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Neural Mechanism of Exercise: Neurovascular Responses to Exercise

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Ti-Fei Yuan
Ti-Fei Yuan
Ti-Fei Yuan
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Nuno Barbosa Ferreira Rocha
Nuno Barbosa Ferreira Rocha
Nuno Barbosa Ferreira Rocha
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Flávia Paes at Federal University of Rio de Janeiro
Flávia Paes
Oscar Arias-Carrión at Instituto Nacional de Rehabilitación, México
Oscar Arias-Carrión
  • Instituto Nacional de Rehabilitación, México
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Abstract

Physical exercise is responsible for different metabolic and hemodynamic changes, including increased cerebral blood flow and perfusion. It is known that running increases vascular endothelial growth factor expression in the brain, which is critical for the anti-depressive effects of adult neurogenesis induced by physical exercise. Both animal and human studies revealed that neurovascular responses to physical exercise are well correlated to adult hippocampal neurogenesis and cognition improvement. Yet it is unknown if the increased blood perfusion to hippocampus is affecting the adult neurogenesis. Manipulating systemic blood pressure, or stimulating the cerebral blood flow with alternative measures, might provide useful tools to understand how much neurovascular plasticity contributes to the brain cognition enhancement by physical exercise. In addition, it will be interesting to examine the responses of brain cells (including neuron, glia and endothelia cells) to increased shear stress and oxygen load, to investigate the underlying molecular mechanisms.
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Commentary
NEURAL MECHANISM OF EXERCISE: NEUROVASCULAR RESPONSES TO
EXERCISE
Ti-Fei Yuan1,*, Nuno Barbosa F. Rocha, Flávia Paes, Oscar Arias-Carrión3, Sergio Machado 2, *,
Alberto Souza de Sá Filho2
1 School of Psychology, Nanjing Normal University, Nanjing, China
2 Institute de Psychiatry, Federal University of Rio de Janeiro, and Salgado de Oliveira
University
3 Unidad de Trastornos del Movimiento y Sueño (TMS), Hospital General Dr. Manuel Gea
González/IFC-UNAM. Mexico City, Mexico
* Corresponding authors: Dr. Ti-Fei Yuan, School of Psychology, Nanjing Normal University,
Nanjing, China, ytf0707@126.com; Sergio Machado, Federal University of Rio de Janeiro,
secm80@gmail.com; Oscar Arias-Carrión; Unidad de Trastornos del Movimiento y Sueño
(TMS), Hospital General Dr. Manuel Gea González/IFC-UNAM. Mexico City, Mexico.
arias@ciencias.unam.mx
Acknowledgements: The study is supported by “Hundred Talents program”, “Qing Lan Project”
of Nanjing Normal University and Jiangsu Provincial Natural Science Foundation (No.
BK20140917) (TY).
Conflicts of Interest: None declared.
Keywords: exercise; blood vessel; depression; hippocampus; cognition;
Physical exercise is responsible for different metabolic and hemodynamic changes,
including increased cerebral blood flow and perfusion [1]. This process is basically the very
stimulation of metabolism leading to a self-regulation mediated flow of cerebral vessels, and
continuous increase in blood perfusion can induce modifications to the neurovascular units,
contributing to the secondary changes of microenvironment for stem cell proliferation and
neurotransmission. It is known that running increases vascular endothelial growth factor (VEGF)
expression in the brain [2], which is critical for the anti-depressive effects of adult neurogenesis
induced by physical exercise. VEGF is also known as induction factor of angiogenesis during
development. It is conceivable that the vascular unit modification is mediated by VEGF signaling
pathways (Figure 1).
Figure 1: Physical exercise increases adult neurogenesis and blood vessel density in dentate
gyrus of hippocampus. Physical exercise increases VEGF signaling and induces angiogenesis,
which are correlated to upregulation of adult neurogenesis in dentate gyrus of hippocampus.
Vasculature is more permeable in neurogenic regions, including dentate gyrus of
hippocampus, rostral migratory stream, and subventricular zone. The blood-brain barrier is
thinner in compared to the cortex, and allows the free exchange of small molecules.
Hippocampus is as well the most important brain region for cognition, including learning and
memory functions, as well as emotion regulation. Therefore hippocampus has been a hotspot to
investigate for the neural mechanisms of physical exercise [3]. In 1990s, it is known that exercise
increase brain volume partly through angiogenesis in motor cortex [4]. In one recent study, Clark
et al. examined the effects of wheel running of hippocampus vasculature and cognitive function.
They found that wheel running increases adult neurogenesis as well as vasculature density in
dentate gyrus of hippocampus [5]. The correlated enhancement of adult neurogenesis implied that
these changes could all be regulated by VEGF signaling pathways.
In human subjects, physical exercise is also known to increase the volume of
hippocampus and prevent the age-dependent cognition decline [1, 3]. Indeed, aerobic exercise
increased the number of small-caliber vessels in healthy aged subjects, revealed by MR
angiography [6], which is in consistent with the fact that new blood vessels are more likely to be
capillaries. Several studies further evaluated the increase of cerebral blood flow in human
subjects during exercise, and confirmed the increase of blood perfusion in hippocampus [7-9].
Notably, dentate gyrus is one primary target of physical exercise, which might explain the
upregulation of adult neurogenesis following exercise [7]. Yet it is unknown if the distinct
vasculature characteristics (such as blood-brain barrier permeability) contribute to the differences
of blood flow in dentate gyrus, in compared to other brain regions.
In another study with healthy aged human subjects, Maass et al. further confirmed the
previous findings that physical exercise modulates hippocampal blood flow, and that this
regulation is preserved during ageing [10]. Therefore, the improved cognition ability following
exercise is well explained by the vasculature plasticity and cellular neurogenesis in aged subjects,
which are well correlated [10].
Was cerebral flow increase contributed to cognition enhancement induced by exercise, or
merely a correlate? An interesting study by Ogoh et al. investigated the question using
hypercapnic gas to control the cerebral blood flow and examine the subsequent effects on brain
functions [11]. They found that hypercapnia-induced increase in cerebral blood perfusion did not
improve human cognition at rest or during exercise load, suggesting that cerebral flow increase
might not be the cause of increased cognitive function during exercise. The authors concluded
that neuronal activities during exercise might be responsible for the improved cognition after
exercise. However, it should be noted that hypercapnia suppresses neuron activities, and therefore
might counteract other positive effects on cognition [12].
In addition to the roles of exercise on neurovascular units under physiological conditions
or normal ageing processes, it is realized that physical exercise at proper time point can be
neuroprotective for brain ischemia or other diseases [13]. Physical exercise decreases neuronal
loss, reduces gliosis, improve the functions of astrocytes and pericytes that repair the blood-brain
barrier [14, 15]. Yet the molecular mechanisms underlying these beneficial effects are to be
investigated.
In conclusion, both animal and human studies revealed that neurovascular responses to
physical exercise are well correlated to adult hippocampal neurogenesis and cognition
improvement. Yet it is unknown if the increased blood perfusion to hippocampus is affecting the
adult neurogenesis. Manipulating systemic blood pressure [16], or stimulating the cerebral blood
flow with alternative measures [17] might provide useful tools to understand how much
neurovascular plasticity contributes to the brain cognition enhancement by physical exercise. In
addition, it will be interesting to examine the responses of brain cells (including neuron, glia and
endothelia cells) to increased shear stress and oxygen load, to investigate the underlying
molecular mechanisms.
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... Therefore, the systemic lactate circulation level during exercise may be subtly altered by 4CIN injection because MCT2 is distributed throughout the mammalian body [20]. Therefore, a plausible change in the dynamics of circulating lactate induced by 4CIN would alter the regulation of vasodilation during exercise [54], which would subsequently affect neurovascular responses to exercise, a modulator of hippocampal neurogenesis [55]. Collectively, the direct action of lactate as a mediator of neurogenesis and the indirect effect of lactate on neurogenesis through changes in hemodynamics induced by 4CIN could not be distinguished in our study. ...
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... [3] Moreover, the rate of evolution from MCI to Alzheimer's disease has been reported to be 15% per year. [4] MCI is linked to neurodegeneration in the hippocampus, and this loss of neurons has been related to mitochondrial defects, as well as oxidative stress that increases levels of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. [5][6][7][8] The result of such alterations is often neuroinflammation and consequently increased activity of microglia. [1,9,10] ...
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Background and Objective: Diabetes has harmful effects on the vascular structure and angiogenesis of various organs, including the hippocampus. In this regard, this study was designed to investigate the effect of non-pharmacological interventions of endurance training (Ex) and Urtica dioica (UD) plant hydroalcoholic extract on the stereological changes of the hippocampal capillaries of diabetic rats. Materials and Methods: 35 Wistar male rats were divided into 5 groups: Healthy control, Diabetes control, Diabetes+Ex, Diabetes+UD, Diabetes+Ex+UD. Diabetes was induced by intraperitoneal injection of streptozotocin. The Ex protocol with moderate intensity and daily gavage of UD hydroalcoholic extract was implemented for six weeks. 48-h after the last session, the rats was sacrificed, and then the hippocampal tissue was removed and placed in 10% formalin for hematoxylin-eosin staining. The stereological changes of the hippocampal tissue were investigated in the parameters of the number of vascular sections, length, volume and area of capillaries. Data analysis was done using repeated measures ANOVA tests for blood glucose variable and Kruskal-Wallis test for stereological studies of hippocampal tissue. Results: Diabetes caused a significant decrease in the number of vascular sections, length, volume and area of hippocampal capillaries (P<0.001). Thus, all stereological parameters in the combined group of Ex+UD were better than the groups that implemented only one of the interventions (P<0.05). The changes of Ex and UD groups in stereological parameters of hippocampal tissue after 6 weeks were not significant. Conclusion: The results obtained in combination effectiveness of Ex and UD on the stereological parameters of the hippocampal tissue of diabetic rats promise to improve the health of the vessels and angiogenesis of the hippocampal tissue by changing the lifestyle of diabetic people. How to cite this article: Gudarzi F, Rahmati M, Roozbahani M, Chehlcheraghi F, Amin Farzaneh Hesari1. The effectiveness of a course of endurance training and Urtica dioica hydroalcoholic extract on the stereological changes of the capillaries of the hippocampal tissue of diabetic rats.
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Alzheimer disease (AD) is the most common type of dementia in individuals over 65 years of age. The neuropathological hallmarks of the condition are Tau neurofibrillary tangles and Amyloid-β senile plaques. Moreover, certain susceptible regions of the brain experience a generalized lack of neural plasticity and marked synaptic alterations during the progression of this as yet incurable disease. One of these regions, the hippocampus, is characterized by the continuous addition of new neurons throughout life. This phenomenon, named adult hippocampal neurogenesis (AHN), provides a potentially endless source of new synaptic elements that increase the complexity and plasticity of the hippocampal circuitry. Numerous lines of evidence show that physical activity and environmental enrichment (EE) are among the most potent positive regulators of AHN. Given that neural plasticity is markedly decreased in many neurodegenerative diseases, the therapeutic potential of making certain lifestyle changes, such as increasing physical activity, is being recognised in several non-pharmacologic strategies seeking to slow down or prevent the progression of these diseases. This review article summarizes current evidence supporting the putative therapeutic potential of EE and physical exercise to increase AHN and hippocampal plasticity both under physiological and pathological circumstances, with a special emphasis on neurodegenerative diseases and AD.
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Vascular hippocampal plasticity after aerobic exercise in older adults
Article
Full-text available
  • Oct 2014
  • MOL PSYCHIATR
Aerobic exercise in young adults can induce vascular plasticity in the hippocampus, a critical region for recall and recognition memory. In a mechanistic proof-of-concept intervention over 3 months, we investigated whether healthy older adults (60-77 years) also show such plasticity. Regional cerebral blood flow (rCBF) and volume (rCBV) were measured with gadolinium-based perfusion imaging (3 Tesla magnetic resonance image (MRI)). Hippocampal volumes were assessed by high-resolution 7 Tesla MRI. Fitness improvement correlated with changes in hippocampal perfusion and hippocampal head volume. Perfusion tended to increase in younger, but to decrease in older individuals. The changes in fitness, hippocampal perfusion and volume were positively related to changes in recognition memory and early recall for complex spatial objects. Path analyses indicated that fitness-related changes in complex object recognition were modulated by hippocampal perfusion. These findings indicate a preserved capacity of the aging human hippocampus for functionally relevant vascular plasticity, which decreases with progressing age.Molecular Psychiatry advance online publication, 14 October 2014; doi:10.1038/mp.2014.114.
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Effect of acupuncture-like stimulation on cortical cerebral blood flow in aged rats
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  • Oct 2014
This study aimed to examine the effect of acupuncture-like stimulation on cortical cerebral blood flow (CBF) in aged rats and the contribution of the intracranial cholinergic vasodilatory system on its response. In urethane-anesthetized rats of 30-37 months of age, manual acupuncture-like stimulation of a forepaw produced an increase in the CBF, independent of systemic arterial pressure. The increase in the CBF induced by forepaw stimulation was abolished by intravenous administration of cholinergic receptor antagonists. Manual acupuncture-like stimulation of a forepaw increased extracellular acetylcholine release in the cerebral cortex. These results suggest that natural somatic afferent stimulation, such as acupuncture-like stimulation, activates the intracranial - most likely, basal forebrain - cholinergic vasodilatory system in the cerebral cortex, even in extremely aged rats.
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The effect of changes in cerebral blood flow on cognitive function during exercise
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  • Sep 2014
No studies have identified the direct effect of changes in cerebral blood flow (CBF) on cognitive function at rest and during exercise. In this study, we manipulated CBF using hypercapnic gas to examine whether an increase in CBF improves cognitive function during prolonged exercise. The speed and the accuracy of cognitive function were assessed using the Stroop color-word test. After the Stroop test at rest, the subjects began exercising on a cycling ergometer in which the workload was increased by 0.5 kilopond every minute until a target heart rate of 140 beats/min was achieved. Then, the subjects continued to cycle at a constant rate for 50 min. At four time points during the exercise (0, 10, 20, 50 min), the subjects performed a Stroop test with and without hypercapnic respiratory gas (2.0% CO2), with a random order of the exposures in the two tests. Despite a decrease in the mean blood flow velocity in the middle cerebral artery (MCA Vmean), the reaction time for the Stroop test gradually decreased during the prolonged exercise without any loss of performance accuracy. In addition, the hypercapnia-induced increase in MCA Vmean produced neither changes in the reaction time nor error in the Stroop test during exercise. These findings suggest that the changes in CBF are unlikely to affect cognitive function during prolonged exercise. Thus, we conclude that improved cognitive function may be due to cerebral neural activation associated with exercise rather than global cerebral circulatory condition.
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Early exercise improves cerebral blood flow through increased angiogenesis in experimental stroke rat model
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Full-text available
  • Apr 2013
  • J NEUROENG REHABIL
Background Early exercise after stroke promoted angiogenesis and increased microvessles density. However, whether these newly formatted vessels indeed give rise to functional vascular and improve the cerebral blood flow (CBF) in impaired brain region is still unclear. The present study aimed to determine the effect of early exercise on angiogenesis and CBF in ischemic region. Methods Adult male Sprague Dawley rats were subjected to 90 min middle cerebral artery occlusion(MCAO)and randomly divided into early exercise and non-exercised control group 24 h later. Two weeks later, CBF in ischemic region was determined by laser speckle flowmetry(LSF). Meantime, micro vessels density, the expression of tie-2, total Akt and phosphorylated Akt (p-Akt), and infarct volume were detected with immunohistochemistry, 2,3,5 triphenyltetrazolium chloride (TTC) staining and western blotting respectively. The function was evaluated by seven point’s method. Results Our results showed that CBF, vessel density and expression of Tie-2, p-Akt in ischemic region were higher in early exercise group compared with those in non-exercise group. Consistent with these results, rats in early exercise group had a significantly reduced infarct volume and better functional outcomes than those in non-exercise group. Conclusions Our results indicated that early exercise after MCAO improved the CBF in ischemic region, reduced infarct volume and promoted the functional outcomes, the underlying mechanism was correlated with angiogenesis in the ischemic cortex.
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Very early-initiated physical rehabilitation protects against ischemic brain injury
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Recent clinical data suggest that very early initiated physical rehabilitation (VEIPR) within 24 hours after stroke may reduce morbidity. However, there is limited evidence to support the beneficial effects of VEIPR and the underlying mechanisms are yet unknown. The present study investigated the effect of VEIPR on brain damage, inflammation, and neurobehavioral outcomes following cerebral ischemia. Rats that underwent transient focal cerebral ischemia (tFCI) were randomly assigned to VEIPR or non-exercise (NE) groups. VEIPR was induced 24 hours after the insult by initiating treadmill training for a maximum of 14 days while the NE group remained sedentary in their cages during this period. The results indicated that VEIPR significantly improved recovery of functional behavior as measured by neurological score, foot fault test, and Morris water maze performance. We also demonstrated that VEIPR significantly reduced infarct volume, brain water content, BBB damage, and acute inflammatory response. In summary, our results provide novel evidence that VEIPR confers marked neuroprotection against experimental stroke by attenuating pro-inflammatory reactions, brain edema, BBB damage, and cognitive and behavioral deficits.
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Beyond vascularization: Aerobic fitness is associated with N-acetylaspartate and working memory
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  • Jan 2012
Aerobic exercise is a promising form of prevention for cognitive decline; however, little is known about the molecular mechanisms by which exercise and fitness impacts the human brain. Several studies have postulated that increased regional brain volume and function are associated with aerobic fitness because of increased vascularization rather than increased neural tissue per se. We tested this position by examining the relationship between cardiorespiratory fitness and N-acetylaspartate (NAA) levels in the right frontal cortex using magnetic resonance spectroscopy. NAA is a nervous system specific metabolite found predominantly in cell bodies of neurons. We reasoned that if aerobic fitness was predominantly influencing the vasculature of the brain, then NAA levels should not vary as a function of aerobic fitness. However, if aerobic fitness influences the number or viability of neurons, then higher aerobic fitness levels might be associated with greater concentrations of NAA. We examined NAA levels, aerobic fitness, and cognitive performance in 137 older adults without cognitive impairment. Consistent with the latter hypothesis, we found that higher aerobic fitness levels offset an age-related decline in NAA. Furthermore, NAA mediated an association between fitness and backward digit span performance, suggesting that neuronal viability as measured by NAA is important in understanding fitness-related cognitive enhancement. Since NAA is found exclusively in neural tissue, our results indicate that the effect of fitness on the human brain extends beyond vascularization; aerobic fitness is associated with neuronal viability in the frontal cortex of older adults.
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Using Network Science to Evaluate Exercise-Associated Brain Changes in Older Adults
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  • Jun 2010
Literature has shown that exercise is beneficial for cognitive function in older adults and that aerobic fitness is associated with increased hippocampal tissue and blood volumes. The current study used novel network science methods to shed light on the neurophysiological implications of exercise-induced changes in the hippocampus of older adults. Participants represented a volunteer subgroup of older adults that were part of either the exercise training (ET) or healthy aging educational control (HAC) treatment arms from the Seniors Health and Activity Research Program Pilot (SHARP-P) trial. Following the 4-month interventions, MRI measures of resting brain blood flow and connectivity were performed. The ET group's hippocampal cerebral blood flow (CBF) exhibited statistically significant increases compared to the HAC group. Novel whole-brain network connectivity analyses showed greater connectivity in the hippocampi of the ET participants compared to HAC. Furthermore, the hippocampus was consistently shown to be within the same network neighborhood (module) as the anterior cingulate cortex only within the ET group. Thus, within the ET group, the hippocampus and anterior cingulate were highly interconnected and localized to the same network neighborhood. This project shows the power of network science to investigate potential mechanisms for exercise-induced benefits to the brain in older adults. We show a link between neurological network features and CBF, and it is possible that this alteration of functional brain networks may lead to the known improvement in cognitive function among older adults following exercise.
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The Effect of Exercise on the Cerebral Vasculature of Healthy Aged Subjects as Visualized by MR Angiography
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  • Aug 2009
  • AM J NEURORADIOL
Prior studies suggest that aerobic exercise may reduce both the brain atrophy and the decline in fractional anisotropy observed with advancing age. It is reasonable to hypothesize that exercise-induced changes to the vasculature may underlie these anatomic differences. The purpose of this blinded study was to compare high-activity and low-activity healthy elderly volunteers for differences in the cerebrovasculature as calculated from vessels extracted from noninvasive MR angiograms (MRAs). Fourteen healthy elderly subjects underwent MRA. Seven subjects reported a high level of aerobic activity (64 +/- 5 years of age; 5 men, 2 women) and 7, a low activity level (68 +/- 6 years of age; 5 women, 2 men). Following vessel segmentation from MRA by an individual blinded to subject activity level, quantitative measures of vessel number, radius, and tortuosity were calculated and histogram analysis of vessel number and radius was performed. Aerobically active subjects exhibited statistically significant reductions in vessel tortuosity and an increased number of small vessels compared with less active subjects. Aerobic activity in elderly subjects is associated with lower vessel tortuosity values and an increase in the number of small-caliber vessels. It is possible that an aerobic exercise program may contribute to healthy brain aging. MRA offers a noninvasive approach to visualizing the cerebral vasculature and may prove useful in future longitudinal investigations.
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Physical exercise training and neurovascular unit in ischemic stroke
Article
  • Apr 2014
Physical exercise could exert neuroprotective effect in both clinical studies and animal experiments. A series of related studies have indicated that physical exercise could reduce the infarct volume, alleviate the neurological deficits, decrease the blood brain barrier dysfunction, promote the angiogenesis in cerebral vascular and increase the survival rate after ischemic stroke. In this review, we summarized the protective effects of physical exercise on neurovascular unit (NVU), including neurons, astrocytes, pericytes and extracellular matrix. Furthermore, it was demonstrated that exercise training could decrease the blood brain barrier dysfunction and promote the angiogenesis in cerebral vascular. An awareness of the exercise intervention benefits pre- and post stroke may lead more stroke patients and people with high risk factors to accept exercise therapy for the prevention and treatment of stroke.
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