ABSTRACT
Background:
Enriched environment (EE) is a simple and effective intervention to improve cognitive function in post-stroke cognitive impairment (PSCI), partly due to the rebalancing of the cholinergic signaling pathway in the hippocampus. α7-nicotinic acetylcholine receptor (α7-nAChR) is a cholinergic receptor whose activation inhibits inflammation and promotes the recovery of neurological function in PSCI patients. However, it is still unclear whether EE can regulate α7-nAChR and activate the cholinergic anti-inflammatory pathway (CAP) in PSCI.
Objective:
To investigate the effects of EE on cognitive impairment, and the role of α7-nAChR in PSCI.
Methods:
A PSCI rat model was induced by middle cerebral artery occlusion and reperfusion (MCAO/R) and were reared in standard environment (SE) or EE for 28d, control group with sham surgery. Cognitive function was determined by Morris water maze test. The long-term potentiation (LTP) was assessed by Electrophysiology. Histopathological methods were used to determine infarct volume, α7-nAChR expression and the cytokines and cholinergic proteins expression.
Results:
Compared with SE group, rats in EE group had better cognitive function, higher expression of α7-nAChR positive neurons in hippocampal CA1 region. In addition, EE attenuated unfavorable changes induced by MCAO/R in cytokines and cholinergic proteins, and also enhanced LTP promoted by nicotine and attenuated by α-BGT; but showed no significantly difference in infarct volume.
Conclusions:
EE markedly improves cognitive impairment and enhances neuroplasticity in PSCI rats, which may be closely related to enhancement of α7-nAChR expression.
Keywords:
Cognitive Dysfunction; Stroke; Hippocampus
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(A) Representative photographs of brain slices that are stained with TTC at 28 days after MCAO/R. The white areas are infracted tissue. EE slightly reduces infarct size, with no significant difference (n=4 rats per group). (B) EE significantly decreases mNSS score at 7, 14 and 28 days after MCAO/R. Date are expressed as mean±SD. **p<0.01, ***p<0.001 vs. SE group of the same time points (n=8 rats per group). (C-D) EE significantly decreases escape latency time and increases crossing platform times. Date are expressed as mean±SD. ***p<0.001 vs. control group of the same time points; #p<0.05, ##p<0.01, ###p<0.001 vs. SE group of the same time points (n=8 rats per group). SE: standard environment; EE: enriched environment, mNSS: Modified neurological severity scores.
(A) Representative images of hippocampal α7-nAChR positive neurons in the hippocampal CA1 region are shown in rats of control group, SE group and EE group at 28 days after MCAO/R (×200). Scale bar=10 μm. EE increases the cell density of α7-nAChR positive neurons in the hippocampus (p<0.05). EE increases ACh content (B) and ChAT activity (C), and decreases AChE activity (D) in hippocampal tissue of MCAO/R rats. Date are expressed as mean±SD, ***p<0.001 vs. control group; ##p<0.01, ###p<0.001 vs. SE group. n=4 samples from 4 rats per group. ACh, acetylcholine; ChAT, choline acetyltransferase; AChE, acetylcholinesterase.
EE significantly decreases serum IL-1β (A), IL-6 (B) and NSE (C) levels, and increases BDNF (D) level in rats at 7, 14 and 28 days after MCAO/R. Date are expressed as mean±SD, ***p<0.001 vs. control group of the same time points; ##p<0.01, ###p<0.001 vs. SE group of the same time points. n=8 samples from 8 rats per group. NSE, c.
(A) Time course and extent of LTP induction in rats 28 days after MCAO/R. fEPSP amplitude is normalized to average baseline. (B) EE increases the fEPSP slope. Date are expresses as mean±SD, ***p<0.001 vs. control group, ##p<0.01 vs. SE group. (C) The effects of EE on LTP are dependent on α7-nAChR. Average fEPSP amplitude at 60 min after HFS by EE are enhanced by cotreatment with nicotine, and attenuated by cotreatment with α-BGT. Date are expressed as mean±SD, *p<0.05, **p<0.01 vs. EE group. n=4 slices from 4 rats per group. α-BGT, α-bungarotoxin; LTP, long-term potentiation; HFS: high frequency stimulation; fEPSP: field excitatory postsynaptic potential.