丰富环境干预对短暂性全脑缺血大鼠认知功能的影响及其机制的研究
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摘要
近年来,缺血性脑血管病患者普遍存在的认知功能障碍严重地影响着人们的身体健康与生活质量。因此,寻求各种促进脑损伤后认知功能恢复的有利因素是目前研究的热点。有研究表明,早期给予动物丰富环境刺激可在一定程度上改善其学习和记忆功能。目前该领域的研究往往着重于行为学方面,而有关海马形态学变化和分子生物学机制的研究鲜有报道。因此,本研究在成功建立短暂性全脑缺血再灌注模型的基础上,采用行为学指标检测、病理学和分子生物学等技术,观察丰富环境干预对短暂性全脑缺血大鼠学习记忆功能的影响,并探讨其作用机制,为临床脑卒中早期积极的环境疗法提供理论依据。
With the changes of social environment and diet composition, there is an increase trend in morbidity, mortality and disability of stroke. Ischemic diseases accounts for appoximately 80%-85% of cerebrovascular diseases. Patients have cognitive impairment in addition to exercise and language disorders, which seriously affect physical fitness and quality of life. Therefore, there is intense interest in searching for reliable interventions associated with recovery enhancement across a variety of neurological disorders.
Hippocampus, which composes of recent memory circuit, is an anatomical base and nerve center of learning and memory. Neurogenesis in the adulthood hippocampus participates in formation of memory. Data from several study indicate that early enriched rehabilitative training has beneficial effects on learning and memory function, including the promotion of hippocampal plasticity.
Although behavioral improvements are well documented, little is known regarding the structural alterations in the hippocampus and the underlying mechanisms, that are responsible for mediating these enhancements in recovery. The aims of the study were to examine the influence and mechanism of behavioral experience in enriched environment after cerebral ischemia, which provide theoretical basis for earlier-period and energetic environmental therapy in clinical strokes.
Adult male Wistar rats were used in the study and transient global cerebral ischemia was induced by the four-vessel occlusion method while control animals were subjected to anesthesia and sham surgery alone. Within 3 days of surgery, rats were randomly assigned to either enriched environment housing or standard condition. All animals were sacrificed 14 days after behavioral training. The methods were as followed:①The learning and memory ability was evaluated by Morris water maze. The pathological changes in hippocampal cells were observed with H-E stain and Nissl stain.②Transmission electron microscopy, Golgi-Cox stain and morphometric analysis were performed to evaluate the changes of hippocampal ultrastructure and dendritic structure.③The number of hippocampal neural precursor cells (NPCs) was evaluated after BrdU immuno- staining. BrdU/GFAP-labeled cells and BrdU/NeuN-labeled cells were detected by double labeling immunofluorescence.④The expression levels of glial fibrillary acid protein (GFAP) mRNA and protein in CA1 region of hippocampus were detected by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), Western blot and immunohistochemistry.
The results were as followed:
1. Even though all animals learned to perform the water maze task over time, the IS group took longer to learn the task while the IE group performed as well as the sham groups.
2. Compared with that in the SS group, the injury of CA1 region of the hippocampus was severe in the IS group. The raritas and disorder of pyramidal cells and swelling and pyknosis of the neuronal cells were seen. The IE group was shown to decrease injury in hippocampal CA1 region cells of the cerebral ischemia rats significantly.
3. Analysis of Nissl-stained tissue sections revealed no cell loss in the sham- operated animals and dramatic neuronal loss in ischemic rats. Ischemia-induced neuronal loss largely involved the CA1 region. The IE group showed that enriched environment can protect CA1 neurons against ischemia damage.
4. The neuronal shrinkage, swellen mitochondria, reduced nerve plexus and synapse, changed synapse structure were observed in the IS group, while neuron and synapse in the IE group were seen no apparent abnormality.
5. The total length of apical dendrite and the mean of basilar dentrite branching points in the IE group were significantly greater than those of other groups (P<0.05).
6. An increased number of BrdU-labeled cells in the subgranular zone (SGZ) of the dentate gyrus in ischemic groups. A significant main effect of ischemia was that the number of BrdU-positive cells per hippocampal volume increased by approximately 40% in all rats subjected to cerebral ischemia compared to the SS group.
7. Examination of cell phenotype showed that only a few BrdU-positive cells colabeled with NeuN. BrdU/NeuN-labeled cells were seen only in the IE and SE groups. No new cells showed GFAP colabeling.
8. When compared to the sham groups, increased levels of GFAP mRNA and protein were observed in all ischemic rats but an overall increased was evident in the IE group (P<0.05).
9. When compared to the sham groups, the number of GFAP immunopositive cells in the IE group enhanced, their staining strong, the cell bodies enlarged the neuritis long and thick (P<0.05).
The conclusions were as followed:
1. Enriched rehabilitative training can improve the ability of learning and memory, on which relieve pathological damage of the hippocampus of rats with transient global cerebral ischemia was one of the reasons.
2. Enriched rehabilitative training can promote the ultrastructure’s recovery and dentritic growth of ischemic rats, in which the re-establishment of neural network and the enhancement of plasticity was one of the mechanisms.
3. The effect of enriched rehabilitative training on the proliferation and differentation of NPCs in the dentate gyrus may be one of the factors which promote the recovery of neural function after transient global cerebral ischemia.
4. Enriched rehabilitative training may accelate the expression of GFAP mRNA and protein in the hippocampus of rats with transient global cerebral ischemia, which can promote the neuronal plasticity and form the material basis of functional recovery after stroke.
With the changes of social environment and diet composition, there is an increase trend in morbidity, mortality and disability of stroke. Ischemic diseases accounts for appoximately 80%-85% of cerebrovascular diseases. Patients have cognitive impairment in addition to exercise and language disorders, which seriously affect physical fitness and quality of life. Therefore, there is intense interest in searching for reliable interventions associated with recovery enhancement across a variety of neurological disorders.
Hippocampus, which composes of recent memory circuit, is an anatomical base and nerve center of learning and memory. Neurogenesis in the adulthood hippocampus participates in formation of memory. Data from several study indicate that early enriched rehabilitative training has beneficial effects on learning and memory function, including the promotion of hippocampal plasticity.
Although behavioral improvements are well documented, little is known regarding the structural alterations in the hippocampus and the underlying mechanisms, that are responsible for mediating these enhancements in recovery. The aims of the study were to examine the influence and mechanism of behavioral experience in enriched environment after cerebral ischemia, which provide theoretical basis for earlier-period and energetic environmental therapy in clinical strokes.
Adult male Wistar rats were used in the study and transient global cerebral ischemia was induced by the four-vessel occlusion method while control animals were subjected to anesthesia and sham surgery alone. Within 3 days of surgery, rats were randomly assigned to either enriched environment housing or standard condition. All animals were sacrificed 14 days after behavioral training. The methods were as followed:①The learning and memory ability was evaluated by Morris water maze. The pathological changes in hippocampal cells were observed with H-E stain and Nissl stain.②Transmission electron microscopy, Golgi-Cox stain and morphometric analysis were performed to evaluate the changes of hippocampal ultrastructure and dendritic structure.③The number of hippocampal neural precursor cells (NPCs) was evaluated after BrdU immuno- staining. BrdU/GFAP-labeled cells and BrdU/NeuN-labeled cells were detected by double labeling immunofluorescence.④The expression levels of glial fibrillary acid protein (GFAP) mRNA and protein in CA1 region of hippocampus were detected by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), Western blot and immunohistochemistry.
The results were as followed:
1. Even though all animals learned to perform the water maze task over time, the IS group took longer to learn the task while the IE group performed as well as the sham groups.
2. Compared with that in the SS group, the injury of CA1 region of the hippocampus was severe in the IS group. The raritas and disorder of pyramidal cells and swelling and pyknosis of the neuronal cells were seen. The IE group was shown to decrease injury in hippocampal CA1 region cells of the cerebral ischemia rats significantly.
3. Analysis of Nissl-stained tissue sections revealed no cell loss in the sham- operated animals and dramatic neuronal loss in ischemic rats. Ischemia-induced neuronal loss largely involved the CA1 region. The IE group showed that enriched environment can protect CA1 neurons against ischemia damage.
4. The neuronal shrinkage, swellen mitochondria, reduced nerve plexus and synapse, changed synapse structure were observed in the IS group, while neuron and synapse in the IE group were seen no apparent abnormality.
5. The total length of apical dendrite and the mean of basilar dentrite branching points in the IE group were significantly greater than those of other groups (P<0.05).
6. An increased number of BrdU-labeled cells in the subgranular zone (SGZ) of the dentate gyrus in ischemic groups. A significant main effect of ischemia was that the number of BrdU-positive cells per hippocampal volume increased by approximately 40% in all rats subjected to cerebral ischemia compared to the SS group.
7. Examination of cell phenotype showed that only a few BrdU-positive cells colabeled with NeuN. BrdU/NeuN-labeled cells were seen only in the IE and SE groups. No new cells showed GFAP colabeling.
8. When compared to the sham groups, increased levels of GFAP mRNA and protein were observed in all ischemic rats but an overall increased was evident in the IE group (P<0.05).
9. When compared to the sham groups, the number of GFAP immunopositive cells in the IE group enhanced, their staining strong, the cell bodies enlarged the neuritis long and thick (P<0.05).
The conclusions were as followed:
1. Enriched rehabilitative training can improve the ability of learning and memory, on which relieve pathological damage of the hippocampus of rats with transient global cerebral ischemia was one of the reasons.
2. Enriched rehabilitative training can promote the ultrastructure’s recovery and dentritic growth of ischemic rats, in which the re-establishment of neural network and the enhancement of plasticity was one of the mechanisms.
3. The effect of enriched rehabilitative training on the proliferation and differentation of NPCs in the dentate gyrus may be one of the factors which promote the recovery of neural function after transient global cerebral ischemia.
4. Enriched rehabilitative training may accelate the expression of GFAP mRNA and protein in the hippocampus of rats with transient global cerebral ischemia, which can promote the neuronal plasticity and form the material basis of functional recovery after stroke.
引文
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