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  • Activation of microglia in the spinal cord after nerve injury found to contribute to pain hypersensitivity
    Visitas: 93
    • Neurociencia
    • Lesión medular
    • Dolor

    UNE 10, 2022 REPORT

    Activation of microglia in the spinal cord after nerve injury found to contribute to pain hypersensitivity

    by Bob Yirka , Medical Xpress

    Activation of microglia in the spinal cord after nerve injury found to contribute to pain hypersensitivity
    A perineuronal net surrounding a projection neuron in the spinal cord and depicts microglia digesting the net. Degradation of the perineuronal net by microglia causes increased neuronal activity and pain. Credit: Designs that Cell

    A team of researchers working at McGill University has found that activation of microglia in the spinal cord following a nerve injury can lead to an increased sensitivity to pain. In their paper published in the journal Science, the group describes their study of nerve cells in injured mice and what it showed them about the possible source of some types of chronic back pain.

    To learn more about the source of some types of chronic back pain, the researchers effectuated backbone nerve injuries in eight 12-week-old mice. They then collected projection neuron samples from them. Such nerve cells are known to transmit pain signals. Next, the researchers applied a stain to the projection neurons still left in the mice. Its purpose was to show whether an outer covering known as perineuronal net (PNN) was present. They found that, after injury, the volume of PNN on the projection neurons fell by 76.3% over three days. They also found that the stain had made its way to microglia—a type of immune cell.

    To learn more about the role that microglia might be playing in the decrease in PNN, the researchers worked with a new group of mice. First, they divided them into two groups. One group had their microglia removed. Testing showed that those mice did not see a drop in PNN after injury, while the other group, which had served as a control, did.

    The researchers then removed the PPN from the projection neurons in a new batch of mice and found that doing so resulted in hypersensitivity to heat (as seen by their facial expressions) and other instances of pain that occurred at random.

    The researchers suggest their work shows that when microglia are activated by an injury they can degrade PPN, leading to chronic pain. They suggest other types of chronic pain may be due to the same process in other parts of the body, even those that are not part of the central nervous system. They note that more research will have to be done to find out if their findings apply to humans, and if so, whether therapies can be designed to prevent overreactions by microglia after injury.


    Explore further

    Targeting brain cells to alleviate neuropathic pain

    More information: Shannon Tansley et al, Microglia-mediated degradation of perineuronal nets promotes pain, Science (2022). DOI: 10.1126/science.abl6773
    Journal information: Science 
  • Study finds that neurotransmitter phenotype switching by excitatory interneurons regulates recovery after spinal lesions
    Visitas: 111
    • Neurociencia
    • Lesión medular

    JUNE 2, 2022 FEATURE

    Study finds that neurotransmitter phenotype switching by excitatory interneurons regulates recovery after spinal lesions

    by Ingrid Fadelli , Medical Xpress

    Study finds that the switching of neurotransmitters by excitatory interneurons regulates recovery after spinal lesions
    vGlut2ON interneurons undergo NT phenotype switch after adult injury. Credit: Bertels et al. (Nature Neuroscience, 2022).

    When adult humans and animals severely injure their spinal cord, they become irreversibly paralyzed and are no longer able to move body parts controlled by the section of the spinal cord below their lesion. To counteract the damage done by the injury, doctors often use pharmacological agents or electrical stimulation tools.

    While these treatments can have some positive effects, they only enable movements temporarily and do not restore full mobility in the long term. Interestingly, studies on rodents have showed that while severe spinal cord injuries cause permanent paralysis in adults, neonatal rodents with spinal cord lesions can recover much of their hindlimb mobility in adulthood, without receiving any targeted treatments.

    Neuroscientists have been trying to understand the biological mechanisms underlying this renewed mobility for some years now. However, the reasons why the same type of injury experienced at different ages can have different long-term consequences on mobility remains unclear.

    A team of researchers at VIB- Neuroelectrics Research Flanders (NERF) and Leuven Brain Institute have recently carried out a study investigating the mechanisms underlying the recovery of hindlimb mobility in neonatal rodents with spinal lesions. Their findings, published in Nature Neuroscience, suggest that this recovery could be regulated by the neurotransmitter phenotype switching of spinal excitatory interneurons.

    In their experiments, the researchers subjected a series of wild mice to a complete spinal cord transection in the lower part of their thorax. The mice they operated on were either adults or five days old.

    Subsequently, the researchers used high-speed cameras to observe and characterize the movements of the mice as they moved on a treadmill, comparing them to those of a control group of mice (i.e., mice with no spinal lesions). Finally, the researchers carried out a series of analyses to determine the biological and kinematic differences between the adult and post-natal mice with spinal cord injuries.

    "We found that adult spinal cord injury prompts neurotransmitter switching of spatially defined excitatory interneurons to an inhibitory phenotype, promoting inhibition at synapses contacting motor neurons," Hannah Bertels, Guillem Vicente-Ortiz, Khadija El Kanbi, and Aya Takeoka wrote in their paper. "In contrast, neonatal spinal cord injury maintains the excitatory phenotype of glitamatergic interneurons and causes synaptic sprouting to facilitate excitation."

    Essentially, the researchers' findings suggest that the recovery of hindlimb mobility in post-natal mice with spinal cord injuries is regulated by the switching of injury-specific neurotransmitter identities and the rearrangements of connectivity among excitatory interneurons. Excitatory interneurons are neurons that connect spinal motor and sensory neurons, which utilize the neurotransmitter glutamine.

    Bertels and her colleagues then performed a series of further tests aimed at understanding their observations more in depth. The findings they collected offer valuable insight that could pave the way for new studies focusing on the consequences of severe spinal cord injuries.

    "Genetic manipulation to mimic the inhibitory phenotype observed in excitatory interneurons after adult spinal cord injury abrogates autonomous locomotor functionality in neonatally injured mice," the researchers added in their paper. "In comparison, attenuating this inhibitory phenotype improves locomotor capacity after adult injury. Together, this data demonstrates that neurotransmitter phenotype of define excitatory interneurons steers locomotor recovery after spinal cord injury."

    In the future, the findings gathered by this team of researchers could potentially help to identify more effective treatments and therapeutic interventions for re-gaining mobility after these injuries. These interventions could specifically target the regulation of interneurons, with the aim of regulating the balance of excitatory interneurons and promoting the recovery of mobility.


    Explore further

    Novel injection repairs severe spinal cord injuries in mice

    More information: Hannah Bertels et al, Neurotransmitter phenotype switching by spinal excitatory interneurons regulates locomotor recovery after spinal cord injury, Nature Neuroscience (2022). DOI: 10.1038/s41593-022-01067-9
    Journal information: Nature Neuroscience 
  • Ven por vez primera la inflamación del cerebro in vivo mediante resonancia magnética
    Visitas: 82
    • Neurociencia
    • Inflamación
    • Imagen
    • Cerebro
    • RMN

    Se ha conseguido visualizar por vez primera y con gran detalle la inflamación cerebral utilizando Resonancia Magnética Ponderada por difusión. Esta detallada radiografía de la inflamación no puede obtenerse con una resonancia magnética convencional, sino que requiere secuencias de adquisición de datos y modelos matemáticos especiales.

     

    Una vez desarrollado el método, los investigadores han podido cuantificar las alteraciones en la morfología de las diferentes poblaciones de células implicadas en el proceso inflamatorio cerebral. Este avance podría llegar a ser decisivo para cambiar el rumbo del estudio y tratamiento de enfermedades neurodegenerativas como el Mal de Alzheimer, el de Parkinson y la esclerosis múltiple.

     

    El logro es obra de la labor conjunta de los laboratorios dirigidos por Silvia de Santis y Santiago Canals, científicos del Instituto de Neurociencias de Alicante, una entidad que depende conjuntamente de la Universidad Miguel Hernández y del Consejo Superior de Investigaciones Científicas (CSIC), en España.

     

    La investigación, cuya primera autora es Raquel Garcia-Hernández, demuestra que la resonancia magnética ponderada por difusión puede detectar de forma no invasiva y diferenciada la activación de las células microgliales y los astrocitos, dos tipos de células del cerebro que están en la base de la neuroinflamación y su progresión. Enfermedades cerebrales degenerativas como la de Alzheimer y otras dolencias neurológicas, como la enfermedad de Parkinson o la esclerosis múltiple, son un problema acuciante y difícil de abordar. La activación sostenida de dos tipos de células del cerebro, las células microgliales y los astrocitos, conduce a una inflamación crónica en el cerebro que es una de las causas de la neurodegeneración y contribuye a su progresión.

     

    Sin embargo, hay una carencia de enfoques no invasivos capaces de caracterizar específicamente la inflamación cerebral in vivo. El estándar de oro actual es la tomografía por emisión de positrones (PET), pero es difícil de generalizar y está asociada a exposición a la radiación ionizante, por lo que su uso está limitado en poblaciones vulnerables y en estudios longitudinales, que requieren el uso de PET de manera repetida durante un período de años, como es el caso de las enfermedades neurodegenerativas.

     

    Otro inconveniente del PET es su baja resolución espacial, que la hace inadecuada para obtener imágenes de estructuras pequeñas, con el inconveniente añadido de que los radiotrazadores específicos de la inflamación se expresan en múltiples tipos de células (microgliales, astrocitos y endoteliales), lo que impide diferenciarlas.

     

    Frente a estos inconvenientes, la resonancia magnética ponderada por difusión tiene la capacidad única de obtener imágenes de la microestructura cerebral in vivo de forma no invasiva y con alta resolución, al capturar el movimiento aleatorio de las moléculas de agua en el parénquima cerebral para generar contraste en las imágenes de resonancia magnética.

     

    [Img #66337]

     

    La intensidad del color (del amarillo al naranja) indica el nivel de inflamación. (Imágenes: IN-CSIC-UMH)

     

    Para el éxito del estudio ha resultado decisiva la estrategia innovadora desarrollada por el equipo de Raquel Garcia-Hernández. Gracias a dicha estrategia, ha sido posible usar la resonancia magnética ponderada por difusión para obtener imágenes de la activación de las células microgliales y de los astrocitos en la materia gris del cerebro.

     

    “Es la primera vez que se demuestra que la señal de este tipo de resonancia magnética (dw-MRI) puede detectar la activación microglial y astrocitaria, con huellas específicas para cada población de células. Esta estrategia que hemos utilizado refleja los cambios morfológicos validados post mortem por inmunohistoquímica cuantitativa”, señalan los investigadores.

     

    También han demostrado que esta técnica es sensible y específica para detectar la inflamación con y sin neurodegeneración, por lo que ambos situaciones pueden ser diferenciadas. Además, permite discriminar entre la inflamación y la desmielinización característica de la esclerosis múltiple.

     

    Este trabajo ha logrado demostrar también el valor traslacional del enfoque utilizado en una cohorte de humanos sanos a alta resolución, “en la que realizamos un análisis de reproducibilidad. La asociación significativa con patrones de densidad de células microgliales conocidos en el cerebro humano apoya la utilidad del método para generar biomarcadores de glía fiables. Creemos que caracterizar, mediante esta técnica, aspectos relevantes de la microestructura tisular durante la inflamación, de forma no invasiva y longitudinal, puede tener un tremendo impacto en nuestra comprensión de la fisiopatología de muchas afecciones cerebrales, y puede transformar la práctica diagnóstica actual y las estrategias de seguimiento del tratamiento de las enfermedades neurodegenerativas”, destaca de Santis.

     

    Para validar el modelo, los investigadores han utilizado un paradigma establecido de inflamación en ratas basado en la administración intracerebral de lipopolisacáridos (LPS). En este paradigma, se preserva la viabilidad y la morfología neuronal, al tiempo que se induce, primero, una activación de las células microgliales (las células del sistema inmune del cerebro), y de manera retardada, una respuesta de los astrocitos. Esta secuencia temporal de eventos celulares permite que las respuestas gliales puedan ser disociadas transitoriamente de la degeneración neuronal y la firma de las células microgliales reactiva investigada independientemente de la astrogliosis.

     

    Para aislar la huella de la activación astrocitaria, los investigadores repitieron el experimento tratando previamente a los animales con un inhibidor que anula temporalmente alrededor del 90% de las células microgliales. Posteriormente, con un paradigma establecido de daño neuronal, comprobaron si el modelo era capaz de desentrañar las huellas neuroinflamatorias con y sin una neurodegeneración concomitante. “Esto es fundamental para demostrar la utilidad de nuestro enfoque como plataforma para el descubrimiento de biomarcadores del estado inflamatorio en las enfermedades neurodegenerativas, donde tanto la activación de la glía como el daño neuronal son actores clave”, aclaran.

     

    Por último, los investigadores utilizaron un paradigma establecido de desmielinización, basado en la administración focal de lisolecitina, para demostrar que los biomarcadores desarrollados no reflejan las alteraciones tisulares que se encuentran frecuentemente en los trastornos cerebrales.

     

    El estudio se titula “Mapping microglia and astrocyte activation in vivo using diffusion MRI” Y se ha publicado en la revista académica Science Advances. (Fuente: Pilar Quijada / Instituto de Neurociencias / CSIC / UMH)

     

  • Diversity of centrosomes delivers new clues for neurological diseases
    Visitas: 68
    • Neurociencia
    • Centrosoma

    JUNE 16, 2022

    Diversity of centrosomes delivers new clues for neurological diseases

    by Helmholtz Association of German Research Centres

    Diversity of centrosomes delivers new clues for neurological diseases
    Image of specific RNAs (magenta) at the centrosome (green) in mouse cortex cells. The cell nucleus is labeled in blue. Credit: Helmholtz Zentrum München / Giulia Antognolli

    Internationally renowned neurobiologist Magdalena Götz is pursuing important leads in her quest to elucidate the causes of neurological diseases. Together with her team at Helmholtz Munich and Ludwig-Maximilians-Universität München, she has gained new insights into the human centrosome, whose malfunction is linked to many neurodevelopmental disorders.

    The centrosome is the organelle responsible for the organization of the cytoskeleton during cell division, an essential function in organisms from yeast to humans. Until now, scientists assumed that the centrosome was very similar in all cells due to its general tasks. However, Götz and her team evaluated this notion in neurons and their developmental precursors, so-called neuronal stem cells. "There is so much we don't yet know about these cells, including how the centrosomes of neurons compare to those of neural stem cells and other cell types," Götz says. Their subsequent discoveries now fundamentally challenge the assumption that all centrosomes are created equal.

    Centrosomes are not 'one type fits all'

    In close collaboration with the Helmholtz Munich Proteomic Core Facility led by Stefanie Hauck, the researchers found that the composition of proteins in centrosomes differs profoundly depending on the cell type.

    "We were surprised not only by the unexpected high degree of heterogeneity of the centrosomes, but also by the discovery of many unexpected proteins associated with them—for example, RNA-binding proteins and even proteins responsible for splicing (the processing of RNA), which normally takes place in the nucleus," Götz explains.

    The location of centrosome-associated proteins is crucial for disease

    The scientists discovered that a specific protein (the ubiquitously expressed splicing protein PRPF6) is enriched at the centrosome in neural stem cells, but not in neurons. A mutation of the protein found in patients with brain malformation periventricular heterotopia also leads to a similar phenotype in animal models.

    Götz says that "this means that the location of a protein is crucial for a disease. With our centrosome analysis, we now have an important resource to test further associations with neuronal diseases. In particular, our research can explain for the first time why a protein that is present in all cells, after mutation, causes a phenotype only in the brain, but not in other organs. This will allow further insights into disease mechanisms—and thus get one step closer to their treatment."

    The research was published in Science.


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    Role for autophagic cellular degradation process in maintaining genomic stability

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