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.

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Reduced EGFR signaling in progenitor cells of the adult subventricular zone attenuates oligodendrogenesis after demyelination

Neuron Glia Biology ◽

10.1017/s1740925x08000082 ◽

2007 ◽

Vol 3 (3) ◽

pp. 209-220 ◽

Cited By ~ 47

Author(s):

Adan Aguirre ◽

Vittorio Gallo

Keyword(s):

Growth Factor ◽

Progenitor Cells ◽

Subventricular Zone ◽

Transforming Growth Factor ◽

Mammalian Brain ◽

Heparin Binding ◽

Egfr Signaling ◽

Transforming Growth Factor Α ◽

Physiological Conditions ◽

Focal Demyelination

AbstractNeural progenitor cells that express the NG2 proteoglycan are present in different regions of the adult mammalian brain where they display distinct morphologies and proliferative rates. In the developing postnatal and adult mouse, NG2+ cells represent a major cell population of the subventricular zone (SVZ). NG2+ cells divide in the anterior and lateral region of the SVZ, and are stimulated to proliferate and migrate out of the SVZ by focal demyelination of the corpus callosum (CC). Many NG2+ cells are labeled by GFP-retrovirus injection into the adult SVZ, demonstrating that NG2+ cells actively proliferate under physiological conditions and after demyelination. Under normal physiological conditions and after focal demyelination, proliferation of NG2+ cells is significantly attenuated in wa2 mice, which are characterized by reduced signaling of the epidermal growth factor receptor (EGFR). This results in reduced SVZ-to-lesion migration of NG2+ cells and oligodendrogenesis in the lesion. Expression of vascular endothelial growth factor (VEGF) and EGFR ligands, such as heparin binding-EGF and transforming growth factor α, is upregulated in the SVZ after focal demyelination of the CC. EGF-induced oligodendrogenesis and myelin protein expression in wild-type SVZ cells in culture are significantly attenuated in wa2 SVZ cells. Our results demonstrate that the response of NG2+ cells in the SVZ and their subsequent differentiation in CC after focal demyelination depend on EGFR signaling.

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A Critical Evaluation of Current Concepts in Cerebral Palsy

Physiology ◽

10.1152/physiol.00054.2018 ◽

2019 ◽

Vol 34 (3) ◽

pp. 216-229 ◽

Cited By ~ 9

Author(s):

Joline E. Brandenburg ◽

Matthew J. Fogarty ◽

Gary C. Sieck

Keyword(s):

Risk Factors ◽

Spinal Cord ◽

Cerebral Palsy ◽

Animal Models ◽

Critical Evaluation ◽

Brain Lesions ◽

Spastic Cerebral Palsy ◽

Diagnostic Symptoms ◽

Brain And Spinal Cord ◽

The Brain

Spastic cerebral palsy (CP), despite the name, is not consistently identifiable by specific brain lesions. CP animal models focus on risk factors for development of CP, yet few reproduce the diagnostic symptoms. Animal models of CP must advance beyond risk factors to etiologies, including both the brain and spinal cord.

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Shaping hippocampal neurogenesis: exercising the brain with cannabinoids

10.14293/s2199-1006.1.sor-.ppvgy4p.v1 ◽

2020 ◽

Author(s):

Rui S Rodrigues ◽

Joao B. Moreira ◽

Ana M. Sebastião ◽

Carlos P. Fitzsimons ◽

Sara Xapelli

Keyword(s):

Physical Exercise ◽

Progenitor Cells ◽

Neurotrophic Factors ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Fine Tuning ◽

Mammalian Brain ◽

Potential Conflict ◽

Brain Physiology ◽

The Brain

Adult neural stem/progenitor cells (NSPC) are present in specialized niches of the mammalian brain and their proliferative and differentiative potential is modulated by a myriad of factors. Recent evidence sheds light on the interaction between cannabinoids and neurotrophic factors underlying a major regulative force of adult hippocampal neurogenesis, with important effects upon cognitive plasticity and mood flexibility. Herein, we aimed at evaluating the actions of cannabinoid type 2 receptor (CB2R) together with exercise upon hippocampal neurogenesis and whether this has significant behavioral implications. Our data suggests a participation of CB2Rs in fine-tuning the actions of physical exercise upon adult hippocampal neurogenesis. Specifically, CB2R ligands as well as exercise-regulated neurotrophic factors promote an acceleration in the differentiation of progenitor cells accompanied by an increase in the number of mature neurons in vitro. Moreover, preliminary results show that CB2Rs play an impactful role in controlling cognitive and depressive-like behavior. This is particularly important because brain physiology and mental health are known to be greatly affected by physical exercise, with adult neurogenesis playing a significant role in this process. Ultimately, this work will contribute to unravel the mechanisms behind the actions of cannabinoids and exercise in the brain and to develop strategies utilizing CB2Rs and physical exercise to boost neural stem cell capacity and treat several brain disorders. Acknowledgements: Supported by Fundação para a Ciência e a Tecnologia (FCT), projects SFRH/BD/129710/2017 and IF/01227/2015. No potential conflict of interest.

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Neuronal Progenitor Cells of the Neonatal Subventricular Zone Differentiate and Disperse following Transplantation into the Adult Rat Striatum

Cell Transplantation ◽

10.1177/096368979800700209 ◽

1998 ◽

Vol 7 (2) ◽

pp. 137-156 ◽

Cited By ~ 23

Author(s):

Tanja Zigova ◽

Viorica Pencea ◽

Ranjita Betarbet ◽

Stanley J. Wiegand ◽

Charlie Alexander ◽

...

Keyword(s):

Progenitor Cells ◽

Subventricular Zone ◽

Anterior Part ◽

Rat Striatum ◽

Mammalian Brain ◽

Adult Rats ◽

Neuronal Phenotype ◽

The Core ◽

Neuronal Progenitor Cells ◽

Neuronal Progenitor

We have investigated the suitability of a recently identified and characterized population of neuronal progenitor cells for their potential use in the replacement of degenerating or damaged neurons in the mammalian brain. The unique population of neuronal progenitor cells is situated in a well-delineated region of the anterior part of the neonatal subventricular zone (referred to as SVZa). This region can be separated from the remaining proliferative, gliogenic, subventricular zone encircling the lateral ventricles of the forebrain. Because the neurons arising from the highly enriched neurogenic progenitor cell population of the SVZa ordinarily migrate considerable distances and ultimately express the neurotransmitters GABA and dopamine, we have examined whether they could serve as an alternative source of tissue for neural transplantation. SVZa cells from postnatal day 0-2 rats, prelabeled by intraperitoneal injections of the cell proliferation marker BrdU, were implanted into the striatum of adult rats approximately 1 mo after unilateral denervation by 6-OHDA. To examine the spatio-temporal distribution and phenotype of the transplanted SVZa cells, the experimental recipients were perfused at short (less than 1 wk), intermediate (2-3 wk) and long (5 mo) postimplantation times. The host brains were sectioned and stained with an antibody to BrdU and one of several cell-type specific markers to determine the phenotypic characteristics of the transplanted SVZa cells. To identify neurons we used the neuron-specific antibody TuJ1, or antimembrane-associated protein 2 (MAP-2), and anti-GFAP was used to identify astrocytic glia. At all studied intervals the majority of the surviving SVZa cells exhibited a neuronal phenotype. Moreover, morphologically they could be distinguished from the cells of the host striatum because they resembled the intrinsic granule cells of the olfactory bulb, their usual fate. At longer times, a greater number of the transplanted SVZa cells had migrated from their site of implantation, often towards an outlying blood vessel, and the density of cells within the core of the transplant was reduced. Furthermore, there were rarely signs of transplant rejection or a glial scar surrounding the transplant. In the core of the transplant there were low numbers of GFAP-positive cells, indicating that the transplanted SVZa cells, predominantly TuJ1-positive/MAP2-positive, express a neuronal phenotype. Collectively, the propensity of the SVZa cells to express a neuronal phenotype and to survive and integrate in the striatal environment suggest that they may be useful in the reconstruction of the brain following CNS injury or disease.

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Glycine exerts potent inhibitory actions on mammalian olfactory bulb neurons

Journal of Neurophysiology ◽

10.1152/jn.1994.71.2.761 ◽

1994 ◽

Vol 71 (2) ◽

pp. 761-767 ◽

Cited By ~ 36

Author(s):

P. Q. Trombley ◽

G. M. Shepherd

Keyword(s):

Spinal Cord ◽

Olfactory Bulb ◽

Hill Coefficient ◽

Mammalian Brain ◽

Glycine Receptors ◽

Low Concentrations ◽

Biological Studies ◽

Tufted Cells ◽

The Brain ◽

Olfactory Bulb Neurons

1. It is generally presumed that gamma-aminobutyric acid (GABA) mediates inhibition in the mammalian brain, whereas glycine is restricted to the brain stem and spinal cord. Recent immunocytochemical and molecular biological studies have demonstrated, however, a widespread distribution of glycine receptors through-out the CNS, including the olfactory bulb. To explore the functional significance of glycine receptors in the olfactory bulb we have used primary culture and whole-cell voltage-clamp recording techniques to test the hypothesis that glycine, as well as GABA, exerts inhibitory actions on olfactory bulb neurons. 2. Cultures of olfactory bulb neurons contain two primary populations of morphologically distinct neurons, mitral/tufted cells and interneurons (granule and periglomerular cells). In all mitral/tufted cells and interneurons examined, both glycine and GABA evoked concentration-dependent desensitizing currents mediated by chloride, similar to those seen in mammalian neurons elsewhere in the brain and spinal cord. 3. The median effective concentration (EC50) for glycine was 125 microM, with a Hill coefficient of 1.7, whereas the EC50 and Hill coefficient for GABA were 52 microM and 1.8, respectively. These values are similar to values previously reported for other central neurons. 4. At moderate concentrations (> 1 microM) strychnine nonselectively antagonized both glycine- and GABA-evoked currents. At low concentrations (< or = 1 microM) strychnine blocked glycine-mediated currents but had little effect on GABA-mediated currents. Similarly, picrotoxin was a nonselective antagonist for glycine- and GABA-mediated currents at high concentrations (100 microM), but was selective for GABA at low concentrations (10 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

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Cortical AAV-CNTF Gene Therapy Combined with Intraspinal Mesenchymal Precursor Cell Transplantation Promotes Functional and Morphological Outcomes after Spinal Cord Injury in Adult Rats

Neural Plasticity ◽

10.1155/2018/9828725 ◽

2018 ◽

Vol 2018 ◽

pp. 1-15 ◽

Cited By ~ 5

Author(s):

Stuart I. Hodgetts ◽

Jun Han Yoon ◽

Alysia Fogliani ◽

Emmanuel A. Akinpelu ◽

Danii Baron-Heeris ◽

...

Keyword(s):

Spinal Cord ◽

Gene Therapy ◽

Cortical Neurons ◽

Viral Vector ◽

Long Distance ◽

Adult Rats ◽

F344 Rat ◽

Mesenchymal Precursor Cells ◽

Cord Injury ◽

Mesenchymal Precursor

Ciliary neurotrophic factor (CNTF) promotes survival and enhances long-distance regeneration of injured axons in parts of the adult CNS. Here we tested whether CNTF gene therapy targeting corticospinal neurons (CSN) in motor-related regions of the cerebral cortex promotes plasticity and regrowth of axons projecting into the female adult F344 rat spinal cord after moderate thoracic (T10) contusion injury (SCI). Cortical neurons were transduced with a bicistronic adeno-associated viral vector (AAV1) expressing a secretory form of CNTF coupled to mCHERRY (AAV-CNTFmCherry) or with control AAV only (AAV-GFP) two weeks prior to SCI. In some animals, viable or nonviable F344 rat mesenchymal precursor cells (rMPCs) were injected into the lesion site two weeks after SCI to modulate the inhibitory environment. Treatment with AAV-CNTFmCherry, as well as with AAV-CNTFmCherry combined with rMPCs, yielded functional improvements over AAV-GFP alone, as assessed by open-field and Ladderwalk analyses. Cyst size was significantly reduced in the AAV-CNTFmCherry plus viable rMPC treatment group. Cortical injections of biotinylated dextran amine (BDA) revealed more BDA-stained axons rostral and alongside cysts in the AAV-CNTFmCherry versus AAV-GFP groups. After AAV-CNTFmCherry treatments, many sprouting mCherry-immunopositive axons were seen rostral to the SCI, and axons were also occasionally found caudal to the injury site. These data suggest that CNTF has the potential to enhance corticospinal repair by transducing parent CNS populations.

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Shock, diaschisis and von Monakow

Arquivos de Neuro-Psiquiatria ◽

10.1590/0004-282x20130067 ◽

2013 ◽

Vol 71 (7) ◽

pp. 487-489 ◽

Cited By ~ 6

Author(s):

Eliasz Engelhardt ◽

Marleide da Mota Gomes

Keyword(s):

Spinal Cord ◽

Blood Flow ◽

18Th Century ◽

Brain Lesions ◽

Spinal Cord Transection ◽

Cerebrovascular Lesions ◽

Injured Area ◽

The Brain

The concept of shock apparently emerged in the middle of the 18th century (Whyett) as an occurrence observed experimentally after spinal cord transection, and identified as "shock" phenomenon one century later (Hall). The concept was extended (Brown-Séquard) and it was suggested that brain lesions caused functional rupture in regions distant from the injured one ("action à distance"). The term "diaschisis" (von Monakow), proposed as a new modality of shock, had its concept broadened, underpinned by observations of patients, aiming at distinguishing between symptoms of focal brain lesions and transitory effects they produced, attributable to depression of distant parts of the brain connected to the injured area. Presently, diaschisis is related mainly to cerebrovascular lesions and classified according to the connection fibers involved, as proposed by von Monakow. Depression of metabolism and blood flow in regions anatomically separated, but related by connections with the lesion, allows observing diaschisis with neuroimaging.

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Diversity of Adult Neural Stem and Progenitor Cells in Physiology and Disease

Cells ◽

10.3390/cells10082045 ◽

2021 ◽

Vol 10 (8) ◽

pp. 2045

Author(s):

Zachary Finkel ◽

Fatima Esteban ◽

Brianna Rodriguez ◽

Tianyue Fu ◽

Xin Ai ◽

...

Keyword(s):

Mechanical Properties ◽

Spinal Cord ◽

Extracellular Matrix ◽

Cerebrospinal Fluid ◽

Growth Factors ◽

Energy Metabolism ◽

Progenitor Cells ◽

Ependymal Cells ◽

Stem And Progenitor Cells ◽

The Brain

Adult neural stem and progenitor cells (NSPCs) contribute to learning, memory, maintenance of homeostasis, energy metabolism and many other essential processes. They are highly heterogeneous populations that require input from a regionally distinct microenvironment including a mix of neurons, oligodendrocytes, astrocytes, ependymal cells, NG2+ glia, vasculature, cerebrospinal fluid (CSF), and others. The diversity of NSPCs is present in all three major parts of the CNS, i.e., the brain, spinal cord, and retina. Intrinsic and extrinsic signals, e.g., neurotrophic and growth factors, master transcription factors, and mechanical properties of the extracellular matrix (ECM), collectively regulate activities and characteristics of NSPCs: quiescence/survival, proliferation, migration, differentiation, and integration. This review discusses the heterogeneous NSPC populations in the normal physiology and highlights their potentials and roles in injured/diseased states for regenerative medicine.

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Neurosyphilis and neuro-AIDS

Oxford Textbook of Medicine ◽

10.1093/med/9780198746690.003.0598 ◽

2020 ◽

pp. 6100-6109

Author(s):

Hadi Manji

Keyword(s):

Spinal Cord ◽

Immune Reconstitution ◽

Brain Lesions ◽

Low Grade ◽

Syphilis Infection ◽

Highly Active ◽

Tabes Dorsalis ◽

The Central Nervous System ◽

Inflammatory Syndrome ◽

The Brain

Invasion of the central nervous system occurs early in the course of syphilis infection. Neurosyphilis causes a meningitis, a myeloradiculopathy due to pachymeningitis, gummatous (granulomatous) cord and brain lesions; endarteritis may cause infarction and a low-grade meningoencephalitis affecting the brain results in dementia (general paralysis of the insane) and in the spinal cord, a sensory ataxic syndrome (tabes dorsalis). The introduction of highly active antiretroviral therapies has greatly reduced the frequency of these complications in patients with access to these treatments. However, newer complications are now increasingly recognized such as neurological immune reconstitution inflammatory syndrome, a compartmentalization syndrome (cerebrospinal fluid escape). This chapter looks at these and other important issues regarding the background, diagnosis, treatment, and outlook for neurosyphilis and neuro-AIDS.

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