Days Of Voluntary Exercise Research Articles

Coping with Exercise Induced Spatial Memory Improvement in Morphine Dependent Rats by Inhibiting Brain Derived Neurotrophic Factor (BDNF)

Background: Addiction as a chronic disorder that requires long treatment. One way to treating this chronic disease is exercise. Chronic exposure to opiates impairs spatial learning and memory. Given the well-known beneficial effects of voluntary exercise on cognitive functions, we investigated whether voluntary exercise would ameliorate the cognitive deficits that are induced by morphine dependence. If an effect of exercise was observed, we aimed to investigate the possible role of hippocampal brain-derived neurotropic factor (BDNF) in the exercise-induced enhancement of learning and memory in morphine-dependent rats. Methods: The rats were injected with bi-daily doses (10 mg/kg, at 12 hr. intervals) of morphine over a period of 10 days of voluntary exercise. Following these injections, a water maze task was performed twice a day for 5 consecutive days, followed by a probe trial 2 days later. A specific BDNF inhibitor (TrkB-IgG chimera) was used to block the hippocampal BDNF action during the 10 days of voluntary exercise. Results: The voluntary exercise diminished the severity of the rats’ dependency on morphine. A blockade of the BDNF action blunted the exercise-induced improvement of spatial memory, hippocampal neuron counting and BDNF protein levels in the dependent rats. Our results indicate that voluntary exercise could be increase the expression of LTP by lowering the induction threshold for LTP in the DG of morphine-dependent rats. Conclusion: Thus, voluntary exercise might be considered as a potential method to ameliorate some of the deleterious behavioral consequences of the abuse of morphine and other opiates.

Voluntary exercise ameliorates synaptic pruning deficits in sleep-deprived adolescent mice

Adolescence is a critical period for brain development and adequate sleep during this period is essential for physical function and mental health. Emerging evidence has detailed the neurological impacts of sleep insufficiency on adolescents, as was unveiled by our previous study, microglia, one of the crucial contributors to synaptic pruning, is functionally disrupted by lack of sleep. Here, we provided evidence featuring the protective effect and the underlying mechanisms of voluntary exercise (VE) on microglial functions in an adolescent 72 h sleep deprivation (SD) model. We identified that the aberrant hippocampal neuronal activity and impaired short-term memory performance in sleep-deprived mice were prevented by 11 days of VE. VE significantly normalized the SD-induced dendritic spine increment and maintained the microglial phagocytic ability in sleep-deprived mice. Moreover, we found that the amendment of the noradrenergic signal in the central nervous system may explain the preventative effects of VE on the abnormalities of microglial and neuronal functions caused by SD. These data suggested that VE may confer protection to the microglia-mediated synaptic pruning in the sleep-deprived adolescent brains. Therefore, physical exercise could be a beneficial health practice for the adolescents that copes the adverse influence of inevitable sleep insufficiency.

Ten Days of Free Wheel Running Alters Cortical Glutamate‐Linked Mitochondrial Respiration in Rat Brain

The mechanisms through which exercise benefits brain function are not completely understood. Appreciation for the role of lactate as a major neuroenergetic fuel, particularly during exercise, has progressed in recent decades; however, the mitochondrial involvement in brain lactate metabolism is not clear. To explore the mechanisms involved, we examined mitochondrial lactate oxidation in brain and skeletal muscle from exercised rats. Respiratory oxygen flux (JO2) was measured in saponin‐permeabilized prefrontal cortex (PFC) and hippocampus (dentate gyrus; DG) samples, as well as red and white gastrocnemius muscle samples from five male Wistar rats (age: approximately 104 days) given access to running wheels. Over ten days of free wheel running, rats attained a maximal daily running distance averaging 2.1 ± 0.5 km. The wheel‐running rats remained relatively weight stable, losing 1.4 ± 3.1 g body mass on average, whereas the five paired control rats gained an average of 39.4 ± 2.8 g over the ten days. On day eleven, high resolution respirometry was performed on exercise and control samples ex vivo. The addition of lactate failed to affect mitochondrial JO2 (ADP + malate) from either brain or muscle in either group. However, JO2 rose significantly following the addition of exogenous NAD+ in each tissue (P < 0.01), implying the lactate dehydrogenase reaction operates outside of the mitochondrial matrix. This interpretation was further supported by inhibition of JO2 following addition of an inhibitor of pyruvate transport, UK‐5099 (P < 0.01). Interestingly, the subsequent addition of glutamate resulted in a disparate increase in mitochondrial JO2 among tissues and treatment. Compared to controls, glutamate‐supported mitochondrial JO2 in wheel runners was significantly greater in PFC (P < 0.05), but not DG. This rise in JO2 likely reflects activation of the malate‐aspartate shuttle through elevated mitochondrial glutamate transport. Paradoxically, wheel runners exhibited lower glutamate‐supported JO2 in red gastrocnemius (P < 0.05). This may be due to the influence of regular exercise on the putative lactate‐malate‐aspartate shuttle. The lactate‐malate‐aspartate shuttle is the interaction between the lactate and malate‐aspartate shuttles to translocate reducing power to the mitochondria. The decline in lactate dehydrogenase activity in skeletal muscle that accompanies aerobic exercise training is expected to negatively influence lactate‐malate‐aspartate shuttling, and may explain our observations in muscle. Collectively, the results of this study suggest that electron shuttling in rat brain following ten days of voluntary exercise is upregulated in PFC. These results also provide further evidence for an indirect mechanism of mitochondrial lactate oxidation in both brain and skeletal muscle.Support or Funding InformationThe Natural Sciences and Engineering Research Council of Canada; The Nova Scotia Health Research Foundation

Abstract 276: Cyclin D2 Is a Critical Mediator of Exercise-Induced Cardiac Hypertrophy

Exercise training activates a number of hypertrophic signaling pathways that can be distinct from those activated by pathologic stimuli. However, there must be some overlap in those pathways underlying myocyte cell growth. Using a number of mouse genetic models, we investigated the role of several molecules implicated in pathologic cardiac hypertrophy for their cardiac responses to exercise. We used three-month-old female transgenic mice expressing the anti-hypertrophic molecules, cardiac-specific constitutively active glycogen synthase kinase-3β (caGSK-3β), an inhibitor of Ca 2+ -calmodulin-dependent protein kinase (CaMKII Inh), and doubly transgenic mice expressing both caGSK-3β and CaMKII inhibition (caGSK-3β/CaMKII Inh). We also studied the exercise responsiveness of mice expressing the pro-hypertrophic cardiac-specific activated (myr)Akt. MAPK/ERK kinase kinase-1 (MEKK1) has been shown to be essential for pathologic cardiac hypertrophy and we therefore studied the requirement of MEKK1 for exercise-induced cardiac growth. Cell cycle regulators such as cyclin D2 have been shown to be required for pathologic cardiac hypertrophy; therefore we studied cyclin D2 null mice. Mice were divided into sedentary and 21 days of voluntary exercise on a cage wheel. Across the seven different mouse models, exercise capacity was similar with regards to running duration, distance, and speed. Importantly, we analyzed the impact of exercise on cardiac hypertrophy by measuring heart weight-to-body weight (HW/BW) ratios of sedentary and exercised mice. While exercise had no impact on body weight, heart weight increased significantly in all mouse models except the cyclin D2 -/- mice. Overall there was a 3.5-fold range of percent increase in HW/BW ratios from the highest (caGSK-3β) to the lowest (cyclin D2 -/- ). In conclusion, genetic manipulation of these hypertrophic signaling pathways has little impact on exercise performance and only the loss of cyclin D2 attenuates exercise-induced cardiac growth. These data establish cyclin D2 as an important regulator of physiological hypertrophy and underscore the differences in pathologic and physiologic cardiac hypertrophy.

Voluntary exercise induces chromatin remodelling in the heart

Chromatin remodelling regulates skeletal muscle adaptations to exercise and the development of pathological cardiac hypertrophy by interactions between repressor element 1‐silencing transcription factor (REST), mSin3A and histone deacetylases (HDAC). It is not known if chromatin remodelling regulates exercise‐induced physiological hypertrophy in the heart. Young male mice exercised on voluntary running wheels for 7 days. Heart weight:body weight and actin protein were not different compared to sedentary controls as overt cardiac hypertrophy does not occur until at least 14 days of exercise. mSin3A was higher in trained hearts but REST was not different between groups. HDAC 3, a pro‐hypertrophic class I HDAC, was higher in exercise‐trained hearts whereas HDAC 4, an anti‐hypertrophic class IIa HDAC, was lower in exercised hearts. To determine if chromatin remodelling is initiated during acute exercise, mice underwent a single bout of treadmill running for either 15 or 30 minutes and hearts were harvested immediately following exercise. Examination of the nuclear fractions revealed that REST, mSin3A and HDAC proteins were not different between groups. These data suggest that 7 days of voluntary exercise induces cardiac chromatin remodelling but that this does not occur immediately following a single exercise bout.

Brain and Spinal Cord Interaction: Protective Effects of Exercise Prior to Spinal Cord Injury

We have investigated the effects of a spinal cord injury on the brain and spinal cord, and whether exercise provided before the injury could organize a protective reaction across the neuroaxis. Animals were exposed to 21 days of voluntary exercise, followed by a full spinal transection (T7–T9) and sacrificed two days later. Here we show that the effects of spinal cord injury go beyond the spinal cord itself and influence the molecular substrates of synaptic plasticity and learning in the brain. The injury reduced BDNF levels in the hippocampus in conjunction with the activated forms of p-synapsin I, p-CREB and p-CaMK II, while exercise prior to injury prevented these reductions. Similar effects of the injury were observed in the lumbar enlargement region of the spinal cord, where exercise prevented the reductions in BDNF, and p-CREB. Furthermore, the response of the hippocampus to the spinal lesion appeared to be coordinated to that of the spinal cord, as evidenced by corresponding injury-related changes in BDNF levels in the brain and spinal cord. These results provide an indication for the increased vulnerability of brain centers after spinal cord injury. These findings also imply that the level of chronic activity prior to a spinal cord injury could determine the level of sensory-motor and cognitive recovery following the injury. In particular, exercise prior to the injury onset appears to foster protective mechanisms in the brain and spinal cord.

Voluntary exercise ameliorates cognitive deficits in morphine dependent rats: The role of hippocampal brain-derived neurotrophic factor

Chronic exposure to opiates impairs spatial learning and memory. Given the well-known beneficial effects of voluntary exercise on cognitive functions, we investigated whether voluntary exercise would ameliorate the cognitive deficits that are induced by morphine dependence. If an effect of exercise was observed, we aimed to investigate the possible role of hippocampal brain-derived neurotrophic factor (BDNF) in the exercise-induced enhancement of learning and memory in morphine-dependent rats. The rats were injected with bi-daily doses (10 mg/kg, at 12 h intervals) of morphine over a period of 10 days of voluntary exercise. Following these injections, a water maze task was performed twice a day for five consecutive days, followed by a probe trial 2 days later. A specific BDNF inhibitor (TrkB–IgG chimera) was used to block the hippocampal BDNF action during the 10 days of voluntary exercise. We found that voluntary exercise blocked the ability of chronic morphine to impair spatial memory retention. A blockade of the BDNF action blunted the exercise-induced improvement of spatial memory in the dependent rats. Moreover, the voluntary exercise diminished the severity of the rats’ dependency on morphine. This study demonstrates that voluntary exercise ameliorates, via a TrkB-mediated mechanism, the cognitive deficits that are induced by chronic morphine. Thus, voluntary exercise might be a potential method to ameliorate some of the deleterious behavioral consequences of the abuse of morphine and other opiates.

Exercise influences hippocampal plasticity by modulating brain-derived neurotrophic factor processing

Exercise has been shown to impact brain plasticity and function by involving the action of brain-derived neurotrophic factor (BDNF); however, mechanisms involved are poorly understood. Two types of BDNF coexist in the brain, the precursor (proBDNF) and its mature product (mBDNF), which preferentially bind specific receptors and exert distinct functions. It is crucial to understand how exercise affects crucial steps in the BDNF processing and signaling to evaluate therapeutic applications. We found that 7 days of voluntary exercise increased both pro and mature BDNF in the rat hippocampus. Exercise also increased the activity of tissue-type plasminogen activator (tPA), a serine proteinase shown to facilitate proBDNF cleavage into mBDNF. The blockade of tPA activity reduced the exercise effects on proBDNF and mBDNF. The tPA blocking also inhibited the activation of TrkB receptor, and the TrkB signaling downstream effectors phospho-ERK, phospho-Akt, and phospho-CaMKII. The blocking of tPA also counteracted the effects of exercise on the plasticity markers phospho-synapsin I and growth-associated protein 43 (GAP-43). These results indicate that the effects of exercise on hippocampal plasticity are dependent on BDNF processing and subsequent TrkB signaling, with important implications for neuronal function.

Exercise increases insulin signaling in the hippocampus: Physiological effects and pharmacological impact of intracerebroventricular insulin administration in mice

Increasing evidence indicates that physical exercise induces adaptations at the cellular, molecular, and systemic levels that positively affect the brain. Insulin plays important functional roles within the brain that are mediated by insulin-receptor (IR) signaling. In the hippocampus, insulin improves synaptic plasticity, memory formation, and learning via direct modulation of GABAergic and glutamatergic receptors. Separately, physical exercise and central insulin administration exert relevant roles in cognitive function. We here use CF1 mice to investigate (i) the effects of voluntary exercise on hippocampal insulin signaling and memory performance and (ii) whether central insulin administration alters the effects of exercise on hippocampal insulin signaling and memory performance. Adult mice performed 30 days of voluntary exercise on running wheel and afterward both, sedentary and exercised groups, received intracerebroventricular (icv) injection of saline or insulin (0.5-5 mU). Memory performance was assessed using the inhibitory avoidance and water maze tasks. Hippocampal tissue was measured for [U-(14)C] glucose oxidation and the immunocontent of insulin receptor/signaling (IR, pTyr, pAktser473). Additionally, the phosphorylation of the glutamate NMDA receptor NR2B subunit and the capacity of glutamate uptake were measured, and immunohistochemistry was used to determine glial reactivity. Exercise significantly increased insulin peripheral sensitivity, spatial learning, and hippocampal IR/pTyrIR/pAktser473 immunocontent. Glucose oxidation, glutamate uptake, and astrocyte number also increased relative to the sedentary group. In both memory tasks, 5 mU icv insulin produced amnesia but only in exercised animals. This amnesia was associated a rapid (15 min) and persistent (24 h) increase in hippocampal pNR2B immunocontent that paralleled the increase in glial reactivity. In conclusion, physical exercise thus increased hippocampal insulin signaling and improved water maze performance. Overstimulation of insulin signaling in exercised animals, however, via icv administration impaired behavioral performance. This effect was likely the result of aberrant phosphorylation of the NR2B subunit.

Voluntary Exercise Increases Oligodendrogenesis in Spinal Cord

ABSTRACTExercise has been shown to increase hippocampal neurogenesis, but the effects of exercise on oligodendrocyte generation have not yet been reported. In this study, we evaluated the hypothesis that voluntary exercise may affect neurogenesis, and more in particular, oligodendrogenesis in the thoracic segment of the intact spinal cord of adult nestin–GFP transgenic mice. Voluntary exercise for 7 and 14 days increased nestin–GFP expression around the ependymal area. In addition, voluntary exercise for 7 days significantly increased nestin–GFP expression in both the white and gray matter of the thoracic segment of the intact spinal cord, whereas, 14-day exercise decreased nestin–GFP expression. Markers for immature oligodendrocytes (transferrin and CNPase) were significantly increased after 7 days of voluntary exercise. These results suggest that voluntary exercise positively influences oligodendrogenesis in the intact spinal cord, emphasizing the beneficial effects of voluntary exercise as a possible co-treatment for spinal cord injury.

Increase in nitric oxide formation after chronic voluntary exercise in spontaneously hypertensive rats.

The effect of chronic voluntary exercise on the plasma level of nitrate, a major stable metabolite of nitric oxide (NO) was studied in spontaneously hypertensive rats (SHR). Exercise consisted of spontaneous running in wheels for 3-35 days. Blood samples were collected after 3, 7, 14, 21 and 35 days of exercise and all samples were drawn after the running wheel had been locked during the preceding 12 h. The plasma nitrate level was significantly (P < 0.05) elevated in SHR after 35 days of exercise. Surprisingly after 7 days of exercise a significant (P < 0.001) decrease in the nitrate level in plasma was noted. Further research is needed to elucidate this biphasic change in nitrate seen in this study. The elevated level of plasma nitrate seen after 35 days of voluntary exercise was still present up to 36 h after termination of exercise. We conclude that exercise training in SHR elicits an enhanced formation of NO.

Modifications in dietary self-selection specifically attributable to voluntary wheel running and exercise training in the rat

To explore the effects of physical exercise on total caloric intake, body weight gain, and dietary self-selection in rats, female rats of the Dark Agouti strain were placed on macronutrient self-selection. They had free access to running wheels during the whole experimental period. After 16 days of voluntary exercise only, they were trained on a motor-driven treadmill (16 m/min) at the beginning of the dark period. Runtime was progressively increased and reached 3 h per day (plateau). When trained, the rats decreased spontaneous wheel running. Voluntary wheel running did not modify body weight gain. However it increased both carbohydrate and total caloric intakes. Exercise training reduced body weight gain, but did not further modify total caloric intake. Moreover it increased protein and reduced fat intakes. Most of the training-induced modifications were not side effects of fasting during exercise training.