C+K) in the trained rats was significantly steeper than that in the controls. During external warming, the magnitude of increase in Thy of the exercise-trained rats was significantly greater than that of the controls. The slope showing the relationship between Thy and (R+C+K) in the trained rats was not different from that in the controls. Changes in evaporative heat loss and heat production during the two types of heat load did not differ between the two groups. The results suggest that, in rats, exercise training with voluntary running improves heat tolerance through enhancing nonevaporative heat loss response. However, this may be the case only when the rats are subjected to a direct internal heat load.

Daily Exercise Enhances Acetylcholine-Induced Dilation in Mesenteric and Hindlimb Vasculature of Hypertensjve Rats

The effect of daily spontaneous running (DSR) on endothelial function was examined in spontaneously hypertensive rats (SHR). Following 8-

Apoptosis of myofibres and satellite cells: exercise-induced damage in skeletal muscle of the mouse.

Apoptosis is well accepted as a type of cell death occurring in the development of mammalian muscles, but the death of adult myofibres in neuromuscular disorders and exercise-induced muscle damage is usually explained in terms of muscle necrosis. The current view that apoptosis precedes necrosis in death of dystrophin-deficient muscle fibres of mdx mouse has been well substantiated. Moreover, apoptotic myonuclei have been reported to increase in mdx mice 2 days after spontaneous exercise. To investigate the contribution of apoptosis to exercise-induced damage of normal muscle fibre a time-course analysis has been performed in adult C57BL/6 mice. Groups of five mice were sacrificed immediately after the end of the exercise, and after a rest period of 6 or 96 h. The amount of apoptosis in leg muscles was assessed by electron microscopy, by the terminal deoxynucleotidyl transferase assay and by electrophoretic detection of fragmented DNA; the expression of Bcl-2, Bax, Fas, ICE, p53 and ubiquitin was examined by immunohistochemistry and Western blot. Absent in muscles of normal 'sedentary' mice, apoptotic myonuclei peak in muscles of normal mice after a night of spontaneous wheel-running (4% +/- 3.5, immediately and 2.5% +/- 1.8 after 6 h rest, P < 0.05 vs non-runner mice); they then decrease but are present 4 days later (0.8% +/- 1.5). Satellite cells are also involved in the apoptotic process. Myofibre content of Bcl-2 decreases whereas Bax, Fas, ICE and ubiquitin modify their pattern of expression in correlation with the changes in apoptotic myonuclei. Apoptosis of endothelial cells is present after the night of wheel-running and with a twofold increase 4 days later (1.5 +/- 2.3 and 4.8 +/- 4.4 P < 0.05, respectively). Satellite cells are also involved in the apoptotic process. Thus, spontaneous running in unaccustomed mice increases the number of apoptotic nuclei in adult muscle fibres and in endothelial cells. It remains to be established whether muscle apoptosis is restricted to the repair mechanisms, as often suggested in many pathologic processes, or it is also part of pathogenesis of muscle damage. Regardless of whether these results are extended to human dystrophies, the clinical implications in terms of secondary pathogenetic mechanisms and muscle training are obvious.

Enhanced response of growth hormone to growth hormone-releasing hormone and a decreased content of hypothalamic somatostatin in a stress-induced rat model of depression.

This study was designed to evaluate changes in the hypothalamic somatostatin-growth hormone axis (SRIF-GH axis) in a stress-induced rat model of depression. We exposed male Wistar rats to intermittent walking stress for two weeks, and then measured their spontaneous running activities for 12 days. We divided the rats into the depression-model group and the partial recovery group according to their spontaneous running activities after the termination of exposure to stress. We examined the secretion of GH from the anterior pituitary by injecting human GH-releasing hormone (hGHRH) with intracardiac cannulae or by applying hGHRH or SRIF to isolated anterior pituitaries using a perifusion system. We also determined SRIF content in the stalk-median eminence (SME) and the plasma concentration of GH. In the depression-model group, intracardiac administration of hGHRH caused the enhanced release of GH into plasma, while application of hGHRH or SRIF to the anterior pituitary in vitro had similar effects on GH release in the control and partial recovery groups. Furthermore, the SRIF content was decreased in the SME and the GH concentration was increased in plasma. The partial recovery group gave similar values to the control group. The enhanced response of GH to hGHRH in the depression-model group might have been caused by the reduced content of SRIF in the SME in view of the unchanged response of GH to the infusion of hGHRH or SRIF in the perifusion system.