Role In Brain Plasticity Research Articles

Experience-Dependent Structural Plasticity in the Visual System.

During development, the environment exerts a profound influence on the wiring of brain circuits. Due to the limited resolution of studies in fixed tissue, this experience-dependent structural plasticity was once thought to be restricted to a specific developmental time window. The recent introduction of two-photon microscopy for in vivo imaging has opened the door to repeated monitoring of individual neurons and the study of structural plasticity mechanisms at a very fine scale. In this review, we focus on recent work showing that synaptic structural rearrangements are a key mechanism mediating neural circuit adaptation and behavioral plasticity in the adult brain. We examine this work in the context of classic studies in the visual systems of model organisms, which have laid much of the groundwork for our understanding of activity-dependent synaptic remodeling and its role in brain plasticity.

Low Circulating Acute Brain-Derived Neurotrophic Factor Levels Are Associated With Poor Long-Term Functional Outcome After Ischemic Stroke

Brain-derived neurotrophic factor (BDNF) plays important roles in brain plasticity and repair, and it influences stroke outcomes in animal models. Circulating BDNF concentrations are lowered in patients with traumatic brain injury, and low BDNF predicts poor recovery after this injury. We sought to investigate whether circulating concentrations of BDNF are altered in the acute phase of ischemic stroke and whether they are associated with short- or long-term functional outcome. Serum concentrations of BDNF were measured in the Sahlgrenska Academy Study on Ischemic Stroke. The main outcomes were modified Rankin Scale (mRS) good (mRS score of 0-2) versus poor (mRS score of 3-6) at 3 months and 2 years after stroke, and good (mRS score of 0-2) versus poor (mRS score of 3-5) at 7 years after stroke. Acute concentrations of BDNF were significantly lower in ischemic stroke cases (n=491) compared with controls (n=513). BDNF concentrations were not significantly associated with 3-month outcome. However, patients with BDNF in the lowest tertile had an increased risk of experiencing a poor outcome both at 2-year and 7-year follow-up, and these associations were independent of vascular risk factors and stroke severity (odds ratio, 2.6; confidence intervals, 1.4-4.9; P=0.002 and odds ratio, 2.1; confidence intervals, 1.1-3.9; P=0.028, respectively). Circulating concentrations of BDNF protein are lowered in the acute phase of ischemic stroke, and low levels are associated with poor long-term functional outcome. Further studies are necessary to confirm these associations and to determine the predictive value of BDNF in stroke outcomes.

Prolyl endopeptidase is involved in the degradation of neural cell adhesion molecules in vitro.

Membrane-associated glycoprotein neural cell adhesion molecule (NCAM) and its polysialylated form (PSA-NCAM) play an important role in brain plasticity by regulating cell-cell interactions. Here, we demonstrate that the cytosolic serine protease prolyl endopeptidase (PREP) is able to regulate NCAM and PSA-NCAM. Using a SH-SY5Y neuroblastoma cell line with stable overexpression of PREP, we found a remarkable loss of PSA-NCAM, reduced levels of NCAM180 and NCAM140 protein species, and a significant increase in the NCAM immunoreactive band migrating at an apparent molecular weight of 120 kDa in PREP-overexpressing cells. Moreover, increased levels of NCAM fragments were found in the concentrated medium derived from PREP-overexpressing cells. PREP overexpression selectively induced an activation of matrix metalloproteinase-9 (MMP-9), which could be involved in the observed degradation of NCAM, as MMP-9 neutralization reduced the levels of NCAM fragments in cell culture medium. We propose that increased PREP levels promote epidermal growth factor receptor (EGFR) signaling, which in turn activates MMP-9. In conclusion, our findings provide evidence for newly-discovered roles for PREP in mechanisms regulating cellular plasticity through NCAM and PSA-NCAM.

Evidence for the existence of dopamine D2R and Sigma 1 allosteric receptor-receptor interaction in the rat brain: role in brain plasticity and cocaine action

Drug addiction is regarded as one of the most important neuropsychiatric diseases afflicting our society today. A prototypic drug of abuse is cocaine which directly acts on the brain reward system. In this work we present evidence on the existence of dopamine D2R- Sigma1R heteroreceptor complexes which may play a role in the etiology of cocaine addiction. By means of BRET D2R-Sigma1R heteromers were demonstrated in HEK293 cells after receptor cotransfection. The existence of D2R-Sigma1R heteroreceptor complexes was demonstrated also in discrete regions of the ventral and dorsal striatum with in situ proximity ligation assay. Through saturation binding assay it was clearly demonstrated that in membrane preparations of HEK293 cells co-expressing D2R-Sigma1R, cocaine (1nM) significantly increased the D2R Bmax values (998±40 fmol/mg protein) over D2R alone cells (664±37 fmol/mg protein). This effect was counteracted by the Sigma1R selective antagonist PD144418 (Bmax value: 728±39 fmol/mg protein). Furthermore, CREB reporter luc-gene assay indicated that the presence of D2R-Sigma1R significantly reduced the potency of the D2R like agonist quinpirole to inhibit the forskolin induced increase of the CREB signal. In contrast, the presence of a low concentration of cocaine (100nM) was found to markedly increase the quinpirole potency to inhibit the forskolin induced increase of the CREB signal in the D2R-Sigma1R cells. These dynamic changes in D2R-Sigma1R signalling produced by cocaine maybe explained by synergistic allosteric receptor-receptor interactions in the D2R-Sigma1R heteroreceptor complexes at the plasma membrane level. An antagonistic allosteric receptor-receptor interaction between the dopamine D2R and the Sigma1R in absence of cocaine instead of can explain the reduced potency of quinpirole. These dual conformational changes in the D2R-Sigma1R heteroreceptor complexes could be associated with the redistribution of both protomers from the intracellular compartment to the plasma membrane as indicated by means of confocal analysis of agonist induced D2RSigma1R trafficking and internalization. Overall, the dynamic of D2R-Sigma1R heteroreceptor complexes may represent a mechanism that shapes neuronal and addictive responses to cocaine.

TNF-A Levels throughout the Critical Period for Experience-Dependent Plasticity in the Rat Primary Auditory Cortex

Tumor necrosis factor- alpha (TNF-α) is likely to play a role in brain plasticity. To determine whether TNF-α levels change throughout a critical period of experience-dependent brain plasticity, we assessed these levels in the primary auditory cortex of rats before, during and after the critical period (at postnatal day 7, postnatal day 12 and at adulthood, respectively). TNF-α levels in the auditory cortex increased from before to after a critical period of brain plasticity. We suggest that TNF-α may play a role in the brain plasticity that occurs in the auditory cortex.

Genetic variation at the BDNF locus: evidence for association with long-term outcome after ischemic stroke.

Background and PurposeRates and extent of recovery after stroke vary considerably between individuals and genetic factors are thought to contribute to post-stroke outcome. Brain-derived neurotrophic factor (BDNF) plays important roles in brain plasticity and repair and has been shown to be involved in stroke severity, recovery, and outcome in animal models. Few clinical studies on BDNF genotypes in relation to ischemic stroke have been performed. The aims of the present study are therefore to investigate whether genetic variation at the BDNF locus is associated with initial stroke severity, recovery and/or short-term and long-term functional outcome after ischemic stroke.MethodsFour BDNF tagSNPs were analyzed in the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS; 600 patients and 600 controls, all aged 18–70 years). Stroke severity was assessed using the NIH Stroke Scale (NIHSS). Stroke recovery was defined as the change in NIHSS over a 3-month period. Short- and long-term functional outcome post-stroke was assessed using the modified Rankin Scale at 3 months and at 2 and 7 years after stroke, respectively.ResultsNo SNP was associated with stroke severity or recovery at 3 months and no SNP had an impact on short-term outcome. However, rs11030119 was independently associated with poor functional outcome 7-years after stroke (OR 0.66, 95% CI 0.46–0.92; P = 0.006).ConclusionsBDNF gene variants were not major contributors to ischemic stroke severity, recovery, or short-term functional outcome. However, this study suggests that variants in the BDNF gene may contribute to poor long-term functional outcome after ischemic stroke.

FOXP2, retinoic acid, and language: a promising direction.

GENERAL COMMENTARY article Front. Cell. Neurosci., 13 November 2014Sec. Cellular Neurophysiology Volume 8 - 2014 | https://doi.org/10.3389/fncel.2014.00387

EN

Growing evidence suggests that small ubiquitin-like modifier (SUMO) conjugation plays a key role in brain plasticity by modulating activity-dependent synaptic transmission. However, these observations are based largely on cell culture experiments. We hypothesized that episodic and fear memories would be affected by silencing SUMO1-3 expression. To investigate the role of SUMO conjugation in neuronal functioning in vivo, we generated a novel Sumo transgenic mouse model in which a Thy1 promoter drives expression of 3 distinct microRNAs to silence Sumo1-3 expression, specifically in neurons. Wild-type and Sumo1-3 knockdown mice were subjected to a battery of behavioural tests to elucidate whether Sumoylation is involved in episodic and emotional memory. Expression of Sumo1-3 microRNAs and the corresponding silencing of Sumo expression were particularly pronounced in hippocampal, amygdala and layer V cerebral cortex neurons. The Sumo knockdown mice displayed anxiety-like responses and were impaired in episodic memory processes, contextual and cued fear conditioning and fear-potentiated startle. Since expression of Sumo1-3 was silenced in this mouse model, we need to verify in future studies which of the SUMO paralogues play the pivotal role in episodic and emotional memory. Our results indicate that a functional SUMO conjugation pathway is essential for emotionality and cognition. This novel Sumo knockdown mouse model and the technology used in generating this mutant may help to reveal novel mechanisms that underlie a variety of neuropsychiatric conditions associated with anxiety and impairment of episodic and emotional memory.

Sleep and synaptic plasticity in the developing and adult brain.

Sleep is hypothesized to play an integral role in brain plasticity. This has traditionally been investigated using behavioral assays. In the last 10-15years, studies combining sleep measurements with in vitro and in vivo models of synaptic plasticity have provided exciting new insights into how sleep alters synaptic strength. In addition, new theories have been proposed that integrate older ideas about sleep function and recent discoveries in the field of synaptic plasticity. There remain, however, important challenges and unanswered questions. For example, sleep does not appear to have a single effect on synaptic strength. An unbiased review of the literature indicates that the effects of sleep vary widely depending on ontogenetic stage, the type of waking experience (or stimulation protocols) that precede sleep and the type of neuronal synapse under examination. In this review, I discuss these key findings in the context of current theories that posit different roles for sleep in synaptic plasticity.

Psychoanalysis and its role in brain plasticity: much more than a simple bla, bla, bla

Psychoanalysis and its role in brain plasticity: much more than a simple bla, bla, bla

Ipsilateral versus contralateral spontaneous post-stroke neuroplastic changes: Involvement of BDNF?

Stroke is a leading cause of death and disability in industrialized countries. Although surviving patients exhibit a certain degree of restoration of function attributable to brain plasticity, the majority of stroke survivors has to struggle with persisting deficits. In order to potentiate post-stroke recovery, several rehabilitation therapies have been undertaken and many experimental studies have reported that brain-derived neurotrophic factor (BDNF) is central to many facets of neuroplastic processes. However, although BDNF role in brain plasticity is well characterized through strategies that manipulate its content, the involvement of this neurotrophin in spontaneous post-stroke recovery remains to be clarified. Besides, while the neuroplastic role of BDNF is restricted to its mature form, most studies investigating the proper effect of ischemia on post-stroke BDNF metabolism focused on mRNA or total protein expressions. In addition, these studies are mainly performed in brain regions collected either at or around the lesion site. Therefore, the objective of the present study was to investigate in both hemispheres, the long-term expression (up to one month) of both pro- and mature BDNF forms in rats subjected to photothrombotic ischemia. These assessments were performed in the cortex and in the hippocampus, two regions known to subserve functional recovery after stroke and were coupled to the study of synaptophysin expression, a marker of synaptogenesis. Our study reports that stroke induces an early and transient increase (4h) in mature BDNF expression in the cortex of both hemispheres that was associated with a delayed rise (30d) in synaptophysin levels ipsilateraly. In both hippocampal territories, the pattern of mature BDNF expression shows a more delayed increase (from 8 to 30d), which coincides with the evolution of synaptophysin expression. Interestingly, in these hippocampal territories, pro-BDNF levels evolve differently suggesting a differential gene regulation between the two hemispheres. While highlighting the complexity of changes in BDNF metabolism after stroke, our data suggest that BDNF involvement in spontaneous post-stroke plasticity is region-dependent.

EphA Signaling Promotes Actin-based Dendritic Spine Remodeling through Slingshot Phosphatase

Actin cytoskeletal remodeling plays a critical role in transforming the morphology of subcellular structures across various cell types. In the brain, restructuring of dendritic spines through actin cytoskeleletal reorganization is implicated in the regulation of synaptic efficacy and the storage of information in neural circuits. However, the upstream pathways that provoke actin-based spine changes remain only partly understood. Here we show that EphA receptor signaling remodels spines by triggering a sequence of events involving actin filament rearrangement and synapse/spine reorganization. Rapid EphA signaling over minutes activates the actin filament depolymerizing/severing factor cofilin, alters F-actin distribution in spines, and causes transient spine elongation through the phosphatases slingshot 1 (SSH1) and calcineurin/protein phosphatase 2B (PP2B). This early phase of spine extension is followed by synaptic reorganization events that take place over minutes to hours and involve the relocation of pre/postsynaptic components and ultimately spine retraction. Thus, EphA receptors utilize discrete cellular and molecular pathways to promote actin-based structural plasticity of excitatory synapses.

Partial reduction in neural cell adhesion molecule (NCAM) in heterozygous mice induces depression-related behaviour without cognitive impairment

The neural cell adhesion molecule (NCAM) plays an important role in brain plasticity. Using mice deficient in all isoforms of NCAM we have previously demonstrated that constitutive deficiency in the NCAM gene (NCAM−/−) resulted in cognitive impairment, anhedonic behaviour and a reduced ability to cope with stress. This was accompanied by reduced basal phosphorylation of the fibroblast growth factor receptor 1 (FGFR1) and reduced phosphorylation of calcium-calmodulin kinase (CaMK) II and IV and cAMP response element binding protein (CREB). The present study was aimed to investigate how partial deficiency in NCAM in mice (NCAM+/−) affected phenotype. We found that NCAM+/− mice showed a longer period of immobility in the tail suspension test, increased latency to feed in the novelty-suppressed feeding test and reduced preference for sucrose in sucrose preference test. Both NCAM+/− and NCAM−/− mice showed reduced extinction of contextual fear. In contrast to NCAM−/− mice, NCAM+/− mice did not demonstrate memory impairment in either object recognition or contextual fear conditioning tests. Levels of phosphorylated FGFR1 in the hippocampus and prefrontal/frontal cortex of NCAM+/− mice were partially reduced and no changes in the phosphorylation of CaMKII, CaMKIV or CREB in the hippocampus were found. We conclude that a constitutive partial reduction in NCAM proteins results in a behavioural phenotype related to depression without impairment in cognitive functions, also affecting the level of FGFR1 phosphorylation without major alterations in CaMKII and CaMKIV intracellular signalling. Partial reduction in FGFR1 phosphorylation might explain the observed behavioural phenotype in NCAM+/− mice.

NREM Sleep Oscillations and Brain Plasticity in Aging

The human electroencephalogram (EEG) during non-rapid eye movement sleep (NREM) is characterized mainly by high-amplitude (>75 μV), slow-frequency (<4 Hz) waves (slow waves), and sleep spindles (∼11–15 Hz; >0.25 s). These NREM oscillations play a crucial role in brain plasticity, and importantly, NREM sleep oscillations change considerably with aging. This review discusses the association between NREM sleep oscillations and cerebral plasticity as well as the functional impact of age-related changes on NREM sleep oscillations. We propose that age-related reduction in sleep-dependent memory consolidation may be due in part to changes in NREM sleep oscillations.

Long-Term Stimulation of Neural Progenitor Cell Migration After Cortical Ischemia in Mice

Cortical ischemia induces neural progenitor cell migration toward the injury site; however, whether these cells are capable of maintaining the migratory response for a longer period after injury remains uncertain. We analyzed progenitor migration up to 1 year after induction of photothrombotic stroke to the mouse neocortex. Migrating progenitors identified as doublecortin positive cells (DCX+) were assessed using the immunohistochemistry and immunofluorescence. The thymidine analogues chlorodeoxyuridine and iododeoxyuridine were used to birth-date the progenitor cells. In the striatum, we detected elevated numbers of DCX+ cells up to 6 weeks postlesion. In the corpus callosum and the peri-infarct cortex (Ctx), DCX+ cell numbers were increased up to 1 year. The orientation of the migrating progenitors was mostly aligned with the corpus callosum fiber tract at all time points; however, in the Ctx, they aligned parallel to the infarct border. The injured cortex continuously receives new progenitors up to 1 year after lesion. Cells born after lesion did not become mature neurons, although a portion of the migrating progenitors showed initial signs of differentiation into neurons. Neural progenitors might have a role in brain plasticity after cortical stroke, especially considering the prolonged window of migratory responses of up to 1 year after stroke lesion.

Stress- and Allostasis-Induced Brain Plasticity

The brain is the key organ of stress processes. It determines what individuals will experience as stressful, it orchestrates how individuals will cope with stressful experiences, and it changes both functionally and structurally as a result of stressful experiences. Within the brain, a distributed, dynamic, and plastic neural circuitry coordinates, monitors, and calibrates behavioral and physiological stress response systems to meet the demands imposed by particular stressors. These allodynamic processes can be adaptive in the short term (allostasis) and maladaptive in the long term (allostatic load). Critically, these processes involve bidirectional signaling between the brain and body. Consequently, allostasis and allostatic load can jointly affect vulnerability to brain-dependent and stress-related mental and physical health conditions. This review focuses on the role of brain plasticity in adaptation to, and pathophysiology resulting from, stressful experiences. It also considers interventions to prevent and treat chronic and prevalent health conditions via allodynamic brain mechanisms.

Doublecortin‐positive cells in the adult primate cerebral cortex and possible role in brain plasticity and development

We have demonstrated that cortical cell autografts might be a useful therapy in two monkey models of neurological disease: motor cortex lesion and Parkinson's disease. However, the origin of the useful transplanted cells obtained from cortical biopsies is not clear. In this report we describe the expression of doublecortin (DCX) in these cells based on reverse-transcription polymerase chain reaction (RT-PCR) and immunodetection in the adult primate cortex and cell cultures. The results showed that DCX-positive cells were present in the whole primate cerebral cortex and also expressed glial and/or neuronal markers such as glial fibrillary protein (GFAP) or neuronal nuclei (NeuN). We also demonstrated that only DCX/GFAP positive cells were able to proliferate and originate progenitor cells in vitro. We hypothesize that these DCX-positive cells in vivo have a role in cortical plasticity and brain reaction to injury. Moreover, in vitro these DCX-positive cells have the potential to reacquire progenitor characteristics that confirm their potential for brain repair.

Glee for Glia

![Figure][1] CREDIT: BEN EMERY (CENTRE FOR NEUROSCIENCE AND FLOREY NEUROSCIENCE INSTITUTES, UNIVERSITY OF MELBOURNE, AUSTRALIA) AND SARA MULINYAWE (STANFORD UNIVERSITY, CALIFORNIA, USA) Research on glial cells has come of age. Until a few years ago, gliobiologists felt they had to justify their existence, often in a department of neuroscience or neurobiology, and they regularly stressed the abundance of glia as compared to that of neurons in the nervous system. Now, however, the outdated notion that glia are simply the glue that holds the nerve cells together but otherwise have no active role in the brain has been laid to rest for good. Years of thorough research and the steady accumulation of solid evidence have confirmed that glia are highly complex cells engaged in a plethora of functions. The role of glia in, among other examples, synapse formation, synapse maturation and plasticity, and the rapid conduction of action potentials, as well as their immunological functions in the nervous system, have by now been unequivocally established. Hence, this year's neuroscience special issue is devoted to glial cells. Astrocytes are an important fraction of glial cells in the brain. The molecular mechanisms underlying astrocyte specification and growth and their interactions with other cell types to assemble the nervous system are still not completely understood. In his Review, Freeman (p. [774][2]) presents and discusses exciting findings and ideas concerning the development, specification, and morphogenesis of astrocytes. Another type of glial cell, oligodendrocytes, is central to the brain's myelination, which ensures the efficiency and speed of action potentials. Emery (p. [779][3]) reviews new approaches to investigating oligodendrocyte differentiation and myelination in the central nervous system. Microglia are another fascinating subpopulation of glial cells. They sense pathological tissue alterations and they can develop into brain macrophages and perform immunological functions. In a Perspective, Graeber (p. [783][4]) outlines the involvement of microglia in the treatment of higher brain functional defects. In the research section of the magazine, Lee et al. (p. [790][5]) report that tonic inhibition in the cerebellum is due to GABA released from glial cells by permeation through the Bestrophin 1 anion channel. Ginhoux et al. (p. [841][6]) investigate the developmental origin of microglia and show that adult microglia derive from primitive myeloid progenitor cells that arise before embryonic day 8. In a Perspective, Fields (p. [768][7]) presents his hypothesis that white matter, which consists mostly of myelinated axons, may play a role in brain plasticity and learning. The 9 November issue of Science Signaling complements this Science special issue on glia with research into signaling pathways involved in drug-resistant glioma, which is a type of aggressive brain cancer ([www.sciencemag.org/special/glia][8]). A Perspective by Ballanyi et al. describes how astrocytes sense changes in pH to stimulate the neurons that control breathing and, in a Podcast, Fields discusses mechanisms by which nerve and glial cells communicate outside of synapses. [1]: pending:yes [2]: /lookup/doi/10.1126/science.1190928 [3]: /lookup/doi/10.1126/science.1190927 [4]: /lookup/doi/10.1126/science.1190929 [5]: /lookup/doi/10.1126/science.1184334 [6]: /lookup/doi/10.1126/science.1194637 [7]: /lookup/doi/10.1126/science.1199139 [8]: http://www.sciencemag.org/special/glia

Short-term nutritional folate deficiency in rats has a greater effect on choline and acetylcholine metabolism in the peripheral nervous system than in the brain, and this effect escalates with age

The hypothesis of this study is that a folate-deficient diet (FD) has a greater effect on cholinergic system in the peripheral nervous system than in the brain, and that this effect escalates with age. It was tested by comparing choline and acetylcholine levels in male Sprague Dawley rats fed either control or folate-deficient diets for 10 weeks, starting at age 4 weeks (the young group) or 9 months (the adult group). Folate-deficient diet consumption resulted in depletion of plasma folate in both age groups. In young folate-deficient rats, liver and lung choline levels were significantly lower than those in the respective controls. No other significant effects of FD on choline and acetylcholine metabolism were found in young rats. In adult rats, FD consumption markedly decreased choline levels in the liver, kidneys, and heart; furthermore, choline levels in the cortex and striatum were moderately elevated, although hippocampal choline levels were not affected. Acetylcholine levels were higher in the heart, cortex, and striatum but lower in the hippocampus in adult folate-deficient rats, as compared to controls. Higher acetylcholine levels in the striatum in adult folate-deficient rats were also associated with higher dopamine release in the striatal slices. Thus, both age groups showed higher cholinergic metabolic sensitivity to FD in the peripheral nervous system than in the brain. However, compensatory abilities appeared to be better in the young group, implicating the adult group as a preferred model for further investigation of folate-choline-acetylcholine interactions and their role in brain plasticity and cognitive functions.

Environmental enrichment enhances directional selectivity of primary auditory cortical neurons in rats

Environment enrichment (EE) has an important role in brain plasticity. Previous research has shown that EE increases the response strength of auditory cortical neurons, but it remains unknown whether EE can affect the directional selectivity of auditory neurons. In this study, rats were exposed to EE conditions during the developmental critical period (EE1) or after the critical period (EE2). By in vivo extracellular recording, we found that EE enhanced the directional selectivity of primary auditory cortical neurons in EE1 rats, which showed a sharper azimuth selectivity curve of auditory cortical neurons compared with normal rats. However, there was no significant difference in directional selectivity between the EE2 rats and age-matched control rats. Our findings indicate that early exposure to EE enhances the directional sensitivity of primary auditory cortical neurons. These results provide an insight into developmental plasticity in the auditory system.