Background and Objective
Endogenous neurogenesis is associated with functional recovery after stroke, but the
roles it plays in such recovery processes are unknown. This study aims to clarify
the roles of endogenous neurogenesis in functional recovery and motor map reorganization
induced by rehabilitative therapy after stroke by using a rat model of cerebral ischemia
(CI).
Methods
Ischemia was induced via photothrombosis in the caudal forelimb area of the rat cortex.
First, we examined the effect of rehabilitative therapy on functional recovery and
motor map reorganization, using the skilled forelimb reaching test and intracortical
microstimulation. Next, using the same approaches, we examined how motor map reorganization
changed when endogenous neurogenesis after stroke was inhibited by cytosine-β-d-arabinofuranoside (Ara-C).
Results
Rehabilitative therapy for 4 weeks after the induction of stroke significantly improved
functional recovery and expanded the rostral forelimb area (RFA). Intraventricular
Ara-C administration for 4-10 days after stroke significantly suppressed endogenous
neurogenesis compared to vehicle, but did not appear to influence non-neural cells
(e.g., microglia, astrocytes, and vascular endothelial cells). Suppressing endogenous
neurogenesis via Ara-C administration significantly inhibited (~50% less than vehicle)
functional recovery and RFA expansion (~33% of vehicle) induced by rehabilitative
therapy after CI.
Conclusions
After CI, inhibition of endogenous neurogenesis suppressed both the functional and
anatomical markers of rehabilitative therapy. These results suggest that endogenous
neurogenesis contributes to functional recovery after CI related to rehabilitative
therapy, possibly through its promotion of motor map reorganization, although other
additional roles cannot be ruled out.
Key Words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of Stroke and Cerebrovascular DiseasesAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Plasticity during stroke recovery: from synapse to behavior.Nat Rev Neurosci. 2009; 10: 861-872
- Neuroplasticity in the context of motor rehabilitation after stroke.Nat Rev Neurol. 2011; 7: 76-85
- Tissue plasminogen activator for acute ischemic stroke.N Engl J Med. 1995; 333: 1581-1588
- Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischemic stroke: a meta-analysis of individual patient data from randomized trials.Lancet. 2014; 384: 1929-1935
- Efficacy of intra-arterial fibrinolysis for acute ischemic stroke: meta-analysis of randomized controlled trials.Stroke. 2014; 41: 932-937
- A randomized trial of intra-arterial treatment for acute ischemic stroke.N Engl J Med. 2015; 372: 11-20
- Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.Stroke. 2013; 44: 870-947
- Comprehensive overview of nursing and interdisciplinary care of the acute ischemic stroke patient: a scientific statement from the American Heart Association.Stroke. 2009; 40: 2911-2944
- Motor recovery after stroke: a systematic review.Lancet Neurol. 2009; 8: 741-754
- Neural substrates for the effects of rehabilitative training on motor recovery after ischemic infarct.Science. 1996; 272: 1791-1794
- Reorganization of remote cortical regions after ischemic brain injury: a potential substrate for stroke recovery.J Neurophysiol. 2003; 89: 3205-3214
- Experience, cortical remapping, and recovery in brain disease.Neurobiol Dis. 2010; 37: 252-258
- Cortical neurogenesis in adult rats after reversible photothrombotic stroke.J Cereb Blood Flow Metab. 2000; 20: 1166-1173
- Neuronal replacement from endogenous precursors in the adult brain after stroke.Nat Med. 2002; 8: 963-970
- Evidence for stroke-induced neurogenesis in the human brain.Proc Natl Acad Sci USA. 2006; 103: 13198-13202
- Physical exercise improves functional recovery through mitigation of autophagy, attenuation of apoptosis and enhancement of neurogenesis after MCAO in rats.BMC Neurosci. 2013; 14: 46
- Physical exercise promotes recovery of neurological function after ischemic stroke in rats.Int J Mol Sci. 2014; 15: 10974-10988
- Transgenic ablation of doublecortin-expressing cells suppresses adult neurogenesis and worsens stroke outcome in mice.Proc Natl Acad Sci USA. 2010; 107: 7993-7998
- Conditional depletion of neurogenesis inhibits long-term recovery after experimental stroke in mice.PLoS ONE. 2012; 7 (e38932)
- Induction of reproducible brain infarction by photochemically initiated thrombosis.Ann Neurol. 1985; 17: 497-504
- The structure of skilled forelimb reaching in the rat: a proximally driven movement with a single distal rotatory component.Behav Brain Res. 1990; 41: 49-59
- Functional reorganization of the rat motor cortex following motor skill learning.J Neurophysiol. 1998; 80: 3321-3325
- The motor cortex of the rat: cytoarchitecture and microstimulation mapping.J Comp Neurol. 1982; 212: 76-88
- Delayed administration of the nucleic acid analog 2Cl-C.OXT-A attenuates brain damage and enhances functional recovery after ischemic stroke.Brain Res. 2013; 1506: 115-1131
- A semiautomated method for measuring brain infarct volume.J Cereb Blood Flow Metab. 1990; 10: 290-293
- Cytarabine induced cerebellar neurobehavioral performance with cellular and genetic alternations.Toxicology. 2012; 11: 41-52
- Remodeling the brain: plastic structural brain changes produced by different motor therapies.Stroke. 2008; 15: 1520-1525
- The basal forebrain cholinergic system is essential for cortical plasticity and functional recovery following brain injury.Neuron. 2005; 21: 173-179
- Post-infarct cortical plasticity and behavioral recovery using concurrent cortical stimulation and rehabilitative training: a feasibility study in primates.Neurol Res. 2003; 25: 801-810
- The evolution of motor cortex and motor systems.in: Kaas J.H. Bullock T.H. Preuss T.M. Evolution of nervous systems. Academic Press, Oxford2006: 373-395
- Middle cerebral artery stroke that includes the premotor cortex reduces mobility outcome.Stroke. 1999; 7: 1380-1383
- Mechanisms of recovery of dexterity following unilateral lesion of the sensorimotor cortex in adult monkeys.Exp Brain Res. 1999; 128: 149-159
- Ablation of proliferating cells in the CNS exacerbates motor neuron disease caused by mutant superoxide dismutase.PLoS ONE. 2012; 4: e34932
- Impact of inhibition of erythropoietin treatment-mediated neurogenesis in the dentate gyrus of the hippocampus on restoration of spatial learning after traumatic brain injury.Exp Neurol. 2012; 235: 336-344
- Tumor necrosis factor-alpha. A mediator of focal ischemic brain injury.Stroke. 1997; 28: 1233-1244
- Stroke and the immune system: from pathophysiology to new therapeutic strategies.Lancet Neurol. 2011; 10: 471-480
- Astroglial networks scale synaptic activity and plasticity.Proc Natl Acad Sci USA. 2011; 108: 8467-8472
- Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation.Lancet Neurol. 2012; 11: 369-380
- Neural stem/precursor cells for the treatment of ischemic stroke.J Neurol Sci. 2008; 265: 73-77
- Electrophysiological neurodifferentiation of subventricular zone-derived precursor cells following stroke.Neurosci Lett. 2008; 442: 305-308
- Interactions between rostral and caudal cortical motor areas in the rat.J Neurophysiol. 2015; 113: 3893-3904
- Reshaping the cortical motor map by unmasking latent intracortical connections.Science. 1991; 251: 944-947
- Effect of brain-derived neurotrophic factor treatment and forced arm use on functional motor recovery after small cortical ischemia.Stroke. 2004; 35: 992-997
- Intravenous brain-derived neurotrophic factor enhances poststroke sensorimotor recovery and stimulates neurogenesis.Stroke. 2007; 38: 2165-2172
- Regulation of stroke-induced neurogenesis in adult brain—recent scientific progress.Cereb Cortex. 2006; 16: i162-i167
Article info
Publication history
Published online: October 13, 2016
Accepted:
September 11,
2016
Received in revised form:
August 31,
2016
Received:
May 13,
2016
Footnotes
This work was supported by the JSPS KAKENHI Grant-in-Aid for Scientific Research (B), Grant Number 24700572.
Identification
DOI: https://doi.org/10.1016/j.jstrokecerebrovasdis.2016.09.016
Copyright
© 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.
