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1.
J Neurotrauma ; 2018 Nov 17.
Artículo en Inglés | MEDLINE | ID: mdl-30226403

RESUMEN

Mild traumatic brain injury (mTBI) constitutes 75 ∼ 90% of all TBI cases and causes various physical, cognitive, emotional, and other psychological symptoms. Nogo receptor 1 (NgR1) is a regulator of structural brain plasticity during development and in adulthood. Here, we used mice that, in the absence of doxycycline, overexpress NgR1 in forebrain neurons (MemoFlex) to determine the role of NgR1 in recovery from mTBI with respect to balance, cognition, memory, and emotion. We compared wild-type (WT), MemoFlex, and MemoFlex + doxycycline mice to the same three groups subjected to mTBI. mTBI was induced by a controlled 30-g weight drop. We found that inability to downregulate NgR1 significantly impairs recovery from mTBI-induced impairments. When the NgR1 transgene was turned off, recovery was similar to that of WT mice. The results suggest that the ability to regulate NgR1 signaling is needed for optimal recovery of motor coordination and balance, spatial memory, cognition, and emotional functions after mTBI.

2.
Front Mol Neurosci ; 11: 42, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29520216

RESUMEN

An appropriate strength of Nogo-like signaling is important to maintain synaptic homeostasis in the CNS. Disturbances have been associated with schizophrenia, MS and other diseases. Blocking Nogo-like signaling may improve recovery after spinal cord injury, stroke and traumatic brain injury. To understand the interacting roles of an increasing number of ligands, receptors and modulators engaged in Nogo-like signaling, the transcriptional activity of these genes in the same brain areas from birth to old age in the normal brain is needed. Thus, we have quantitatively mapped the innate expression of 11 important genes engaged in Nogo-like signaling. Using in situ hybridization, we located and measured the amount of mRNA encoding Nogo-A, OMgp, NgR1, NgR2, NgR3, Lingo-1, Troy, Olfactomedin, LgI1, ADAM22, and MAG, in 18 different brain areas at six different ages (P0, 1, 2, 4, 14, and 104 weeks). We show gene- and area-specific activities and how the genes undergo dynamic regulation during postnatal development and become stable during adulthood. Hippocampal areas underwent the largest changes over time. We only found differences between individual cortical areas in Troy and MAG. Subcortical areas presented the largest inter-regional differences; lateral and basolateral amygdala had markedly higher expression than other subcortical areas. The widespread differences and unique expression patterns of the different genes involved in Nogo-like signaling suggest that the functional complexes could look vastly different in different areas.

3.
Front Mol Neurosci ; 10: 94, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28442990

RESUMEN

Inhibition of nerve growth and plasticity in the CNS is to a large part mediated by Nogo-like signaling, now encompassing a plethora of ligands, receptors, co-receptors and modulators. Here we describe the distribution and levels of mRNA encoding 11 key genes involved in Nogo-like signaling (Nogo-A, Oligodendrocyte-Myelin glycoprotein (OMgp), Nogo receptor 1 (NgR1), NgR2, NgR3, Lingo-1, TNF receptor orphan Y (Troy), Olfactomedin, Lateral olfactory tract usher substance (Lotus) and membrane-type matrix metalloproteinase-3 (MT3-MPP)), as well as BDNF and GAPDH. Expression was analyzed in nine different brain areas before, and at eight time points during the first 3 days after a strong neuroexcitatory stimulation, caused by one kainic acid injection. A temporo-spatial pattern of orderly transcriptional regulations emerges that strengthens the role of Nogo-signaling mechanisms for synaptic plasticity in synchrony with transcriptional increases of BDNF mRNA. For most Nogo-type signaling genes, the largest alterations of mRNA levels occur in the dentate gyrus, with marked alterations also in the CA1 region. Changes occurred somewhat later in several areas of the cerebral cortex. The detailed spatio-temporal pattern of mRNA presence and kainic acid-induced transcriptional response is gene-specific. We reveal that several different gene alterations combine to decrease (and later increase) Nogo-like signaling, as expected to allow structural plasticity responses. Other genes are altered in the opposite direction, suggesting that the system prepares in advance in order to rapidly restore balance. However, the fact that Lingo-1 shows a seemingly opposite, plasticity inhibiting response to kainic acid (strong increase of mRNA in the dentate gyrus), may instead suggest a plasticity-enhancing intracellular function of this presumed NgR1 co-receptor.

4.
Cereb Cortex ; 26(4): 1804-17, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26838771

RESUMEN

Nogo receptor 1 (NgR1) is expressed in forebrain neurons and mediates nerve growth inhibition in response to Nogo and other ligands. Neuronal activity downregulates NgR1 and the inability to downregulate NgR1 impairs long-term memory. We investigated behavior in a serial behavioral paradigm in mice that overexpress or lack NgR1, finding impaired locomotor behavior and recognition memory in mice lacking NgR1 and impaired sequential spatial learning in NgR1 overexpressing mice. We also investigated a role for NgR1 in drug-mediated sensitization and found that repeated cocaine exposure caused stronger locomotor responses but limited development of stereotypies in NgR1 overexpressing mice. This suggests that NgR1-regulated synaptic plasticity is needed to develop stereotypies. Ex vivo magnetic resonance imaging and diffusion tensor imaging analyses of NgR1 overexpressing brains did not reveal any major alterations. NgR1 overexpression resulted in significantly reduced density of mature spines and dendritic complexity. NgR1 overexpression also altered cocaine-induced effects on spine plasticity. Our results show that NgR1 is a negative regulator of both structural synaptic plasticity and dendritic complexity in a brain region-specific manner, and highlight anterior cingulate cortex as a key area for memory-related plasticity.


Asunto(s)
Encéfalo/metabolismo , Dendritas/fisiología , Locomoción , Plasticidad Neuronal , Receptor Nogo 1/metabolismo , Reconocimiento (Psicología)/fisiología , Aprendizaje Espacial/fisiología , Animales , Encéfalo/efectos de los fármacos , Cocaína/administración & dosificación , Dendritas/efectos de los fármacos , Imagen de Difusión Tensora , Femenino , Giro del Cíngulo/efectos de los fármacos , Giro del Cíngulo/metabolismo , Locomoción/efectos de los fármacos , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Noqueados , Plasticidad Neuronal/efectos de los fármacos , Receptor Nogo 1/genética , Prueba de Desempeño de Rotación con Aceleración Constante
5.
PLoS One ; 8(4): e60892, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23593344

RESUMEN

Nogo Receptor 1 (NgR1) mRNA is downregulated in hippocampal and cortical regions by increased neuronal activity such as a kainic acid challenge or by exposing rats to running wheels. Plastic changes in cerebral cortex in response to loss of specific sensory inputs caused by spinal cord injury are also associated with downregulation of NgR1 mRNA. Here we investigate the possible regulation by neuronal activity of the homologous receptors NgR2 and NgR3 as well as the endogenous NgR1 antagonist LOTUS and the ligand Nogo. The investigated genes respond to kainic acid by gene-specific, concerted alterations of transcript levels, suggesting a role in the regulation of synaptic plasticity, Downregulation of NgR1, coupled to upregulation of the NgR1 antagonist LOTUS, paired with upregulation of NgR2 and 3 in the dentate gyrus suggest a temporary decrease of Nogo/OMgp sensitivity while CSPG and MAG sensitivity could remain. It is suggested that these activity-synchronized temporary alterations may serve to allow structural alterations at the level of local synaptic circuitry in gray matter, while maintaining white matter pathways and that subsequent upregulation of Nogo-A and NgR1 transcript levels signals the end of such a temporarily opened window of plasticity.


Asunto(s)
Encéfalo/metabolismo , Regulación de la Expresión Génica/fisiología , ARN Mensajero/metabolismo , Receptores de Superficie Celular/metabolismo , Análisis de Varianza , Animales , Encéfalo/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Hibridación in Situ , Ácido Kaínico/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas de la Mielina/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas Nogo , Proteína NgR2 , Oligonucleótidos/genética
6.
J Alzheimers Dis ; 33(1): 145-55, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-22903127

RESUMEN

In the search for molecules that may alter the formation of amyloid-ß (Aß) protofibrils, it has been shown that the Nogo-system can interact and bind to amyloid-ß protein precursor and thus affect the amount of Aß that is formed and deposited in the brain. To further address this issue in vivo, we crossed mice that overexpress Nogo receptor 1 (NgR1), "MemoFlex", in forebrain neurons, with plaque forming APPswe/PSEN1(ΔE9) mice, to investigate if increased levels of NgR1 would influence plaque load or cognitive function in the resulting MemoFlex/APPswe/PSEN1(ΔE9) transgenic mice. We used a radial arm water maze and the Morris water maze to measure cognitive function. We did not find any significant effect of NgR1 overexpression on the performance of APPswe/PSEN1(ΔE9) mice in the radial arm water maze test. However, MemoFlex/APPswe/PSEN1(ΔE9) mice were found to be significantly impaired in the Morris water maze. We also analyzed the amount of plaques in the two mouse models without finding any significant difference in plaque load in the cerebral cortex or the hippocampal formation. It therefore appears that overexpression of NgR1 in APPswe/PSEN1(ΔE9) mice does not have any marked effects on Aß levels, yet appears to impair spatial cognitive abilities. We conclude that strong overexpression of NgR1 in forebrain neurons impairs aspects of cognitive function but does not markedly alter plaque load in plaque-forming APPswe/PSEN1(ΔE9) mice. Thus high levels of membrane-bound NgR1 present since early postnatal life does not influence the development of plaques in mice carrying the two human plaque-causing mutations APPswe and PSEN1(ΔE9).


Asunto(s)
Precursor de Proteína beta-Amiloide , Cognición/fisiología , Proteínas de la Mielina/biosíntesis , Placa Amiloide/metabolismo , Presenilina-1 , Receptores de Superficie Celular/biosíntesis , Conducta Espacial/fisiología , Precursor de Proteína beta-Amiloide/genética , Animales , Proteínas Ligadas a GPI/biosíntesis , Proteínas Ligadas a GPI/genética , Regulación de la Expresión Génica , Ratones , Ratones Transgénicos , Proteínas de la Mielina/genética , Neuronas/metabolismo , Receptor Nogo 1 , Placa Amiloide/genética , Presenilina-1/genética , Desempeño Psicomotor/fisiología , Receptores de Superficie Celular/genética
7.
Proc Natl Acad Sci U S A ; 106(48): 20476-81, 2009 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-19915139

RESUMEN

Formation of lasting memories is believed to rely on structural alterations at the synaptic level. We had found that increased neuronal activity down-regulates Nogo receptor-1 (NgR1) in brain regions linked to memory formation and storage, and postulated this to be required for formation of lasting memories. We now show that mice with inducible overexpression of NgR1 in forebrain neurons have normal long-term potentiation and normal 24-h memory, but severely impaired month-long memory in both passive avoidance and swim maze tests. Blocking transgene expression normalizes these memory impairments. Nogo, Lingo-1, Troy, endogenous NgR1, and BDNF mRNA expression levels were not altered by transgene expression, suggesting that the impaired ability to form lasting memories is directly coupled to inability to down-regulate NgR1. Regulation of NgR1 may therefore serve as a key regulator of memory consolidation. Understanding the molecular underpinnings of synaptic rearrangements that carry lasting memories may facilitate development of treatments for memory dysfunction.


Asunto(s)
Regulación de la Expresión Génica/fisiología , Memoria/fisiología , Proteínas de la Mielina/fisiología , Prosencéfalo/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cromatografía Líquida de Alta Presión , Electrofisiología , Immunoblotting , Inmunohistoquímica , Hibridación in Situ , Aprendizaje por Laberinto/fisiología , Proteínas de la Membrana/metabolismo , Ratones , Ratones Transgénicos , Proteínas de la Mielina/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas Nogo , Receptores del Factor de Necrosis Tumoral/metabolismo , Prueba de Desempeño de Rotación con Aceleración Constante , Transgenes/genética
8.
Stem Cells ; 25(6): 1539-45, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17379767

RESUMEN

The potential of embryonic stem cells to differentiate to all cell types makes them an attractive model for development and a potential source of cells for transplantation therapies. Candidate approaches have identified individual genes and proteins that promote the differentiation of embryonic stem cells to desired fates. Here, we describe a rapid large-scale screening strategy for the identification of genes that influence the pluripotency and differentiation of embryonic stem cells to specific fates, and we use this approach to identify genes that induce neuron formation. The power of the strategy is validated by the fact that, of the 15 genes that resulted in the largest increase in neuron number, 8 have previously been implicated in neuronal differentiation or survival, whereas 7 represent novel genes or known genes not previously implicated in neuronal development. This is a simple, fast, and generally applicable strategy for the identification of genes promoting the formation of any specific cell type from embryonic stem cells. Disclosure of potential conflicts of interest is found at the end of this article.


Asunto(s)
Diferenciación Celular/genética , Células Madre Embrionarias/citología , Perfilación de la Expresión Génica/métodos , Genes del Desarrollo , Neuronas/citología , Animales , Linaje de la Célula/genética , Células Cultivadas , Ratones , Modelos Biológicos , Especificidad de Órganos/genética , Transfección/métodos
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