Effects of vagus nerve stimulation on cognitive functioning in rats with cerebral ischemia reperfusion.
BACKGROUND
Vagus nerve stimulation (VNS) has become the most common non-pharmacological treatment for intractable drug-resistant epilepsy. However, the contribution of VNS to neurological rehabilitation following stroke has not been thoroughly examined. Therefore, we investigated the specific role of acute VNS in the recovery of cognitive functioning and the possible mechanisms involved using a cerebral ischemia/reperfusion (I/R) injury model in rats.


METHODS
The I/R-related injury was modeled using occlusion and reperfusion of the middle cerebral artery (MCAO/R) in Sprague-Dawley rats. VNS was concurrently applied to the vagus nerve using a stimulation intensity of 1 mA at a fixed frequency of 20 Hz with a 0.4-ms bipolar pulse width. The stimulation duration and inter-train interval were both 3 s. Next, Morris water maze and shuttle-box behavioral experiments were conducted to assess the effects of VNS on the recovery of learning, memory, and inhibitory avoidance following I/R injury. Intracerebroventricular injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4), a selective neurotoxin for noradrenergic neurons, was used to evaluate the role of norepinephrine (NE) as a mediator of therapeutic effects of VNS on cognitive recovery.


RESULTS
Compared with the MCAO/R group, the VNS+MCAO/R group had improved spatial memory as indicated by swimming path lengths and escape latencies in the Morris water maze, and fear memory, as indicated by the avoidance conditioned response rate, mean shock duration, and avoidance time in shuttle-box behavior experiments. Compared with the VNS+MCAO/R group, the DSP-4+VNS+MCAO/R group, which had reduced NE levels in cortical and hippocampal brain regions, showed a reversal of the VNS-induced benefits on spatial and fear memory performance.


CONCLUSIONS
VNS improves spatial and fear memory in a rat model of MCAO/R injury. However, a reduction in NE from the administration of DSP-4 blocks these protective effects, suggesting that NE may contribute to the influence exhibited by VNS on memory performance in rats with cerebral I/R-related injury.
Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan, 430030, Hubei, China.|Basic Medical Research Centre, Medical College of Nantong University, Nantong, 226001, Jiangsu, China.
Ai-fen
AF
Liu
Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan, 430030, Hubei, China.|Basic Medical Research Centre, Medical College of Nantong University, Nantong, 226001, Jiangsu, China.
Feng-bo
FB
Zhao
Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan, 430030, Hubei, China.
Jing
J
Wang
Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan, 430030, Hubei, China.
Yi-Fan
YF
Lu
Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan, 430030, Hubei, China.
Jian
J
Tian
Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan, 430030, Hubei, China.
Yin
Y
Zhao
Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan, 430030, Hubei, China.
Yan
Y
Gao
Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan, 430030, Hubei, China.
Xia-jun
XJ
Hu
Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan, 430030, Hubei, China.
Xiao-yan
XY
Liu
Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan, 430030, Hubei, China.
Jie
J
Tan
Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan, 430030, Hubei, China.
Yun-li
YL
Tian
Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan, 430030, Hubei, China. sj@mails.tjmu.edu.cn.
Jing
J
Shi
D000818:Animals; D001596:Benzylamines / Q000633:toxicity; D002545:Brain Ischemia / Q000150:complications* / Q000503:physiopathology*; D003071:Cognition / Q000187:drug effects; D005239:Fear / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000503:physiopathology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009638:Norepinephrine / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000150:complications* / Q000503:physiopathology*; D065852:Spatial Memory / Q000187:drug effects; D055536:Vagus Nerve Stimulation / Q000379:methods*
D001596:Benzylamines; C012102:DSP 4; D009638:Norepinephrine
DSP-4; MCAO/R; Norepinephrine; Vagus nerve stimulation