Voluntary exercise following traumatic brain injury: brain-derived neurotrophic factor upregulation and recovery of function

doi:10.1016/j.neuroscience.2004.01.030

Neuroscience

Volume 125, Issue 1, 2004, Pages 129-139

https://doi.org/10.1016/j.neuroscience.2004.01.030 Get rights and content

Abstract

Voluntary exercise leads to an upregulation of brain-derived neurotrophic factor (BDNF) and associated proteins involved in synaptic function. Activity-induced enhancement of neuroplasticity may be considered for the treatment of traumatic brain injury (TBI). Given that during the first postinjury week the brain is undergoing dynamic restorative processes and energetic changes that may influence the outcome of exercise, we evaluated the effects of acute and delayed exercise following experimental TBI. Male Sprague–Dawley rats underwent either sham or lateral fluid-percussion injury (FPI) and were housed with or without access to a running wheel (RW) from postinjury days 0–6 (acute) or 14–20 (delayed). FPI alone resulted in significantly elevated levels of hippocampal phosphorylated synapsin I and phosphorylated cyclic AMP response element-binding-protein (CREB) at postinjury day 7, of which phosphorylated CREB remained elevated at postinjury day 21. Sham and delayed FPI-RW rats showed increased levels of BDNF, following exercise. Exercise also increased phosphorylated synapsin I and CREB in sham rats. In contrast to shams, the acutely exercised FPI rats failed to show activity-dependent BDNF upregulation and had significant decreases of phosphorylated synapsin I and total CREB. Additional rats were cognitively assessed (learning acquisition and memory) by utilizing the Morris water maze after acute or delayed RW exposure. Shams and delayed FPI-RW animals benefited from exercise, as indicated by a significant decrease in the number of trials to criterion (ability to locate the platform in 7 s or less for four consecutive trials), compared with the delayed FPI-sedentary rats. In contrast, cognitive performance in the acute FPI-RW rats was significantly impaired compared with all the other groups. These results suggest that voluntary exercise can endogenously upregulate BDNF and enhance recovery when it is delayed after TBI. However, when exercise is administered to soon after TBI, the molecular response to exercise is disrupted and recovery may be delayed.

Section snippets

Subjects

A total of 161 male Sprague–Dawley adult rats (mean weight: 312 g) were utilized in these experiments. Rats underwent lateral fluid-percussion injury (FPI; n=89) or sham (n=72) injury and were housed with or without access to a running wheel (RW) at different postinjury times. In order to control for motor impairments that may have an effect on RW activity, rats were tested for motor skills before and after injury. All animals were continually monitored and cared for by an Institutional

Results

Animals sustaining injury exhibited a period of unconsciousness ranging from 15 to 180 s (mean: 82 s; standard deviation: 54 s) and apnea time ranging from 5 to 50 s (mean: 14 s; standard deviation: 11 s). All animals displayed normal behavior after recovery from anesthesia. Motor impairments were not observed in the injured rats. Injured rats that were exposed to exercise acutely tended to exercise less than the sham animals during the first night, thus this did not reach statistical

Discussion

The beneficial effects of exercise on the healthy brain are well recognized; however, the action of voluntary exercise on the injured brain remains largely unexplored. The suitability of exercise to help the injured brain is complex due to dynamic neurochemical and metabolic alterations elicited by TBI that may interfere with the effects of exercise. The present results indicate that in order for exercise to prove beneficial, it must be administered at the appropriate post-injury time window.

References (61)

T Abel et al.
Positive and negative regulatory mechanisms that mediate long-term memory storage
Brain Res Brain Res Rev
(1998)
C.R Almli et al.
BDNF protects against spatial memory deficits following neonatal hypoxia-ischemia
Exp Neurol
(2000)
Y.A Barde
Trophic factors and neuronal survival
Neuron
(1989)
G.R Blaha et al.
Brain-derived neurotrophic factor administration after traumatic brain injury in the rat does not protect against behavioral or histological deficits
Neuroscience
(2000)
I Fineman et al.
Concussive brain injury is associated with a prolonged accumulation of calciumA ca-45 autoradiographic study
Brain Res
(1993)
S Finkbeiner et al.
CREBA major mediator of neuronal neurotrophin responses
Neuron
(1997)
D.E Fordyce et al.
Physical activity enhances spatial learning performance with an associated alteration in hippocampal protein kinase C activity in C57BL/6 and DBA/2 mice
Brain Res
(1993)
F Gomez-Pinilla et al.
Spatial learning induces neurotrophin receptor and synapsin I in the hippocampus
Brain Res
(2001)
M.A Grealy et al.
Improving cognitive function after brain injuryThe use of exercise and virtual reality
Arch Phys Med Rehabil
(1999)
A Hicks et al.
Synapsin I and syntaxin 1BKey elements in the control of neurotransmitter release are regulated by neuronal activation and long-term potentiation in vivo
Neuroscience
(1997)

J.L Humm et al.

Use-dependent exaggeration of brain injuryIs glutamate involved?

Exp Neurol

(1999)

T.L Ivanco et al.

Physiological consequences of morphologically detectable synaptic plasticityPotential uses for examining recovery following damage

Neuropharmacology

(2000)

E.M Jansen et al.

Quantitative analysis of contralateral hemisphere hypertrophy and sensorimotor performance in adult rats following unilateral neonatal ischemic-hypoxic brain injury

Brain Res

(1996)

T Kawamata et al.

Lactate accumulation following concussive brain injuryThe role of ionic fluxes induced by excitatory amino acids

Brain Res

(1995)

D.A Kozlowski et al.

Relationship between dendritic pruning and behavioral recovery following sensorimotor cortex lesions

Behav Brain Res

(1998)

R.H Melloni et al.

Dynamics of synapsin I gene expression during the establishment and restoration of functional synapses in the hippocampus

Neuroscience

(1994)

T Samorajski et al.

Effect of exercise on longevity, body weight, locomotor performance, and passive-avoidance memory of C57BL/6J mice

Neurobiol Aging

(1985)

H Shen et al.

Physical activity elicits sustained activation of the cyclic AMP response element-binding protein and mitogen-activated protein kinase in the rat hippocampus

Neuroscience

(2001)

L.C Schmued et al.

Fluoro-Jade BA high affinity fluorescent marker for the localization of neuronal degeneration

Brain Res

(2000)

A Yoshino et al.

Dynamic changes in local cerebral glucose utilization following cerebral conclusion in ratsEvidence of a hyper- and subsequent hypometabolic state

Brain Res

(1991)

B.C Albensi

Models of brain injury and alterations in synaptic plasticity

J Neurosci Res

(2001)

F.M Bareyre et al.

DNase I disinhibition is predominantly associated with actin hyperpolymerization after traumatic brain injury

J Neurochem

(2001)

M Bergsneider et al.

Cerebral hyperglycolysis following severe traumatic brain injury in humansA positron emission tomography study

J Neurosurg

(1997)

F.W Booth et al.

Waging war on physical inactivityUsing modern molecular ammunition against an ancient enemy

J Appl Physiol

(2002)

D Chu et al.

Reorganization of the hand somatosensory cortex following perinatal unilateral brain injury

Neuropediatrics

(2000)

A Czurko et al.

Sustained activation of hippocampal pyramidal cells by ‘space clamping’ in a running wheel

Eur J Neurosci

(1999)

L.A De Bruin et al.

Effects of stress and exercise on rat hippocampus and striatum extracellular lactate

Am J Physiol

(1990)

S Finkbeiner

Calcium regulation of the brain-derived neurotrophic factor gene

Cell Mol Life Sci

(2000)

R.P Friedland et al.

Patients with Alzheimer's disease have reduced activities in midlife compared with healthy control-group members

Proc Natl Acad Sci USA

(2001)

M.D Ginsberg et al.

Uncoupling of local cerebral glucose metabolism and blood flow after acute fluid-percussion injury in rats

Am J Physiol Heart Circ Physiol

(1997)

Cited by (398)

Efficacy of a music-based intervention in a preclinical model of traumatic brain injury: An initial foray into a novel and non-pharmacological rehabilitative therapy
2023, Experimental Neurology
Traumatic brain injury (TBI) causes neurobehavioral and cognitive impairments that negatively impact life quality for millions of individuals. Because of its pernicious effects, numerous pharmacological interventions have been evaluated to attenuate the TBI-induced deficits or to reinstate function. While many such pharmacotherapies have conferred benefits in the laboratory, successful translation to the clinic has yet to be achieved. Given the individual, medical, and societal burden of TBI, there is an urgent need for alternative approaches to attenuate TBI sequelae and promote recovery. Music based interventions (MBIs) may hold untapped potential for improving neurobehavioral and cognitive recovery after TBI as data in normal, non-TBI, rats show plasticity and augmented cognition. Hence, the aim of this study was to test the hypothesis that providing a MBI to adult rats after TBI would improve cognition, neurobehavior, and histological endpoints. Adult male rats received a moderate-to-severe controlled cortical impact injury (2.8 mm impact at 4 m/s) or sham surgery (n = 10–12 per group) and 24 h later were randomized to classical Music or No Music (i.e., ambient room noise) for 3 h/day from 19:00 to 22:00 h for 30 days (last day of behavior). Motor (beam-walk), cognitive (acquisition of spatial learning and memory), anxiety-like behavior (open field), coping (shock probe defensive burying), as well as histopathology (lesion volume), neuroplasticity (BDNF), and neuroinflammation (Iba1, and CD163) were assessed. The data showed that the MBI improved motor, cognitive, and anxiety-like behavior vs. No Music (p's < 0.05). Music also reduced cortical lesion volume and activated microglia but increased resting microglia and hippocampal BDNF expression. These findings support the hypothesis and provide a compelling impetus for additional preclinical studies utilizing MBIs as a potential efficacious rehabilitative therapy for TBI.
How to boost the effects of exercise to favor traumatic brain injury outcome
2022, Sports Medicine and Health Science
Citation Excerpt :
Exercise is also perceived as one of the most effective therapies to reduce depression across the lifespan.18 Furthermore, studies in rodents have shown the utility of exercise to promote cognitive recovery from a brain injury.19–21 Importantly, the memory improvements induced by physical exercise are accompanied by increases in cell proliferation, neurogenesis, dendritic complexity, and spine density.8,22,23
Physical rehabilitation is an effective therapy to normalize weaknesses encountered with neurological disorders such as traumatic brain injury (TBI). However, the efficacy of exercise is limited during the acute period of TBI because of metabolic dysfunction, and this may further compromise neuronal function. Here we discuss the possibility to normalize brain metabolism during the early post-injury convalescence period to support functional plasticity and prevent long-term functional deficits. Although BDNF possesses the unique ability to support molecular events involved with the transmission of information across nerve cells through activation of its TrkB receptor, the poor pharmacokinetic profile of BDNF has limited its therapeutic applicability. The flavonoid derivative, 7,8-dihydroxyflavone (7,8-DHF), signals through the same TrkB receptors and results in the activation of BDNF signaling pathways. We discuss how the pharmacokinetic limitations of BDNF may be avoided by the use of 7,8-DHF, which makes it a promising pharmacological agent for supporting activity-based rehabilitation during the acute post-injury period after TBI. In turn, docosahexaenoic acid (C22:6n-3; DHA) is abundant in the phospholipid composition of plasma membranes in the brain and its action is important for brain development and plasticity. DHA is a major modulator of synaptic membrane fluidity and function, which is fundamental for supporting cell signaling and synaptic plasticity. Exercise influences DHA function by normalizing DHA content in the brain, such that the collaborative action of exercise and DHA can be instrumental to boost BDNF function with strong therapeutic potential for reducing the deleterious effects of TBI on synaptic plasticity and cognition.
The benefits of exercise for outcome improvement following traumatic brain injury: Evidence, pitfalls and future perspectives
2022, Experimental Neurology
Traumatic brain injury (TBI), also known as a silent epidemic, is currently a substantial public health problem worldwide. Given the increased energy demands following brain injury, relevant guidelines tend to recommend absolute physical and cognitive rest for patients post-TBI. Nevertheless, recent evidence suggests that strict rest does not provide additional benefits to patients' recovery. By contrast, as a cost-effective non-pharmacological therapy, exercise has shown promise for enhancing functional outcomes after injury. This article summarizes the most recent evidence supporting the beneficial effects of exercise on TBI outcomes, focusing on the efficacy of exercise for cognitive recovery after injury and its potential mechanisms. Available evidence demonstrates the potential of exercise in improving cognitive impairment, mood disorders, and post-concussion syndrome following TBI. However, the clinical application for exercise rehabilitation in TBI remains challenging, particularly due to the inadequacy of the existing clinical evaluation system. Also, a better understanding of the underlying mechanisms whereby exercise promotes its most beneficial effects post-TBI will aid in the development of new clinical strategies to best benefit of these patients.
Physical exercise: Effects on cognitive function after traumatic brain injury
2022, Cellular, Molecular, Physiological, and Behavioral Aspects of Traumatic Brain Injury
Persistent cognitive dysfunction (long-term memory, working memory, executive function, attention, visuospatial function, etc.) is present in a substantial proportion of traumatic brain injury patients. Animal studies have demonstrated that aerobic physical exercise can reduce some of the cognitive deficits associated with brain damage (particularly hippocampal-dependent memory), although there are still multiple issues to be resolved with regard to the optimal parameters of this type of intervention. The neural mechanisms involved in the cognitive benefits of exercise are varied and include factors that generally relate to neuroprotection against secondary injury (reduced chronic neuroinflammation, reduced neuron and myelin loss, preserved integrity of brain vasculature, and cerebral blood flow, etc.) and to neurorepair (increased neuroplasticity and neurogenesis). Despite the encouraging results from animal research, there has only been limited success in translating these to the clinical setting. It is expected that further research on animals and humans will contribute to the designing of effective exercise interventions as part of comprehensive patient-rehabilitation strategies.
Electroacupuncture improves cognitive function in a rat model of mild traumatic brain injury by regulating the SIRT-1/PGC-1α/mitochondrial pathway
2024, Chinese Medical Journal
Brain-Derived Neurotrophic Factor in Pediatric Acquired Brain Injury and Recovery
2024, Biomolecules

View all citing articles on Scopus

View full text

Voluntary exercise following traumatic brain injury: brain-derived neurotrophic factor upregulation and recovery of function

Abstract

Section snippets

Subjects

Results

Discussion

Brain Res Brain Res Rev

Exp Neurol

Neuron

Neuroscience

Brain Res

Neuron

Brain Res

Brain Res

Arch Phys Med Rehabil

Neuroscience

Exp Neurol

Neuropharmacology

Brain Res

Brain Res

Behav Brain Res

Neuroscience

Neurobiol Aging

Neuroscience

Brain Res

Brain Res

Models of brain injury and alterations in synaptic plasticity

J Neurosci Res

DNase I disinhibition is predominantly associated with actin hyperpolymerization after traumatic brain injury

J Neurochem

Cerebral hyperglycolysis following severe traumatic brain injury in humansA positron emission tomography study

J Neurosurg

Waging war on physical inactivityUsing modern molecular ammunition against an ancient enemy

J Appl Physiol

Reorganization of the hand somatosensory cortex following perinatal unilateral brain injury

Neuropediatrics

Sustained activation of hippocampal pyramidal cells by ‘space clamping’ in a running wheel

Eur J Neurosci

Effects of stress and exercise on rat hippocampus and striatum extracellular lactate

Am J Physiol

Calcium regulation of the brain-derived neurotrophic factor gene

Cell Mol Life Sci

Patients with Alzheimer's disease have reduced activities in midlife compared with healthy control-group members

Proc Natl Acad Sci USA

Uncoupling of local cerebral glucose metabolism and blood flow after acute fluid-percussion injury in rats

Am J Physiol Heart Circ Physiol