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The effect of enriched environment on gene expression and stroke recovery
Umeå University, Faculty of Medicine, Public Health and Clinical Medicine.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Stroke is the third leading cause of death and the major course of long-term disabilities in industrialized countries. Most surviving stroke patients show some degree of spontaneous recovery, but persistent symptoms in sensorimotor and cognitive functions are common. The symptoms can be reproduced in experimental stroke models in rats by occlusion of the middle cerebral artery. Housing rats in an enriched environment (EE), i.e. group housing in a large cage with toys that are changed daily, increases neuronal plasticity in healthy rats and can also improve functional recovery after experimental stroke.

The present thesis investigates the effect of EE on the recovery of sensorimotor and cognitive functions one month after focal cerebral ischemia in rats, with emphasis on the underlying molecular mechanisms. Furthermore, EE-induced effect on gene expression in healthy rats was investigated after different periods of EE-housing and at different time points of the day.

We show an improved recovery of both sensorimotor and cognitive functions in rats housed in EE for one month after focal cerebral ischemia. The recovery of sensorimotor function correlated significantly to mRNA expression of the plasticity associated transcription factors NGFI-A and NGFI-B in hippocampus and cortical regions outside the infarct. Social interaction seems to be an important component for the beneficial effects of EE after focal cerebral ischemia. Microarray analysis of hippocampal gene expression after one month of postischemic environmental enrichment revealed no confirmable EE-induced changes that could explain the improved recovery in spatial memory. Interestingly, healthy rats housed in EE showed increased mRNA expression of NGFI-A and Krox-20 exclusively during the dark period of the day compared to rats housed in isolation. In addition, EE housed rats had a substantial diurnal variation in NGFI-A, Krox-20 and NGFI-B mRNA expression; this was absent in single-housed rats. EE-induced changes in gene expression are more evident during the dark period of the day, when rats are more active and can benefit from the stimulating environment. This is important to consider in future investigation of putative mediators of the EE-induced neuronal plasticity.

In summary, these findings may contribute to an increased understanding of the underlying molecular mechanisms behind improved functional recovery in rats housed in enriched environment after focal cerebral ischemia.

Place, publisher, year, edition, pages
2004. , 115 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 883
Keyword [en]
Medicine, experimental stroke, recovery, memory, inducible transcription factors
Keyword [sv]
Medicin
National Category
Dermatology and Venereal Diseases
Identifiers
URN: urn:nbn:se:umu:diva-278ISBN: 91-7305-626-X (print)OAI: oai:DiVA.org:umu-278DiVA: diva2:142931
Public defence
2004-06-04, Sal B, plan 9, By 1D, Tandläkarhögskolan, Norrlands universitetssjukhus, Umeå, 13:00
Opponent
Supervisors
Available from: 2004-05-12 Created: 2004-05-12Bibliographically approved
List of papers
1. Effects of postischemic environment on transcription factor and serotonin receptor expression after permanent focal cortical ischemia in rats
Open this publication in new window or tab >>Effects of postischemic environment on transcription factor and serotonin receptor expression after permanent focal cortical ischemia in rats
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2003 (English)In: Neuroscience, Vol. 119, no 3, 643-652 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-3996 (URN)
Available from: 2004-05-12 Created: 2004-05-12 Last updated: 2014-03-11Bibliographically approved
2. Environmental enrichment reverses learning impairment in the Morris water maze after focal cerebral ischemia in rats
Open this publication in new window or tab >>Environmental enrichment reverses learning impairment in the Morris water maze after focal cerebral ischemia in rats
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2004 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 19, no 8, 2288-2298 p.Article in journal (Refereed) Published
Abstract [en]

Cognitive impairment is common after ischemic stroke. In rodent stroke models using occlusion of the middle cerebral artery (MCA) this is reflected by impaired spatial memory associated with the size of the ischemic lesion. Housing in an enriched environment enhances brain plasticity and improves recovery of sensorimotor functions after experimental stroke in rats. In this study we report that postischemic housing in an enriched environment also attenuates the long-term spatial memory impairment after MCA occlusion and extinguishes the association between spatial memory and infarct volume. An enriched environment did not significantly alter the expression of selected neuronal plasticity-associated genes 1 month after MCA occlusion, indicating that most of the adaptive changes induced by an enriched environment have already occurred at this time point. We conclude that the attenuated memory impairment induced by environmental enrichment after MCA occlusion provides a useful model for further studies on the neurobiological mechanisms of recovery of cognitive functions after ischemic stroke.

Keyword
animals, brain ischemia/metabolism/*psychology, cognition/physiology, environment, male, maze learning/*physiology, memory disorders/metabolism/prevention & control/*psychology, rats, sprague-dawley, synapsins/biosynthesis
National Category
Clinical Medicine
Identifiers
urn:nbn:se:umu:diva-3997 (URN)10.1111/j.0953-816X.2004.03248.x (DOI)15090055 (PubMedID)
Available from: 2004-05-12 Created: 2004-05-12 Last updated: 2010-08-19Bibliographically approved
3. Gene expression profiling of the rat hippocampus one month after focal cerebral ischemia followed by enriched environment
Open this publication in new window or tab >>Gene expression profiling of the rat hippocampus one month after focal cerebral ischemia followed by enriched environment
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2005 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 385, no 2, 173-178 p.Article in journal (Refereed) Published
Abstract [en]

Functional recovery after experimental stroke in rats is enhanced by environmental enrichment by stimulating plastic changes in brain regions outside the lesion, but the molecular mechanisms are not known. We investigated the effect of environmental enrichment after focal cerebral ischemia on cognitive recovery and hippocampal gene expression using microarray analysis. Rats placed in enriched environment (EE) for 1 month after middle cerebral artery occlusion (MCAo) showed significantly improved spatial memory in the Morris water maze compared to rats housed alone after MCAo. Microarray analysis suggested several EE-induced differences in neuronal plasticity-related genes, but these changes could not be confirmed by quantitative real-time PCR. This study highlights some of the potential problems associated with gene expression profiling of brain tissues. Further studies at earlier time points and in additional subregions of the brain are of interest in the search for molecular mechanisms behind EE-induced neuronal plasticity after ischemic stroke.

Keyword
animals, brain ischemia/*genetics/metabolism/therapy, cerebral infarction/*genetics/metabolism/therapy, disease models; animal, environment design, gene expression profiling, gene expression regulation/genetics, hippocampus/*metabolism/pathology/physiopathology, infarction; middle cerebral artery/genetics/metabolism/therapy, male, maze learning/physiology, memory disorders/genetics/metabolism/therapy, nerve tissue proteins/*genetics, neuronal plasticity/*genetics, oligonucleotide array sequence analysis, rats, Sprague-Dawley, recovery of function/genetics, time factors
Identifiers
urn:nbn:se:umu:diva-3998 (URN)10.1016/j.neulet.2005.05.016 (DOI)15964140 (PubMedID)
Note
Artikeln har vid publicering fått en annan titel än den hade vid publiceringen av avhandlingen.Available from: 2004-05-12 Created: 2004-05-12 Last updated: 2010-08-20Bibliographically approved
4. Diurnal effects of enriched environment in immediate early gene expression in the rat brain
Open this publication in new window or tab >>Diurnal effects of enriched environment in immediate early gene expression in the rat brain
2005 (English)In: Brain research, ISSN 0006-8993, Vol. 1046, no 1-2, 137-144 p.Article in journal (Refereed) Published
Abstract [en]

Rodents housed in an enriched environment (EE) show increased neuronal plasticity with enhanced long-term potentiation and memory performance. We report an EE-induced increase in NGFI-A and Krox-20 mRNA expression exclusively during the dark period of the day. In addition, EE-housed rats showed considerable diurnal variation in NGFI-A, Krox-20, and NGFI-B mRNA expression which was absent in single-housed rats. Thus, EE-induced molecular changes are more evident during the dark phase when the rats have higher motor and exploratory activity. This is important to take into account in future studies of molecular mediators of experience-dependent neuronal plasticity.

Keyword
analysis of variance, animals, brain/metabolism, circadian rhythm/genetics/*physiology, DNA-binding proteins/genetics/*metabolism, darkness, early growth response protein 1, early growth response protein 2, environment, gene expression/physiology, immediate-early proteins/genetics/*metabolism, male, neuronal plasticity/physiology, RNA, messenger/analysis, rats, sprague-dawley, Receptors, cytoplasmic and nuclear/genetics/metabolism, receptors, steroid/genetics/metabolism, transcription factors/genetics/*metabolism
Identifiers
urn:nbn:se:umu:diva-3999 (URN)doi:10.1016/j.brainres.2005.03.051 (DOI)15927552 (PubMedID)
Available from: 2004-05-12 Created: 2004-05-12 Last updated: 2010-08-19Bibliographically approved

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