Abstract
We modeled prolonged cerebral hypoperfusion in mice using bilateral common carotid artery stenosis (BCAS) and electroacupuncture (EA) stimulation was applied at two acupoints, Baihui (GV20) and Dazhui (GV14). In behavioral tests of memory, BCAS produced impairments in spatial and short-term memory in mice that were attenuated by therapeutic EA stimulation. Therapeutic use of EA in BCAS also enhanced oligodendrocyte (OL) differentiation from oligodendrocyte precursor cells (OPCs), in association with white matter improvements in the corpus callosum (CC). In PCR analyses of growth factor gene expression, significant positive changes in 3 genes were observed following EA stimulation in BCAS, and here we highlight alterations in neurotrophin-4/5 (NT4/5). We confirmed EA-mediated positive changes in the expression of NT4/5 and its receptor, tyrosine receptor kinase B (TrkB). Treatment of naïve and BCAS + EA animals with a selective TrkB antagonist, ANA-12, produced losses of myelin and cognitive function that were ameliorated by EA therapy. Moreover, following BCAS we observed an EA-dependent increase in phospho-activated CREB (a downstream mediator of NT4/5-TrkB signaling) in OPCs and OLs of the CC. Our results suggest that EA stimulation promotes the recovery of memory function following white matter injury via a mechanism that promotes oligodendrocyte regeneration and involves NT4/5-TrkB signaling.
Highlights
The development of therapies that enhance OL regeneration and myelination have profound utility for the treatment of CNS white matter injury
Cognitive impairments typical of vascular dementia and white matter injury are modeled in mice by prolonged cerebral hypoperfusion, which is achieved through the surgical induction of bilateral common carotid artery stenosis (BCAS)[4,21,22,23,24]
In probe testing conducted over 3 days, the percent time spent in proximity to the platform location was significantly increased on days 14 and 26 post-BCAS induction in groups receiving EA stimulation (Fig. S2B,D)
Summary
The development of therapies that enhance OL regeneration and myelination have profound utility for the treatment of CNS white matter injury. Cognitive impairments typical of vascular dementia and white matter injury are modeled in mice by prolonged cerebral hypoperfusion, which is achieved through the surgical induction of bilateral common carotid artery stenosis (BCAS)[4,21,22,23,24]. We utilized the BCAS model to evaluate the ability of EA stimulation to attenuate memory impairments and white matter damage resultant from prolonged cerebral hypoperfusion. A greater understanding of the molecular mechanisms and beneficial outcomes of EA in white matter dysfunction will aid the development of new therapeutic approaches for vascular dementia[22]
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