The sigma-1 receptor enhances brain plasticity and functional recovery after experimental stroke.

Stroke leads to brain damage with subsequent slow and incomplete recovery of lost brain functions. Enriched housing of stroke-injured rats provides multi-modal sensorimotor stimulation, which improves recovery, although the specific mechanisms involved have not been identified. In rats housed in an enriched environment for two weeks after permanent middle cerebral artery occlusion, we found increased sigma-1 receptor expression in peri-infarct areas. Treatment of rats subjected to permanent or transient middle cerebral artery occlusion with 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride, an agonist of the sigma-1 receptor, starting two days after injury, enhanced the recovery of lost sensorimotor function without decreasing infarct size. The sigma-1 receptor was found in the galactocerebroside enriched membrane microdomains of reactive astrocytes and in neurons. Sigma-1 receptor activation increased the levels of the synaptic protein neurabin and neurexin in membrane rafts in the peri-infarct area, while sigma-1 receptor silencing prevented sigma-1 receptor-mediated neurite outgrowth in primary cortical neuronal cultures. In astrocytic cultures, oxygen and glucose deprivation induced sigma-1 receptor expression and actin dependent membrane raft formation, the latter blocked by sigma-1 receptor small interfering RNA silencing and pharmacological inhibition. We conclude that sigma-1 receptor activation stimulates recovery after stroke by enhancing cellular transport of biomolecules required for brain repair, thereby stimulating brain plasticity. Pharmacological targeting of the sigma-1 receptor provides new opportunities for stroke treatment beyond the therapeutic window of neuroprotection.

Regeneration and plasticity in the brain and spinal cord.

The concept of brain plasticity covers all the mechanisms involved in the capacity of the brain to adjust and remodel itself in response to environmental requirements, experience, skill acquisition, and new challenges including brain lesions. Advances in neuroimaging and neurophysiologic techniques have increased our knowledge of task-related changes in cortical representation areas in the intact and injured human brain. The recognition that neuronal progenitor cells proliferate and differentiate in the subventricular zone and dentate gyrus in the adult mammalian brain has raised the hope that regeneration may be possible after brain lesions. Regeneration will require that new cells differentiate, survive, and integrate into existing neural networks and that axons regenerate. To what extent this will be possible is difficult to predict. Current research explores the possibilities to modify endogenous neurogenesis and facilitate axonal regeneration using myelin inhibitory factors. After apoptotic damage in mice new cortical neurons can form long-distance connections. Progenitor cells from the subventricular zone migrate to cortical and subcortical regions after ischemic brain lesions, apparently directed by signals from the damaged region. Postmortem studies on human brains suggest that neurogenesis may be altered in degenerative diseases. Functional and anatomic data indicate that myelin inhibitory factors, cell implantation, and modification of extracellular matrix may be beneficial after spinal cord lesions. Neurophysiologic data demonstrating that new connections are functioning are needed to prove regeneration. Even if not achieving the goal, methods aimed at regeneration can be beneficial by enhancing plasticity in intact brain regions.

On neural plasticity, new neurons and the postischemic milieu: an integrated view on experimental rehabilitation.

This review discusses actual and potential contributors to functional improvement after stroke injuries. Topics that will be covered are neuronal re-organization and sprouting, neural stem/progenitor cell activation and neuronal replacement, as well as the neuronal milieu defined by glia, inflammatory cells and blood vessel supply. It is well established that different types of neuronal plasticity ultimately lead to post-stroke recovery. However, an untapped potential which only recently has started to be extensively explored is neuronal replacement through endogenous or exogenous resources. Major experimental efforts are needed to achieve progress in this burgeoning area. The review stresses the importance of applying neurodevelopmental principles as well as performing a characterization of the role of the postischemic milieu when studying adult brain neural stem/progenitor cells. Integrated and multifaceted experimentation, incorporating actual and possible poststroke function modulators, will be necessary in order to determine future strategies that will ultimately enable considerable progress in the field of neurorehabilitation.

Enriched environment after focal cortical ischemia enhances the generation of astroglia and NG2 positive polydendrocytes in adult rat neocortex.

Environmental enrichment (EE) alleviates sensorimotor deficits after brain infarcts but the cellular correlates are not well-known. This study aimed to test the effects of postischemic EE on neocortical cell genesis. A neocortical infarct was caused by distal ligation of the middle cerebral artery in adult spontaneously hypertensive rats, subsequently housed in standard environment or EE. Bromodeoxyuridine (BrdU) was administered during the first postischemic week to label proliferating cells and BrdU incorporation was quantified 4 weeks later in the periinfarct, ipsilateral medial and contralateral cortex. Immunohistochemistry and confocal microscopy were used to analyze co-localization of BrdU with neuronal (calbindin D28k, calretinin, parvalbumin, glutamic acid decarboxylase, tyrosine hydroxylase), astrocytic (glial fibrillary acidic protein, glutamine synthetase, vimentin, nestin), microglia/macrophage (CD11b/Ox-42, CD68/ED-1), oligodendrocyte progenitor/polydendrocyte (NG2, platelet-derived growth factor alpha receptor) or mature oligodendrocyte (myelin basic protein) markers. BrdU positive cells were increased in all analyzed cortical regions in stroke EE rats compared with stroke standard environment rats. Newly born cells in the periinfarct cortex were mostly reactive astroglia. Occasionally, BrdU positive cells in the periinfarct cortex that were negative for glial or microglia/macrophage markers co-expressed markers typical for interneurons but did not express appropriate functional markers. The majority of BrdU positive cells in intact cortical regions, ipsi- and contralaterally, were identified as NG2 positive polydendrocytes. Perineuronally situated newly born cells and polydendrocytes were found to be brain-derived neurotrophic factor immunoreactive. In conclusion, EE enhanced newborn glial scar astroglia and NG2+ polydendrocytes in the postischemic neocortex which might be beneficial for brain repair and poststroke plasticity.

Cultural and linguistic influence on brain organization for language and possible consequences for dyslexia: a review.

Current neuroimaging and neurophysiologic techniques have substantially increased our possibilities to study processes related to various language functions in the intact human brain. Learning to read and write influences the functional organization of the brain. What is universal and what is specific in the languages of the world are important issues. Most studies on healthy bilinguals indicate that essentially the same neural mechanisms are used for first and second languages, albeit with some linguistic and cultural influences related to speech and writing systems, particularly between alphabetical and nonalphabetical languages. Proficiency, age of acquisition, and amount of exposure can affect the cerebral representations of the languages. Accumulating data support the important role of working memory for acquiring high proficiency in the reading of native and second languages. It is proposed that longitudinal studies on second language acquisition are essential and that the specific problems related to second language learning in dyslexic children should have high priority.

Postischemic exercise attenuates whereas enriched environment has certain enhancing effects on lesion-induced subventricular zone activation in the adult rat.

Experimental stroke increases cell proliferation and neurogenesis in the subventricular zone (SVZ) and in the dentate gyrus subgranular zone (SGZ) in the adult mammalian brain. This study examined the effects of postischemic voluntary exercise (running wheel) and environmental enrichment on the SVZ and SGZ 1 week after focal cortical ischemia in adult spontaneously hypertensive rats. Immunohistochemical labeling was performed for incorporation of specific cell markers such as Ki67 and 5-bromodeoxyuridine (proliferating and newborn cells), terminal deoxynucleotidyl transferase-mediated dUTP in situ nick-end labeling (apoptotic cells), Sox-2 and glial fibrillary acidic protein (neural stem and progenitor cells), polysialylated neural cell adhesion molecule and doublecortin (neuroblasts). Postischemic exercise and environmental enrichment differentially modulated SVZ cell genesis but lacked effects on the SGZ. Lesion-induced proliferation of neural stem/progenitor cells and neuronal precursors was attenuated in stroke runners without any effects on apoptosis or neuronal migration in the forebrain. Running activity did not affect the SVZ in intact rats. In contrast to postischemic wheel running, postischemic environmental enrichment did not have attenuating effects on the ipsilateral SVZ and increased proliferating putative neural stem cells and neuronal precursors contralaterally. A significant functional improvement, assessed using a rotating pole, was observed only in the postischemically enriched group and was likely due to other types of plasticity than neuronal replacement at this early time point. It may be concluded that in contrast to enriched environment, exercise during the first postischemic week might be detrimental for regenerative processes initiated in the SVZ after stroke.

Enriched environment increases neural stem/progenitor cell proliferation and neurogenesis in the subventricular zone of stroke-lesioned adult rats.

BACKGROUND AND PURPOSE: The subventricular zone in the adult brain is identified as an endogenous resource of neuronal precursors that can be recruited to adjacent lesioned areas. The hypothesis was tested that postischemic environmental enrichment might enhance subventricular zone cell genesis. METHODS: A cortical infarct was induced in adult spontaneously hypertensive rats by ligating the middle cerebral artery distal to the striatal branches, after which animals were housed in either standard or enriched environment and allowed to survive for 5 weeks. The thymidine analogue bromodeoxyuridine was administered during the first postischemic week. The generation of neural stem/progenitor cells and neuronal precursors in the subventricular zone were studied with cell specific markers such as Ki67 and phosphorylated histone H3 (cell proliferation), Sox-2 (neural stem/progenitor cells), bromodeoxyuridine (slowly cycling, nonmigratory putative neural stem cells), and doublecortin (newborn immature neurons). RESULTS: Proliferating cells in the subventricular zone were identified as chiefly neural progenitors but also putative neural stem cells and neuronal precursors. Five weeks after stroke, proliferation in the subventricular zone was lower in stroke-lesioned rats housed in standard environment compared with nonlesioned rats. Postischemic environmental enrichment normalized cell proliferation levels, increased the numbers of putative neural stem cells as assessed with bromodeoxyuridine, and increased doublecortin-positive neuroblasts, which extended in migratory chains toward the infarct. CONCLUSIONS: Enriched environment increased the neural stem/progenitor cell pool and neurogenesis in the adult subventricular zone 5 weeks after a cortical stroke. This might be of potential importance for tissue regeneration.

Functional and cellular effects of environmental enrichment after experimental brain infarcts.

Our genes interact with environmental stimuli throughout our lives. The attitude and reaction to an acute cerebral trauma or stroke, as well as the pre-lesion life event and activities, can influence functional outcome. Although difficult to separate in adult human beings, genetic and environmental factors can be selectively evaluated in animal studies. Post-ischemic housing in an enriched environment, i.e. larger cages which allow both social interaction and various activities improves functional outcome, modifies gene activation, and increases dendrite branching and number of dendritic spines in pyramidal neurons in layers II-III in the contra-lateral cortex. Furthermore, it alters lesion-induced progenitor cell differentiation and interacts with neocortical transplantation, drug treatment and training. It is proposed that the interaction between environment and specific treatment needs more clinical attention, and that a general stimulating and positive environment is the optimal base for specific interventions in neurological rehabilitation.

Enriched environment influences adrenocortical response to immune challenge and glutamate receptor gene expression in rat hippocampus.

Housing of animals in an enriched environment (EE) has many positive effects on brain structure and function and can facilitate recovery from various brain injuries. The purpose of this study was to evaluate whether enriched rearing could alter the stress response induced by repeated immune challenge and to investigate the influence of EE and immune challenge on glutamate receptor gene expression in the hippocampus. Male 2-mo-old Wistar rats were kept under standard conditions (SC) or in an EE for 5 weeks. Immune challenge was performed by Escherichia coli lipopolysaccharide (LPS) injected repeatedly (ip) in increasing doses (10, 20, and 40 microg/kg/mL) once daily for five consecutive days. The animals were decapitated 2 h after the last injection. Blood samples, adrenals, and hippocampi were collected. LPS induced an increase in plasma and adrenal levels of corticosterone and a transient decrease in body weight of animals kept under SC, but not in an EE. Enriched housing resulted in an increase in adrenal weights and enhanced gene expression of hippocampal AMPA GluR1 receptor subunit. Concerning the LPS treatment, no effects on adrenal and thymus weights and glutamate receptor mRNA levels in the hippocampus were noticed. Thus, vulnerability to some negative effects of repeated immune challenge may be modified by environmental conditions associated with changes in brain plasticity. The fact that differences in housing conditions change stress response has to be considered in biomedical research.

Brain plasticity in health and disease.

Research during the last decades has greatly increased our understanding of brain plasticity, i.e. how neuronal circuits can be modified by experience, learning and in response to brain lesions. Currently available neuroimaging techniques that make it possible to study the function of the human brain in vivo have had an important impact. Cross-modal plasticity during development is demonstrated by cortical reorganization in blind or deaf children. Early musical training has lasting effects in shaping the brain. Albeit the plasticity is largest during childhood, the adult brain retains a capacity for functional and structural reorganization that earlier has been underestimated. Recent research on Huntington's disease has revealed the possibility of environmental interaction even with dominant genes. Scientifically based training methods are now being applied in rehabilitation of patients after stroke and trauma, and in the sensory retraining techniques currently applied in the treatment of focal hand dystonia as well as in sensory re-education after nerve repair in hand surgery. There is evidence that frequent participation in challenging and stimulating activities is associated with reduced cognitive decline during aging. The current concept of brain plasticity has wide implication for areas outside neuroscience and for all human life.

Environmental influence on recovery after brain lesions--experimental and clinical data.

One aim of rehabilitation after brain lesions should be to optimise the function of the remaining intact brain. Experimental studies on focal cerebral infarcts in the rat have demonstrated that postischemic environmental enrichment significantly improves functional outcome, increases dendrite branching and number of dendritic spines in the contralateral cortex, influences expression of many genes and modifies lesion-induced stem cell differentiation in the hippocampus. Furthermore, environmental factors can interact with specific interventions such as necrotic grafting and drug treatment, which underlines the importance of general stimulation and activation in rehabilitation after brain damage. Animal laboratories often provide an environment with little stimulation. This should be taken into account when evaluating the clinical relevance of animal studies on long-term functional outcome after brain lesions.

Effects of cortical ischemia and postischemic environmental enrichment on hippocampal cell genesis and differentiation in the adult rat.

The study aimed to elucidate the effects of cortical ischemia and postischemic environmental enrichment on hippocampal cell genesis. A cortical infarct was induced by a permanent ligation of the middle cerebral artery distal to the striatal branches in 6-month-old spontaneously hypertensive rats. Bromodeoxyuridine (BrdU) was administered as 7 consecutive daily injections starting 24 hours after surgery and animals were housed in standard or enriched environment. Four weeks after completed BrdU administration, BrdU incorporation and its co-localization with the neuronal markers NeuN and calbindin D28k, and the astrocytic marker glial fibrillary acidic protein in the granular cell layer and subgranular zone of the hippocampal dentate gyrus were determined with immunohistochemistry and were quantified stereologically. Compared with sham-operated rats, rats with cortical infarcts had a five-to sixfold ipsilateral increase in BrdU-labeled cells. About 80% of the new cells were neurons. Differential postischemic housing did not influence significantly the total number of surviving BrdU-labeled cells or newborn neurons. However, postischemic environmental enrichment increased the ipsilateral generation of astrocytes normalizing the astrocyte-to-neuron ratio, which was significantly reduced in rats housed in standard environment postischemically.

Environmental influences on functional outcome after a cortical infarct in the rat.

The effect of postoperative housing conditions on functional outcome and brain-derived neurotrophic factor (BDNF) gene expression was evaluated 1 month after a distal ligation of the right middle cerebral artery (MCA) in spontaneously hypertensive rats. Two days postoperatively the rats were randomized into four groups; individually housed with no equipment (deprived group), individually housed with free access to a connected running wheel (running group), housed together in a large cage with no equipment (social group) or in the same size of cage furnished with bars, chains and various things to manipulate (enriched group). The enriched rats had significantly higher scores when crossing a rotating horizontal rod than deprived and running rats. The social group performed significantly better than the deprived group. The BDNF gene expression in the ipsi- and contralateral cortex, thalamus, hippocampus and cerebellum did not significantly differ between the groups. The weight of the adrenal glands was significantly increased in running rats suggesting that postischemic running may be stressful. We conclude that the beneficial effect of postischemic environmental enrichment is likely to be a combination of social and various physical activities, and that BDNF gene expression 1 month after a cortical infarct did not correlate with functional outcome.

Neuronal plasticity and dendritic spines: effect of environmental enrichment on intact and postischemic rat brain.

The authors compared the influence of environmental enrichment on intact and lesioned brain, and tested the hypothesis that postischemic exposure to an enriched environment can alter dendritic spine density in pyramidal neurons contralateral to a cortical infarct. The middle cerebral artery was occluded distal to the striatal branches in spontaneously hypertensive rats postoperatively housed either in a standard or in an enriched environment. Intact rats were housed in the same environment. Three weeks later the brains were perfused in situ. The dendritic and spine morphology was studied with three-dimensional confocal laser scanning microscopy after microinjection of Lucifer yellow in pyramidal neurons in layers II/III and V/VI in the somatosensory cortex. In intact rats, the number of dendritic spines was significantly higher in the enriched group than in the standard group in all layers ( P < 0.05). Contralateral to the infarct, pyramidal neurons in layers II/III, which have extensive intracortical connections that may play a role in cortical plasticity, had significantly more spines in the enriched group than in the standard group ( P < 0.05). No difference was observed in layers V/VI. They conclude that housing rats in an enriched environment significantly increases spine density in superficial cortical layers in intact and lesioned brain, but in deeper layers of intact brain.